{"gene":"HMGN1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1980,"finding":"HMG-14 (HMGN1) binds specifically to nucleosome core particles; two molecules bind tightly but reversibly per core particle with higher affinity than for histone-free DNA; nucleosome-HMG complexes are enriched in transcriptionally active gene sequences (beta-globin).","method":"Thermal denaturation, nuclease digestion, nucleosome reconstitution, and gene-sequence enrichment assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with multiple orthogonal methods; foundational binding characterization replicated across labs","pmids":["6449690"],"is_preprint":false},{"year":1980,"finding":"HMG-14 is intrinsically disordered in free solution and binds DNA primarily through its N-terminal half, with the interaction disrupted at 0.3 M NaCl (the same ionic strength used to extract the protein from chromatin).","method":"270-MHz NMR, circular dichroism","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR and CD with structural and functional validation of binding domain","pmids":["6257511"],"is_preprint":false},{"year":1994,"finding":"HMG-14 (HMGN1) footprints on nucleosome cores and chromatosomes map to positions ~25 bp from the DNA ends and near the nucleosomal dyad axis; two HMG-14 molecules bridge two adjacent DNA strands on the nucleosome surface, with binding sites overlapping those of linker histones near the dyad.","method":"Hydroxyl radical footprinting of HMG-14 on nucleosome cores and chromatosomes","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — direct structural footprinting with defined position mapping","pmids":["8107104"],"is_preprint":false},{"year":1994,"finding":"HMG-14 (HMGN1) stimulates RNA polymerase II elongation rate on chromatin templates but not on naked DNA templates, and does not affect initiation of transcription.","method":"In vitro transcription assay on in vivo-assembled chromatin vs. DNA templates","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with chromatin vs. DNA templates distinguishing elongation from initiation","pmids":["8047885"],"is_preprint":false},{"year":1994,"finding":"Upon mitogenic stimulation, HMG-14 (HMGN1) — but not HMG-17 — is serine-phosphorylated in its basic N-terminal region; mononucleosome-associated HMG-14 carries a mitogen-activated kinase that phosphorylates HMG-14 in vitro at the same sites as in intact cells.","method":"In vivo labeling, micrococcal nuclease fractionation to mononucleosomes, in vitro kinase assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay on mononucleosomes corroborating in vivo phosphorylation site","pmids":["7925294"],"is_preprint":false},{"year":1994,"finding":"Single point mutations in the nucleosomal binding domain (NBD) of HMG-14 at positions A21P or K26C reduce cooperative binding to nucleosome cores 6.7- and 3-fold respectively, demonstrating that the NBD conformation is critical for nucleosome interaction.","method":"Site-directed mutagenesis, nucleosome core mobility-shift assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — reconstituted binding assay with mutagenesis establishing structure-function of NBD","pmids":["7971283"],"is_preprint":false},{"year":1997,"finding":"The acidic C-terminal region of HMG-14 (HMGN1) alleviates histone H1-mediated transcriptional repression and partially disrupts H1-dependent chromatin compaction; transcriptional and chromatin-unfolding activities are maintained when the C-terminal fragment is replaced by acidic regions from GAL4 or HMG-2.","method":"In vitro transcription on SV40 minichromosomes, chromatin compaction assay, domain-swap mutagenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro transcription and chromatin compaction with domain-swap and mutagenesis","pmids":["9315642"],"is_preprint":false},{"year":1998,"finding":"The N-terminal domain of HMG-14 contacts histone H2B, while the C-terminal chromatin-unfolding domain contacts the N-terminal tail of histone H3 in nucleosome cores, as determined by protein photocrosslinking.","method":"Protein photocrosslinking in nucleosome cores","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — direct photocrosslinking identifying specific histone contacts for each domain","pmids":["9576905"],"is_preprint":false},{"year":1998,"finding":"HMG-14 and HMG-17 (HMGN1/HMGN2) are released from chromatin during mitosis (absent from metaphase/anaphase chromosomes), re-associate with DNA in late telophase, and are actively imported into the nucleus via a bipartite nuclear localization signal requiring importin alpha and energy.","method":"Immunofluorescence cell-cycle staging, reconstituted nuclei import assay, permeabilized cells, energy/importin depletion","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — direct localization with functional import assay using multiple mechanistic controls","pmids":["9852141"],"is_preprint":false},{"year":2000,"finding":"The histone acetyltransferase p300 acetylates HMG-14 (HMGN1) at 7 sites, including 3 within the nucleosomal binding domain and 4 near bipartite nuclear localization domains; acetylation of the NBD by p300 weakens HMG-14 interaction with nucleosome cores.","method":"In vitro acetylation by p300, identification of acetylation sites, nucleosome binding assay with acetylated vs. unacetylated protein","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro acetyltransferase assay with site identification and functional binding consequence","pmids":["10753971"],"is_preprint":false},{"year":2002,"finding":"Mitotic phosphorylation of the nucleosomal binding domain (NBD) of HMGN1 prevents nuclear re-entry in late telophase and promotes interaction with specific 14-3-3 isotypes; this is a phosphorylation-dependent (not charge-dependent) effect.","method":"Immunofluorescence, in vitro nuclear import with wild-type and NBD-phosphomimetic/mutant proteins, affinity chromatography with nuclear extracts from logarithmic vs. mitotic cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding assay plus functional import assay with mutant controls","pmids":["12215538"],"is_preprint":false},{"year":2003,"finding":"MSK1 and MSK2 are the major kinases responsible for phosphorylation of HMG-14 (HMGN1) in response to mitogenic and stress stimuli; phosphorylation is severely reduced or abolished in MSK1/MSK2 double-knockout mouse fibroblasts.","method":"Genetic knockout (MSK1-/-, MSK2-/- mice), in vivo phosphorylation assay, comparison with Coffin-Lowry (RSK2-deficient) cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with defined biochemical phenotype, replicated in multiple cell lines","pmids":["12773393"],"is_preprint":false},{"year":2003,"finding":"HMGN1 enhances the rate of nucleotide excision repair (NER) of UV-induced photoproducts in chromatin by reducing chromatin compaction, thereby increasing accessibility to damaged DNA; Hmgn1-/- MEFs are UV hypersensitive and show slower photoproduct removal; rescue requires nucleosome-binding-competent HMGN1.","method":"Hmgn1-/- mouse embryonic fibroblasts, UV survival, slot-blot photoproduct removal assay, host cell reactivation, transfection with wild-type vs. chromatin-binding-deficient mutants","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — KO + rescue with domain-specific mutants providing mechanistic evidence","pmids":["12660172"],"is_preprint":false},{"year":2004,"finding":"HMGN1 reduces the steady-state levels and rate of stress-induced phosphorylation of histone H3 Ser10 by impeding kinase access to nucleosomal (but not free) H3; stress-induced phosphorylation of HMGN1 transiently weakens its chromatin binding, enabling improved kinase access to H3.","method":"Hmgn1-/- MEFs, in vitro kinase assay on nucleosomal vs. free H3, anisomycin treatment kinetics, chromatin fractionation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro nucleosomal kinase assay + KO genetic evidence with temporal ordering of PTMs","pmids":["15327773"],"is_preprint":false},{"year":2005,"finding":"HMGN1 enhances acetylation of histone H3 lysine 14 (H3K14ac) in vivo; in vitro, HMGN1 enhances the ability of the HAT PCAF to acetylate nucleosomal H3 but not free H3; this requires chromatin-binding-competent HMGN1.","method":"Hmgn1-/- MEFs, re-expression of wild-type vs. chromatin-binding mutant HMGN1, in vitro PCAF acetylation assay on nucleosomes vs. free H3","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted acetyltransferase assay + genetic KO/rescue with domain-specific mutant","pmids":["16096646"],"is_preprint":false},{"year":2005,"finding":"HMGN1 loss increases sensitivity to ionizing radiation and disrupts G2/M checkpoint activation in fibroblasts; rescue requires nucleosome-binding-competent HMGN1, placing chromatin binding as essential for DNA damage checkpoint function.","method":"Hmgn1-/- mouse fibroblasts, IR sensitivity, G2/M checkpoint assay, rescue with wild-type vs. NBD-mutant HMGN1","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — KO + rescue with domain-specific mutant and defined checkpoint phenotype","pmids":["16061652"],"is_preprint":false},{"year":2005,"finding":"HMGN1 acts as a negative regulator of N-cadherin expression in mouse embryonic fibroblasts; loss of HMGN1 increases N-cadherin levels and alters cell adhesion, motility, and aggregation; rescue requires chromatin-binding-competent HMGN1.","method":"Hmgn1-/- MEFs, DNA microarray, RT-PCR, western blot, re-expression with wild-type vs. chromatin-binding mutant","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 — KO with defined phenotypic and molecular readout; single lab, multiple methods","pmids":["16279949"],"is_preprint":false},{"year":2006,"finding":"HMGN1 modulates phosphorylation of histone H2A serine 1; in Hmgn1-/- cells, H2AS1ph is elevated throughout the cell cycle; in vitro, HMGN1 reduces Rsk2- and Msk1-mediated phosphorylation of nucleosomal (but not free) H2A, and HMGN2 shows the same effect.","method":"Hmgn1-/- cells, in vitro kinase assay (Rsk2, Msk1) on nucleosomal vs. free H2A, chromatin-binding mutant HMGN1","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro nucleosomal kinase assay + KO evidence; mechanism mirrors H3 phosphorylation modulation","pmids":["17154547"],"is_preprint":false},{"year":2006,"finding":"During embryogenesis, HMGN1 binds Sox9 chromatin in cells poised to express Sox9; loss of HMGN1 accelerates chondrogenic differentiation and elevates HMGN2 occupancy at Sox9; wild-type but not chromatin-binding-deficient HMGN1 rescues the effect on Sox9 expression.","method":"Hmgn1-/- limb bud micromass cultures, ChIP, re-expression with wild-type vs. mutant HMGN1","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — ChIP + KO/rescue with mutant controls establishing direct chromatin occupancy and functional consequence","pmids":["16382150"],"is_preprint":false},{"year":2007,"finding":"HMGN1 physically interacts with estrogen receptor alpha (ERα) and serum response factor (SRF) both in vitro and in vivo; at the TFF1 promoter, ERα recruits HMGN1 upon estrogen treatment; HMGN1 limits estrogen-induced gene activation and reduces H3K9 acetylation at target promoters.","method":"Co-IP in vivo and in vitro pulldown, knockdown and overexpression, ChIP for HMGN1 and H3K9ac, phosphomimetic mutant HMGN1","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP + ChIP + functional assays with mutants identifying transcription factor interactions","pmids":["17938209"],"is_preprint":false},{"year":2008,"finding":"HMGN1 enhances heat shock-induced remodeling of Hsp70 chromatin by promoting H3K14 acetylation at the Hsp70 promoter; HDAC inhibitors abrogate the HMGN1 effect, placing H3K14 acetylation downstream of HMGN1 in this pathway.","method":"Hmgn1-/- and +/+ fibroblasts, RT-PCR for Hsp70 transcripts, ChIP for H3K14ac at Hsp70 promoter, HDAC inhibitor treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — ChIP + genetic KO + pharmacological epistasis identifying H3K14ac as downstream effector","pmids":["18218636"],"is_preprint":false},{"year":2010,"finding":"HMGN1 is not randomly distributed across the genome but preferentially localizes to DNase I hypersensitive sites, promoters, functional enhancers, and transcription factor binding sites.","method":"Genome-wide ChIP-seq for HMGN1 compared to regulatory chromatin marks","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — genome-wide ChIP-seq providing direct occupancy data","pmids":["21173166"],"is_preprint":false},{"year":2011,"finding":"HMGN1 acts as a negative regulator of MeCP2 expression; alterations in HMGN1 levels change chromatin structure and histone modifications at the MeCP2 promoter; both overexpression and loss of HMGN1 alter mouse behavior.","method":"Hmgn1 overexpressor and KO mice, quantitative PCR, western blot, ChIP for histone modifications at MeCP2 promoter, behavioral assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — ChIP at target promoter + gain- and loss-of-function with defined behavioral phenotype","pmids":["22009741"],"is_preprint":false},{"year":2012,"finding":"HMGN1 stimulates PARP-1 self-PARylation; HMGN1 and PARP-1 interact directly in binding assays; purified HMGN1 stimulates purified PARP-1 self-PARylation in vitro; loss of HMGN1 reduces PARylation at laser-induced DNA damage sites in cells.","method":"Hmgn1-/- and +/+ cells, co-immunoprecipitation, in vitro PARylation assay with purified proteins, laser micro-irradiation imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted PARylation assay + co-IP + KO cellular phenotype","pmids":["22736760"],"is_preprint":false},{"year":2012,"finding":"HMGN1 interacts with PCNA and enhances PCNA binding to chromatin (but not to purified DNA); two tetrapeptides in the conserved domain of HMGN1 are required for this interaction; loss of HMGN1 decreases PCNA recruitment to UV-damaged DNA sites.","method":"Co-IP/pulldown assay, deletion mutagenesis, live-cell imaging of PCNA recruitment after laser-induced damage, chromatin vs. DNA binding assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — co-IP + mutagenesis identifying interaction domain + KO live imaging of PCNA recruitment","pmids":["22393258"],"is_preprint":false},{"year":2013,"finding":"HMGN1 preferentially binds CpG island-containing promoters and affects nucleosome organization at transcription start sites (including an unstable nucleosome), DNase I hypersensitivity genome-wide, and the transcriptional profile of embryonic stem cells and neural progenitors.","method":"Hmgn1-/- ESCs, ChIP-seq, MNase-seq for nucleosome positioning, DNase-seq, RNA-seq","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — genome-wide multi-omics in KO vs. WT with mechanistic links between HMGN1, nucleosome position, and chromatin accessibility","pmids":["23775126"],"is_preprint":false},{"year":2014,"finding":"HMGN1 overexpression (from chr21q22 triplication) suppresses H3K27 trimethylation in progenitor B cells and promotes B cell proliferation and B-ALL in vivo; bivalent genes marked by H3K27me3 are preferentially derepressed by HMGN1 overexpression.","method":"Mouse trisomy model, HMGN1 overexpression in B cells, ChIP for H3K27me3, B-ALL transplantation model","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — ChIP + in vivo leukemia model + genetic overexpression demonstrating HMGN1 suppresses PRC2-mediated H3K27me3","pmids":["24747640"],"is_preprint":false},{"year":2017,"finding":"HMGN1 and HMGN2 counteract linker histone H1-dependent stabilization of higher-order chromatin structures without displacing H1; they do not disturb H1 globular domain contacts with nucleosomal DNA but alter condensation of the H1 C-terminal domain and redirect core histone tails to more interior positions on the nucleosome.","method":"In vitro reconstitution, sedimentation assay, hydroxyl radical footprinting, histone tail accessibility assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with multiple biochemical and structural methods","pmids":["28973435"],"is_preprint":false},{"year":2018,"finding":"HMGN1 overexpression globally amplifies transcription and causes a global increase in H3K27 acetylation as revealed by exogenous spike-in normalized ChIP-seq; HMGN1 is necessary for B cell phenotypes in DS trisomy models.","method":"Spike-in normalized RNA-seq and ChIP-Rx for H3K27ac, HMGN1 overexpression and knockdown in DS B cell models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — absolute-normalized ChIP-seq revealing global H3K27ac increase causally linked to HMGN1","pmids":["30428356"],"is_preprint":false},{"year":2021,"finding":"Phosphorylation of serines in the nucleosomal binding domain of HMGN1 decreases helical propensity of the NBD and disrupts its interaction with the nucleosome acidic patch, as shown by NMR spectroscopy; PTMs in N- or C-termini cause conformational perturbations up to 50-60 residues distant from the modification site.","method":"Protein semi-synthesis with site-specific PTMs, segmental isotope labeling, NMR spectroscopy, circular dichroism, nucleosome binding assays","journal":"RSC chemical biology","confidence":"High","confidence_rationale":"Tier 1 — NMR with site-specific PTMs and functional binding assay","pmids":["34458797"],"is_preprint":false},{"year":2024,"finding":"Phosphorylation of the HMGN1 NBD decreases helical propensity and disrupts the interface with the nucleosome acidic patch as shown by NMR spectroscopy and circular dichroism, providing atomic-level detail of how phosphorylation reduces nucleosome binding.","method":"NMR spectroscopy, circular dichroism, AlphaFold3 modelling of HMGN1-nucleosome interface","journal":"Chembiochem : a European journal of chemical biology","confidence":"High","confidence_rationale":"Tier 1 — NMR + CD with mechanistic structural detail of PTM-induced conformational changes","pmids":["39186607"],"is_preprint":false},{"year":2025,"finding":"HMGN1 upregulation in trisomy 21 shifts AVC cardiomyocytes toward a ventricular cardiomyocyte transcriptional state; CRISPR-activation screen identified HMGN1 as the causal chr21 gene; reducing HMGN1 dosage from trisomic levels restores normal AVC gene expression and rescues valvuloseptal defects in a mouse trisomy 21 model.","method":"Human iPSC and mouse trisomy 21 models, single-cell RNA-seq, CROP-seq CRISPR-activation screen, allelic HMGN1 deletion/rescue","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — CROP-seq causal gene screen + isogenic rescue with defined transcriptional and structural cardiac phenotype","pmids":["41125893"],"is_preprint":false},{"year":2025,"finding":"HMGN1 (and HMGN2) function in activation of transcription initiation at over a thousand specific promoters and enhancers; they have shared and unique target genes; HMGN null cells generated by simultaneous deletion of multiple HMGN genes show preferential downregulation of target genes.","method":"HMGN null human cell line generation, isogenic rescue lines, genome-wide RNA-seq","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — clean HMGN null cell line with genome-wide transcriptomics; preprint, not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"HMGN1 and HMGN2 preferentially bind nucleosomes containing acetylated H3 tail residues and the histone variant H2A.Z; in vitro, HMGN1 and HMGN2 binding to nucleosomes reduces p300-mediated acetylation of H3K18, H3K23, and H3K27; Hmgn1/Hmgn2 double KO mESCs show increased H3K27me2 and H3K27me3.","method":"Nucleosome binding assays with modified and variant nucleosomes, in vitro p300 acetylation assay, epiproteomic mass spectrometry, Hmgn1-/-, Hmgn2-/-, and double KO mESCs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted acetylation assay + nucleosome binding preference assay + KO epiproteomic validation","pmids":["41325801"],"is_preprint":false},{"year":2024,"finding":"HMGN1 binds HBV cccDNA in the nucleus; silencing HMGN1 increases CLK2 kinase-mediated H3 phosphorylation and reduces cccDNA accessibility; HMGN1 promotes HBV transcription and replication through its nucleosomal binding domain.","method":"Biotin-avidin enrichment, ChIP, fluorescent in situ hybridization, HMGN1 knockdown and mutant transfection in HBV-infected cells, in vivo HBV mouse model","journal":"Antiviral research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP + FISH + mutant rescue; single lab, specific functional domain identified","pmids":["38181856"],"is_preprint":false},{"year":2020,"finding":"In human cells, HMGN1 (alone or combined with HMGN2 knockout) is not required for transcription-coupled nucleotide excision repair (TC-NER); HMGN1 is not recruited to UV-induced DNA damage sites and does not associate with the TC-NER complex; this contrasts with findings in mouse cells.","method":"HMGN1/HMGN2 KO and knockdown human cells, UV/Illudin S survival, transcription restart assay, GFP-HMGN1 live-cell recruitment at UV damage, co-IP with TC-NER factors","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — clean KO + live imaging + co-IP with multiple negative-result controls; establishes species-specific mechanistic difference","pmids":["32152397"],"is_preprint":false}],"current_model":"HMGN1 is a nucleosome-binding architectural protein that binds specifically to nucleosome core particles (2 molecules per core) via its nucleosomal binding domain (NBD), localizes preferentially to active promoters, enhancers, and DNase I hypersensitive sites, and modulates the chromatin modification landscape by (i) hindering kinase access to nucleosomal H3-S10 and H2A-S1, thereby reducing their phosphorylation; (ii) enhancing HAT (PCAF/p300) access to nucleosomal H3-K14, promoting its acetylation and stimulating H3K27 acetylation globally; (iii) antagonizing PRC2 to reduce H3K27 trimethylation; (iv) unfolding higher-order chromatin structure through its acidic C-terminal domain targeting the H3 N-terminal tail; (v) facilitating DNA repair by increasing chromatin accessibility to NER factors and stimulating PARP-1 auto-PARylation; and (vi) cycling on and off chromatin in a cell-cycle-dependent manner regulated by mitotic phosphorylation of the NBD (which promotes 14-3-3 binding and blocks nuclear re-import) and by p300-mediated acetylation of the NBD (which weakens nucleosome affinity)."},"narrative":{"teleology":[{"year":1980,"claim":"Establishing that HMGN1 is a specific nucleosome-binding protein—rather than a general DNA-binding factor—answered whether its chromatin association is structural and selective, showing two molecules bind cooperatively per core particle with preference for transcriptionally active sequences.","evidence":"Thermal denaturation, nuclease digestion, and nucleosome reconstitution with gene-sequence enrichment; NMR/CD showing intrinsic disorder and N-terminal DNA contact","pmids":["6449690","6257511"],"confidence":"High","gaps":["Precise residues mediating nucleosome specificity not yet mapped","In vivo stoichiometry not confirmed","Mechanism of preference for active chromatin unknown"]},{"year":1994,"claim":"Mapping HMGN1 footprints on nucleosomes and demonstrating that it enhances RNA Pol II elongation on chromatin templates (not naked DNA) established the structural basis and functional consequence of nucleosome binding, while mutagenesis of the NBD proved this domain is essential for cooperative binding.","evidence":"Hydroxyl radical footprinting on cores/chromatosomes; in vitro transcription on chromatin vs DNA templates; site-directed mutagenesis with mobility-shift assays","pmids":["8107104","8047885","7971283"],"confidence":"High","gaps":["How NBD conformation enables cooperative binding at atomic level not resolved","Whether elongation enhancement operates in vivo unclear"]},{"year":1994,"claim":"Discovery that mitogen-stimulated serine phosphorylation of HMGN1 occurs in its N-terminal region, catalyzed by a nucleosome-associated kinase, revealed that post-translational modification regulates HMGN1–chromatin dynamics.","evidence":"In vivo metabolic labeling with mononucleosome fractionation and in vitro kinase assay","pmids":["7925294"],"confidence":"High","gaps":["Identity of the kinase not yet determined","Functional consequence of phosphorylation for chromatin structure unknown"]},{"year":1997,"claim":"Showing that the acidic C-terminal domain alleviates H1-mediated transcriptional repression and disrupts chromatin compaction—with function maintained when replaced by heterologous acidic domains—established a modular architecture: NBD for nucleosome targeting, C-terminal domain for chromatin unfolding.","evidence":"In vitro transcription on SV40 minichromosomes, chromatin compaction assay, domain-swap mutagenesis","pmids":["9315642"],"confidence":"High","gaps":["Direct histone contacts of C-terminal domain not mapped","Whether H1 is displaced or merely antagonized in cis unknown"]},{"year":1998,"claim":"Photocrosslinking identified specific histone contacts—N-terminal domain to H2B and C-terminal chromatin-unfolding domain to the H3 N-terminal tail—providing the first molecular map of how HMGN1 domains interact with distinct histone surfaces.","evidence":"Protein photocrosslinking in reconstituted nucleosome cores","pmids":["9576905"],"confidence":"High","gaps":["Atomic-resolution structure of full complex not available","Whether contacts differ in dinucleosome/chromatin fiber context unknown"]},{"year":1998,"claim":"Demonstrating that HMGN1 dissociates from chromosomes during mitosis and re-enters nuclei via an importin-α-dependent NLS pathway established that chromatin binding is cell-cycle regulated.","evidence":"Immunofluorescence cell-cycle staging, reconstituted nuclei import assay with energy/importin depletion","pmids":["9852141"],"confidence":"High","gaps":["What triggers mitotic release not identified","Whether re-association is random or targeted to specific loci unknown"]},{"year":2000,"claim":"Identification of p300-mediated acetylation of HMGN1 at seven sites including three in the NBD, with acetylation weakening nucleosome binding, revealed a second PTM axis (alongside phosphorylation) that tunes HMGN1–chromatin affinity.","evidence":"In vitro p300 acetylation, site identification, nucleosome binding assay comparing acetylated and unacetylated protein","pmids":["10753971"],"confidence":"High","gaps":["In vivo acetylation dynamics not characterized","Whether acetylation and phosphorylation act combinatorially unknown"]},{"year":2002,"claim":"Showing that mitotic NBD phosphorylation prevents nuclear re-entry via phosphorylation-dependent 14-3-3 binding (not charge effects) explained how HMGN1 is excluded from reforming nuclei until dephosphorylation occurs.","evidence":"In vitro nuclear import with phosphomimetic mutants, affinity chromatography with mitotic vs logarithmic extracts","pmids":["12215538"],"confidence":"High","gaps":["Identity of the phosphatase that restores import competence unknown","Which 14-3-3 isotype is physiologically relevant in vivo not resolved"]},{"year":2003,"claim":"MSK1 and MSK2 were identified as the major kinases for HMGN1 phosphorylation upon mitogenic and stress stimulation, resolving the kinase identity question; separately, HMGN1 was shown to enhance nucleotide excision repair by reducing chromatin compaction, with Hmgn1-/- cells UV-hypersensitive.","evidence":"MSK1/MSK2 double-KO mouse fibroblasts with in vivo phosphorylation assay; Hmgn1-/- MEFs with UV survival and photoproduct removal assays, rescue with WT vs NBD-mutant","pmids":["12773393","12660172"],"confidence":"High","gaps":["Whether MSK1/2 phosphorylation of HMGN1 directly enables NER factor access not tested","Species specificity of NER role not yet apparent"]},{"year":2004,"claim":"Demonstrating that HMGN1 reduces H3-S10 phosphorylation by sterically impeding kinase access to nucleosomal (but not free) H3, and that stress-induced HMGN1 phosphorylation transiently relieves this block, established a dynamic gating mechanism for histone modification.","evidence":"Hmgn1-/- MEFs, in vitro kinase assay on nucleosomal vs free H3, anisomycin kinetics, chromatin fractionation","pmids":["15327773"],"confidence":"High","gaps":["Whether this gating applies genome-wide or at specific loci unknown","Which kinases are gated in vivo not fully defined"]},{"year":2005,"claim":"HMGN1 was shown to enhance PCAF-mediated H3K14 acetylation on nucleosomes (not free H3), increase ionizing radiation sensitivity with impaired G2/M checkpoint activation, and negatively regulate N-cadherin expression—broadening its functional scope to HAT facilitation, DNA damage checkpoints, and cell adhesion.","evidence":"Hmgn1-/- MEFs with in vitro PCAF acetylation on nucleosomes, IR survival and checkpoint assay, microarray and RT-PCR for N-cadherin, rescue with WT vs mutant HMGN1","pmids":["16096646","16061652","16279949"],"confidence":"High","gaps":["Whether HAT facilitation and kinase gating are mechanistically linked not tested","Checkpoint phenotype not connected to specific histone modifications"]},{"year":2006,"claim":"Extension of the kinase-gating model to H2A-S1 phosphorylation (elevated in Hmgn1-/- cells) and the discovery that HMGN1 occupies Sox9 chromatin during embryogenesis to restrain chondrogenic differentiation established HMGN1 as a lineage-specific chromatin modulator.","evidence":"In vitro Rsk2/Msk1 kinase assay on nucleosomal vs free H2A; Hmgn1-/- limb bud micromass cultures with ChIP at Sox9 locus, rescue with WT vs mutant","pmids":["17154547","16382150"],"confidence":"High","gaps":["Whether HMGN1 directly competes with HMGN2 at Sox9 in a zero-sum manner not resolved","How HMGN1 is targeted to Sox9 versus other loci unknown"]},{"year":2007,"claim":"Physical interaction of HMGN1 with ERα and SRF, with estrogen-dependent recruitment to the TFF1 promoter where HMGN1 limits gene activation and H3K9 acetylation, established that transcription factors can recruit HMGN1 to act as a context-dependent transcriptional modulator.","evidence":"Reciprocal co-IP, in vitro pulldown, ChIP for HMGN1 and H3K9ac, knockdown/overexpression, phosphomimetic mutant","pmids":["17938209"],"confidence":"High","gaps":["How HMGN1 simultaneously enhances some acetylation marks and limits others at different promoters not reconciled","Genome-wide scope of TF-mediated HMGN1 recruitment unknown"]},{"year":2010,"claim":"Genome-wide ChIP-seq revealed that HMGN1 is not randomly distributed but preferentially localizes to DNase I hypersensitive sites, promoters, and functional enhancers, establishing that its chromatin occupancy is targeted to regulatory regions.","evidence":"Genome-wide ChIP-seq for HMGN1 compared to regulatory chromatin marks","pmids":["21173166"],"confidence":"High","gaps":["Mechanism of preferential targeting (sequence vs chromatin features) not resolved","Dynamic redistribution upon stimulation not captured"]},{"year":2012,"claim":"Discovery that HMGN1 directly stimulates PARP-1 auto-PARylation and interacts with PCNA to enhance its chromatin recruitment at damage sites extended the DNA repair role beyond chromatin accessibility to direct protein–protein facilitation of repair factors.","evidence":"In vitro PARylation with purified proteins, co-IP, laser micro-irradiation imaging of PARP-1 PARylation and PCNA recruitment in Hmgn1-/- cells, deletion mutagenesis","pmids":["22736760","22393258"],"confidence":"High","gaps":["Whether PARP-1 stimulation and PCNA recruitment are independent or sequential not determined","Crystal structure of HMGN1–PCNA complex lacking"]},{"year":2013,"claim":"Multi-omic analysis in Hmgn1-/- ESCs showed that HMGN1 preferentially binds CpG island-containing promoters and affects nucleosome positioning at TSSs, DNase I hypersensitivity, and transcription in stem and progenitor cells, linking it to epigenetic regulation of cell identity.","evidence":"Hmgn1-/- ESCs with ChIP-seq, MNase-seq, DNase-seq, RNA-seq","pmids":["23775126"],"confidence":"High","gaps":["Whether nucleosome positioning changes are a direct structural consequence of HMGN1 binding or indirect unknown","Functional consequence for differentiation potential quantitatively undefined"]},{"year":2014,"claim":"HMGN1 overexpression (modeling chr21 trisomy) was shown to suppress H3K27me3 at bivalent genes and promote B-ALL, establishing HMGN1 as a dosage-sensitive oncogene whose overexpression derepresses PRC2 targets.","evidence":"Mouse trisomy model, HMGN1 overexpression in B cells, ChIP for H3K27me3, B-ALL transplantation","pmids":["24747640"],"confidence":"High","gaps":["Whether HMGN1 directly antagonizes PRC2 binding or acts indirectly through acetylation not resolved","Relevance to human B-ALL beyond Down syndrome not established"]},{"year":2017,"claim":"In vitro reconstitution showed HMGN1/HMGN2 counteract H1-dependent higher-order chromatin folding without displacing H1, by altering H1 C-terminal domain condensation and redirecting core histone tails inward, clarifying the non-competitive mechanism of chromatin decompaction.","evidence":"Sedimentation assay, hydroxyl radical footprinting, histone tail accessibility assays on reconstituted chromatin","pmids":["28973435"],"confidence":"High","gaps":["Whether this mechanism operates at all genomic loci or preferentially at regulatory elements not tested in vivo"]},{"year":2018,"claim":"Spike-in normalized ChIP-seq demonstrated that HMGN1 overexpression causes a global (not locus-specific) increase in H3K27 acetylation, resolving whether the transcriptional amplification effect is quantitative and genome-wide.","evidence":"ChIP-Rx for H3K27ac with exogenous spike-in, HMGN1 overexpression and knockdown in DS B cell models","pmids":["30428356"],"confidence":"High","gaps":["Which HATs mediate the global H3K27ac increase not identified","Whether global acetylation increase is direct or secondary to H3K27me3 loss unclear"]},{"year":2020,"claim":"Human HMGN1/HMGN2 KO cells showed no defect in transcription-coupled NER, and HMGN1 was not recruited to UV damage sites in human cells, establishing a species-specific difference from the mouse NER phenotype.","evidence":"HMGN1/HMGN2 KO human cells, UV/Illudin S survival, transcription restart, GFP-HMGN1 live imaging, co-IP with TC-NER factors","pmids":["32152397"],"confidence":"High","gaps":["Whether global NER (as opposed to TC-NER) is affected in human cells not fully tested","Molecular basis for species difference not identified"]},{"year":2021,"claim":"NMR of semi-synthesized HMGN1 with site-specific PTMs revealed that NBD phosphorylation reduces helical propensity and disrupts the nucleosome acidic patch interface, providing the first atomic-level explanation for how phosphorylation abolishes nucleosome binding.","evidence":"Protein semi-synthesis, segmental isotope labeling, NMR, CD, nucleosome binding assays","pmids":["34458797"],"confidence":"High","gaps":["Full high-resolution structure of HMGN1 bound to nucleosome not available","How long-range conformational effects of terminal PTMs propagate structurally is incompletely understood"]},{"year":2025,"claim":"CRISPR-activation screening identified HMGN1 as the causal chr21 gene for atrioventricular canal defects in Down syndrome; reducing HMGN1 dosage from trisomic levels rescued valvuloseptal defects and restored cardiomyocyte transcriptional identity, establishing HMGN1 as a dosage-sensitive driver of congenital heart disease.","evidence":"Human iPSC and mouse trisomy 21 models, scRNA-seq, CROP-seq CRISPRa screen, allelic HMGN1 deletion/rescue","pmids":["41125893"],"confidence":"High","gaps":["Downstream chromatin targets mediating the cardiac phenotype not fully defined","Whether HMGN1 dosage sensitivity operates through H3K27me3 or H3K27ac changes in cardiomyocytes not resolved"]},{"year":2025,"claim":"HMGN1 and HMGN2 preferentially bind nucleosomes containing acetylated H3 tails and H2A.Z, yet reduce p300-mediated acetylation of H3K18/K23/K27 on nucleosomes in vitro; double KO mESCs show elevated H3K27me2/me3, revealing a nuanced dual role in both reading and constraining acetylation.","evidence":"Nucleosome binding assays with modified/variant nucleosomes, in vitro p300 acetylation, epiproteomic MS, Hmgn1/Hmgn2 DKO mESCs","pmids":["41325801"],"confidence":"High","gaps":["How HMGN1 simultaneously enhances PCAF-mediated H3K14ac but reduces p300-mediated H3K18/K23/K27ac is mechanistically unresolved","Whether preferential binding to acetylated nucleosomes is cause or consequence of acetylation state unknown"]},{"year":null,"claim":"Key unresolved questions include: (1) the full atomic structure of HMGN1 bound to a nucleosome, (2) how HMGN1 is targeted to specific regulatory regions rather than binding all nucleosomes, (3) reconciliation of its apparently opposing effects on different histone acetylation marks (enhancing H3K14ac via PCAF while reducing H3K18/K23/K27ac via p300), and (4) the molecular basis for species-specific differences in its DNA repair functions.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution cryo-EM or crystal structure of HMGN1–nucleosome complex","Targeting mechanism to specific loci unresolved","Opposing acetylation effects for different HATs mechanistically unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,2,5,7,27,29,30,33]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13,14,17,26,28,33]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[6,27]}],"localization":[{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,2,21,25]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,10]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[21,25]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[6,13,14,17,26,27,28,33]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,19,22,25]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[12,23,24]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[18,31]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8,10,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[26,31]}],"complexes":[],"partners":["PARP1","PCNA","ESR1","SRF","PCAF","EP300","YWHAB"],"other_free_text":[]},"mechanistic_narrative":"HMGN1 is a nucleosome-binding architectural protein that modulates chromatin accessibility, histone modification landscapes, and transcriptional output across diverse cellular contexts including DNA repair, cell-cycle progression, and differentiation. It binds specifically to nucleosome core particles (two molecules per core) via its nucleosomal binding domain (NBD), which contacts the nucleosome acidic patch and histone H2B, while its acidic C-terminal domain contacts the histone H3 N-terminal tail to counteract linker histone H1-mediated chromatin compaction without displacing H1 [PMID:6449690, PMID:9576905, PMID:28973435]. HMGN1 shapes the histone modification landscape by hindering kinase access to nucleosomal H3-S10 and H2A-S1 (reducing their phosphorylation), enhancing HAT-mediated acetylation of H3K14, stimulating global H3K27 acetylation, and antagonizing PRC2-dependent H3K27 trimethylation—activities that preferentially target active promoters, CpG island-containing promoters, enhancers, and DNase I hypersensitive sites [PMID:15327773, PMID:16096646, PMID:24747640, PMID:30428356, PMID:21173166]. Its chromatin association is dynamically regulated: mitotic phosphorylation of the NBD by MSK1/MSK2 reduces helical propensity, disrupts the acidic-patch interface, promotes 14-3-3 binding to block nuclear re-import, and p300-mediated acetylation of the NBD independently weakens nucleosome affinity; overexpression of HMGN1 from chromosome 21 trisomy drives B-cell acute lymphoblastic leukemia in mouse models and causes valvuloseptal heart defects in Down syndrome by shifting cardiomyocyte transcriptional identity [PMID:12215538, PMID:34458797, PMID:24747640, PMID:41125893]."},"prefetch_data":{"uniprot":{"accession":"P05114","full_name":"Non-histone chromosomal protein HMG-14","aliases":["High mobility group nucleosome-binding domain-containing protein 1"],"length_aa":100,"mass_kda":10.7,"function":"Binds to the inner side of the nucleosomal DNA thus altering the interaction between the DNA and the histone octamer. May be involved in the process which maintains transcribable genes in a unique chromatin conformation. Inhibits the phosphorylation of nucleosomal histones H3 and H2A by RPS6KA5/MSK1 and RPS6KA3/RSK2 (By similarity)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P05114/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HMGN1","classification":"Not Classified","n_dependent_lines":144,"n_total_lines":1090,"dependency_fraction":0.13211009174311927},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HMGN1","total_profiled":1310},"omim":[{"mim_id":"605036","title":"ZINC FINGER PROTEIN 219; ZNF219","url":"https://www.omim.org/entry/605036"},{"mim_id":"604502","title":"HIGH MOBILITY GROUP NUCLEOSOMAL BINDING PROTEIN 3; HMGN3","url":"https://www.omim.org/entry/604502"},{"mim_id":"602915","title":"GUIDED ENTRY OF TAIL-ANCHORED PROTEINS FACTOR 1; GET1","url":"https://www.omim.org/entry/602915"},{"mim_id":"190685","title":"DOWN SYNDROME","url":"https://www.omim.org/entry/190685"},{"mim_id":"163920","title":"HIGH MOBILITY GROUP NUCLEOSOMAL BINDING PROTEIN 1; HMGN1","url":"https://www.omim.org/entry/163920"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HMGN1"},"hgnc":{"alias_symbol":["FLJ27265","FLJ31471","MGC104230","MGC117425"],"prev_symbol":["HMG14"]},"alphafold":{"accession":"P05114","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P05114","model_url":"https://alphafold.ebi.ac.uk/files/AF-P05114-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P05114-F1-predicted_aligned_error_v6.png","plddt_mean":63.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HMGN1","jax_strain_url":"https://www.jax.org/strain/search?query=HMGN1"},"sequence":{"accession":"P05114","fasta_url":"https://rest.uniprot.org/uniprotkb/P05114.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P05114/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P05114"}},"corpus_meta":[{"pmid":"12773393","id":"PMC_12773393","title":"MSK2 and MSK1 mediate the mitogen- and stress-induced phosphorylation of histone H3 and 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during neural crest and craniofacial development.","date":"2021","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/34478234","citation_count":2,"is_preprint":false},{"pmid":"37043098","id":"PMC_37043098","title":"The growth hormone receptor interacts with transcriptional regulator HMGN1 upon GH-induced nuclear translocation.","date":"2023","source":"Journal of cell communication and signaling","url":"https://pubmed.ncbi.nlm.nih.gov/37043098","citation_count":2,"is_preprint":false},{"pmid":"38710740","id":"PMC_38710740","title":"HMGN1 loss sensitizes lung cancer cells to chemotherapy.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38710740","citation_count":2,"is_preprint":false},{"pmid":"34527443","id":"PMC_34527443","title":"Camostat mesilate inhibits pro-inflammatory cytokine secretion and improves cell viability by regulating MFGE8 and HMGN1 in lipopolysaccharide-stimulated DF-1 chicken embryo 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chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/39186607","citation_count":1,"is_preprint":false},{"pmid":"2226652","id":"PMC_2226652","title":"Expression of human chromosomal proteins HMG-14 and HMG-17 in Saccharomyces cerevisiae.","date":"1990","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/2226652","citation_count":1,"is_preprint":false},{"pmid":"8670211","id":"PMC_8670211","title":"Chromosomal proteins HMG-14 and HMG-17 are synthesized throughout the S-phase in Burkitt's lymphoma.","date":"1996","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8670211","citation_count":1,"is_preprint":false},{"pmid":"12136729","id":"PMC_12136729","title":"[State of the \"protein kinase CK2-HMG14\" system in age-dependent amnesia in rats].","date":"2002","source":"Rossiiskii fiziologicheskii zhurnal imeni I.M. Sechenova","url":"https://pubmed.ncbi.nlm.nih.gov/12136729","citation_count":0,"is_preprint":false},{"pmid":"41833635","id":"PMC_41833635","title":"Chromatin-binding protein HMGN1 promotes HCC tumorigenesis via histone methylation-induced RALB transcriptional suppression.","date":"2026","source":"Journal of genetics and genomics = Yi chuan xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/41833635","citation_count":0,"is_preprint":false},{"pmid":"41325801","id":"PMC_41325801","title":"HMGN1 and HMGN2 are recruited to acetylated and histone variant H2A.Z-containing nucleosomes to regulate chromatin state and transcription.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41325801","citation_count":0,"is_preprint":false},{"pmid":"38284254","id":"PMC_38284254","title":"[High mobility group nucleosome binding protein 1 (HMGN1) induces activation of mouse BV2 microglia and upregulates their pro-inflammatory mediator expression by activating TLR4/MyD88/NF-κB p65/IKK-β signal pathway].","date":"2024","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38284254","citation_count":0,"is_preprint":false},{"pmid":"41252680","id":"PMC_41252680","title":"Identification of a Novel RUNX1::HMGN1 Fusion in Therapy Acute Myeloid Leukemia.","date":"2025","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/41252680","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.27.690916","title":"The HMGN Proteins Are Transcriptional Regulatory Factors in Humans","date":"2025-11-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.27.690916","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":42463,"output_tokens":8196,"usd":0.125165},"stage2":{"model":"claude-opus-4-6","input_tokens":11985,"output_tokens":5806,"usd":0.307613},"total_usd":0.432778,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1980,\n      \"finding\": \"HMG-14 (HMGN1) binds specifically to nucleosome core particles; two molecules bind tightly but reversibly per core particle with higher affinity than for histone-free DNA; nucleosome-HMG complexes are enriched in transcriptionally active gene sequences (beta-globin).\",\n      \"method\": \"Thermal denaturation, nuclease digestion, nucleosome reconstitution, and gene-sequence enrichment assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple orthogonal methods; foundational binding characterization replicated across labs\",\n      \"pmids\": [\"6449690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1980,\n      \"finding\": \"HMG-14 is intrinsically disordered in free solution and binds DNA primarily through its N-terminal half, with the interaction disrupted at 0.3 M NaCl (the same ionic strength used to extract the protein from chromatin).\",\n      \"method\": \"270-MHz NMR, circular dichroism\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR and CD with structural and functional validation of binding domain\",\n      \"pmids\": [\"6257511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"HMG-14 (HMGN1) footprints on nucleosome cores and chromatosomes map to positions ~25 bp from the DNA ends and near the nucleosomal dyad axis; two HMG-14 molecules bridge two adjacent DNA strands on the nucleosome surface, with binding sites overlapping those of linker histones near the dyad.\",\n      \"method\": \"Hydroxyl radical footprinting of HMG-14 on nucleosome cores and chromatosomes\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct structural footprinting with defined position mapping\",\n      \"pmids\": [\"8107104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"HMG-14 (HMGN1) stimulates RNA polymerase II elongation rate on chromatin templates but not on naked DNA templates, and does not affect initiation of transcription.\",\n      \"method\": \"In vitro transcription assay on in vivo-assembled chromatin vs. DNA templates\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with chromatin vs. DNA templates distinguishing elongation from initiation\",\n      \"pmids\": [\"8047885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Upon mitogenic stimulation, HMG-14 (HMGN1) — but not HMG-17 — is serine-phosphorylated in its basic N-terminal region; mononucleosome-associated HMG-14 carries a mitogen-activated kinase that phosphorylates HMG-14 in vitro at the same sites as in intact cells.\",\n      \"method\": \"In vivo labeling, micrococcal nuclease fractionation to mononucleosomes, in vitro kinase assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay on mononucleosomes corroborating in vivo phosphorylation site\",\n      \"pmids\": [\"7925294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Single point mutations in the nucleosomal binding domain (NBD) of HMG-14 at positions A21P or K26C reduce cooperative binding to nucleosome cores 6.7- and 3-fold respectively, demonstrating that the NBD conformation is critical for nucleosome interaction.\",\n      \"method\": \"Site-directed mutagenesis, nucleosome core mobility-shift assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted binding assay with mutagenesis establishing structure-function of NBD\",\n      \"pmids\": [\"7971283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The acidic C-terminal region of HMG-14 (HMGN1) alleviates histone H1-mediated transcriptional repression and partially disrupts H1-dependent chromatin compaction; transcriptional and chromatin-unfolding activities are maintained when the C-terminal fragment is replaced by acidic regions from GAL4 or HMG-2.\",\n      \"method\": \"In vitro transcription on SV40 minichromosomes, chromatin compaction assay, domain-swap mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro transcription and chromatin compaction with domain-swap and mutagenesis\",\n      \"pmids\": [\"9315642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The N-terminal domain of HMG-14 contacts histone H2B, while the C-terminal chromatin-unfolding domain contacts the N-terminal tail of histone H3 in nucleosome cores, as determined by protein photocrosslinking.\",\n      \"method\": \"Protein photocrosslinking in nucleosome cores\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct photocrosslinking identifying specific histone contacts for each domain\",\n      \"pmids\": [\"9576905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"HMG-14 and HMG-17 (HMGN1/HMGN2) are released from chromatin during mitosis (absent from metaphase/anaphase chromosomes), re-associate with DNA in late telophase, and are actively imported into the nucleus via a bipartite nuclear localization signal requiring importin alpha and energy.\",\n      \"method\": \"Immunofluorescence cell-cycle staging, reconstituted nuclei import assay, permeabilized cells, energy/importin depletion\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional import assay using multiple mechanistic controls\",\n      \"pmids\": [\"9852141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The histone acetyltransferase p300 acetylates HMG-14 (HMGN1) at 7 sites, including 3 within the nucleosomal binding domain and 4 near bipartite nuclear localization domains; acetylation of the NBD by p300 weakens HMG-14 interaction with nucleosome cores.\",\n      \"method\": \"In vitro acetylation by p300, identification of acetylation sites, nucleosome binding assay with acetylated vs. unacetylated protein\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro acetyltransferase assay with site identification and functional binding consequence\",\n      \"pmids\": [\"10753971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mitotic phosphorylation of the nucleosomal binding domain (NBD) of HMGN1 prevents nuclear re-entry in late telophase and promotes interaction with specific 14-3-3 isotypes; this is a phosphorylation-dependent (not charge-dependent) effect.\",\n      \"method\": \"Immunofluorescence, in vitro nuclear import with wild-type and NBD-phosphomimetic/mutant proteins, affinity chromatography with nuclear extracts from logarithmic vs. mitotic cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assay plus functional import assay with mutant controls\",\n      \"pmids\": [\"12215538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MSK1 and MSK2 are the major kinases responsible for phosphorylation of HMG-14 (HMGN1) in response to mitogenic and stress stimuli; phosphorylation is severely reduced or abolished in MSK1/MSK2 double-knockout mouse fibroblasts.\",\n      \"method\": \"Genetic knockout (MSK1-/-, MSK2-/- mice), in vivo phosphorylation assay, comparison with Coffin-Lowry (RSK2-deficient) cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined biochemical phenotype, replicated in multiple cell lines\",\n      \"pmids\": [\"12773393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HMGN1 enhances the rate of nucleotide excision repair (NER) of UV-induced photoproducts in chromatin by reducing chromatin compaction, thereby increasing accessibility to damaged DNA; Hmgn1-/- MEFs are UV hypersensitive and show slower photoproduct removal; rescue requires nucleosome-binding-competent HMGN1.\",\n      \"method\": \"Hmgn1-/- mouse embryonic fibroblasts, UV survival, slot-blot photoproduct removal assay, host cell reactivation, transfection with wild-type vs. chromatin-binding-deficient mutants\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO + rescue with domain-specific mutants providing mechanistic evidence\",\n      \"pmids\": [\"12660172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HMGN1 reduces the steady-state levels and rate of stress-induced phosphorylation of histone H3 Ser10 by impeding kinase access to nucleosomal (but not free) H3; stress-induced phosphorylation of HMGN1 transiently weakens its chromatin binding, enabling improved kinase access to H3.\",\n      \"method\": \"Hmgn1-/- MEFs, in vitro kinase assay on nucleosomal vs. free H3, anisomycin treatment kinetics, chromatin fractionation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro nucleosomal kinase assay + KO genetic evidence with temporal ordering of PTMs\",\n      \"pmids\": [\"15327773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HMGN1 enhances acetylation of histone H3 lysine 14 (H3K14ac) in vivo; in vitro, HMGN1 enhances the ability of the HAT PCAF to acetylate nucleosomal H3 but not free H3; this requires chromatin-binding-competent HMGN1.\",\n      \"method\": \"Hmgn1-/- MEFs, re-expression of wild-type vs. chromatin-binding mutant HMGN1, in vitro PCAF acetylation assay on nucleosomes vs. free H3\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted acetyltransferase assay + genetic KO/rescue with domain-specific mutant\",\n      \"pmids\": [\"16096646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HMGN1 loss increases sensitivity to ionizing radiation and disrupts G2/M checkpoint activation in fibroblasts; rescue requires nucleosome-binding-competent HMGN1, placing chromatin binding as essential for DNA damage checkpoint function.\",\n      \"method\": \"Hmgn1-/- mouse fibroblasts, IR sensitivity, G2/M checkpoint assay, rescue with wild-type vs. NBD-mutant HMGN1\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO + rescue with domain-specific mutant and defined checkpoint phenotype\",\n      \"pmids\": [\"16061652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HMGN1 acts as a negative regulator of N-cadherin expression in mouse embryonic fibroblasts; loss of HMGN1 increases N-cadherin levels and alters cell adhesion, motility, and aggregation; rescue requires chromatin-binding-competent HMGN1.\",\n      \"method\": \"Hmgn1-/- MEFs, DNA microarray, RT-PCR, western blot, re-expression with wild-type vs. chromatin-binding mutant\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined phenotypic and molecular readout; single lab, multiple methods\",\n      \"pmids\": [\"16279949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HMGN1 modulates phosphorylation of histone H2A serine 1; in Hmgn1-/- cells, H2AS1ph is elevated throughout the cell cycle; in vitro, HMGN1 reduces Rsk2- and Msk1-mediated phosphorylation of nucleosomal (but not free) H2A, and HMGN2 shows the same effect.\",\n      \"method\": \"Hmgn1-/- cells, in vitro kinase assay (Rsk2, Msk1) on nucleosomal vs. free H2A, chromatin-binding mutant HMGN1\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro nucleosomal kinase assay + KO evidence; mechanism mirrors H3 phosphorylation modulation\",\n      \"pmids\": [\"17154547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"During embryogenesis, HMGN1 binds Sox9 chromatin in cells poised to express Sox9; loss of HMGN1 accelerates chondrogenic differentiation and elevates HMGN2 occupancy at Sox9; wild-type but not chromatin-binding-deficient HMGN1 rescues the effect on Sox9 expression.\",\n      \"method\": \"Hmgn1-/- limb bud micromass cultures, ChIP, re-expression with wild-type vs. mutant HMGN1\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + KO/rescue with mutant controls establishing direct chromatin occupancy and functional consequence\",\n      \"pmids\": [\"16382150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HMGN1 physically interacts with estrogen receptor alpha (ERα) and serum response factor (SRF) both in vitro and in vivo; at the TFF1 promoter, ERα recruits HMGN1 upon estrogen treatment; HMGN1 limits estrogen-induced gene activation and reduces H3K9 acetylation at target promoters.\",\n      \"method\": \"Co-IP in vivo and in vitro pulldown, knockdown and overexpression, ChIP for HMGN1 and H3K9ac, phosphomimetic mutant HMGN1\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP + ChIP + functional assays with mutants identifying transcription factor interactions\",\n      \"pmids\": [\"17938209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HMGN1 enhances heat shock-induced remodeling of Hsp70 chromatin by promoting H3K14 acetylation at the Hsp70 promoter; HDAC inhibitors abrogate the HMGN1 effect, placing H3K14 acetylation downstream of HMGN1 in this pathway.\",\n      \"method\": \"Hmgn1-/- and +/+ fibroblasts, RT-PCR for Hsp70 transcripts, ChIP for H3K14ac at Hsp70 promoter, HDAC inhibitor treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + genetic KO + pharmacological epistasis identifying H3K14ac as downstream effector\",\n      \"pmids\": [\"18218636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HMGN1 is not randomly distributed across the genome but preferentially localizes to DNase I hypersensitive sites, promoters, functional enhancers, and transcription factor binding sites.\",\n      \"method\": \"Genome-wide ChIP-seq for HMGN1 compared to regulatory chromatin marks\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq providing direct occupancy data\",\n      \"pmids\": [\"21173166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HMGN1 acts as a negative regulator of MeCP2 expression; alterations in HMGN1 levels change chromatin structure and histone modifications at the MeCP2 promoter; both overexpression and loss of HMGN1 alter mouse behavior.\",\n      \"method\": \"Hmgn1 overexpressor and KO mice, quantitative PCR, western blot, ChIP for histone modifications at MeCP2 promoter, behavioral assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP at target promoter + gain- and loss-of-function with defined behavioral phenotype\",\n      \"pmids\": [\"22009741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HMGN1 stimulates PARP-1 self-PARylation; HMGN1 and PARP-1 interact directly in binding assays; purified HMGN1 stimulates purified PARP-1 self-PARylation in vitro; loss of HMGN1 reduces PARylation at laser-induced DNA damage sites in cells.\",\n      \"method\": \"Hmgn1-/- and +/+ cells, co-immunoprecipitation, in vitro PARylation assay with purified proteins, laser micro-irradiation imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted PARylation assay + co-IP + KO cellular phenotype\",\n      \"pmids\": [\"22736760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HMGN1 interacts with PCNA and enhances PCNA binding to chromatin (but not to purified DNA); two tetrapeptides in the conserved domain of HMGN1 are required for this interaction; loss of HMGN1 decreases PCNA recruitment to UV-damaged DNA sites.\",\n      \"method\": \"Co-IP/pulldown assay, deletion mutagenesis, live-cell imaging of PCNA recruitment after laser-induced damage, chromatin vs. DNA binding assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP + mutagenesis identifying interaction domain + KO live imaging of PCNA recruitment\",\n      \"pmids\": [\"22393258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HMGN1 preferentially binds CpG island-containing promoters and affects nucleosome organization at transcription start sites (including an unstable nucleosome), DNase I hypersensitivity genome-wide, and the transcriptional profile of embryonic stem cells and neural progenitors.\",\n      \"method\": \"Hmgn1-/- ESCs, ChIP-seq, MNase-seq for nucleosome positioning, DNase-seq, RNA-seq\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide multi-omics in KO vs. WT with mechanistic links between HMGN1, nucleosome position, and chromatin accessibility\",\n      \"pmids\": [\"23775126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HMGN1 overexpression (from chr21q22 triplication) suppresses H3K27 trimethylation in progenitor B cells and promotes B cell proliferation and B-ALL in vivo; bivalent genes marked by H3K27me3 are preferentially derepressed by HMGN1 overexpression.\",\n      \"method\": \"Mouse trisomy model, HMGN1 overexpression in B cells, ChIP for H3K27me3, B-ALL transplantation model\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + in vivo leukemia model + genetic overexpression demonstrating HMGN1 suppresses PRC2-mediated H3K27me3\",\n      \"pmids\": [\"24747640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HMGN1 and HMGN2 counteract linker histone H1-dependent stabilization of higher-order chromatin structures without displacing H1; they do not disturb H1 globular domain contacts with nucleosomal DNA but alter condensation of the H1 C-terminal domain and redirect core histone tails to more interior positions on the nucleosome.\",\n      \"method\": \"In vitro reconstitution, sedimentation assay, hydroxyl radical footprinting, histone tail accessibility assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple biochemical and structural methods\",\n      \"pmids\": [\"28973435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HMGN1 overexpression globally amplifies transcription and causes a global increase in H3K27 acetylation as revealed by exogenous spike-in normalized ChIP-seq; HMGN1 is necessary for B cell phenotypes in DS trisomy models.\",\n      \"method\": \"Spike-in normalized RNA-seq and ChIP-Rx for H3K27ac, HMGN1 overexpression and knockdown in DS B cell models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — absolute-normalized ChIP-seq revealing global H3K27ac increase causally linked to HMGN1\",\n      \"pmids\": [\"30428356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Phosphorylation of serines in the nucleosomal binding domain of HMGN1 decreases helical propensity of the NBD and disrupts its interaction with the nucleosome acidic patch, as shown by NMR spectroscopy; PTMs in N- or C-termini cause conformational perturbations up to 50-60 residues distant from the modification site.\",\n      \"method\": \"Protein semi-synthesis with site-specific PTMs, segmental isotope labeling, NMR spectroscopy, circular dichroism, nucleosome binding assays\",\n      \"journal\": \"RSC chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR with site-specific PTMs and functional binding assay\",\n      \"pmids\": [\"34458797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Phosphorylation of the HMGN1 NBD decreases helical propensity and disrupts the interface with the nucleosome acidic patch as shown by NMR spectroscopy and circular dichroism, providing atomic-level detail of how phosphorylation reduces nucleosome binding.\",\n      \"method\": \"NMR spectroscopy, circular dichroism, AlphaFold3 modelling of HMGN1-nucleosome interface\",\n      \"journal\": \"Chembiochem : a European journal of chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR + CD with mechanistic structural detail of PTM-induced conformational changes\",\n      \"pmids\": [\"39186607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HMGN1 upregulation in trisomy 21 shifts AVC cardiomyocytes toward a ventricular cardiomyocyte transcriptional state; CRISPR-activation screen identified HMGN1 as the causal chr21 gene; reducing HMGN1 dosage from trisomic levels restores normal AVC gene expression and rescues valvuloseptal defects in a mouse trisomy 21 model.\",\n      \"method\": \"Human iPSC and mouse trisomy 21 models, single-cell RNA-seq, CROP-seq CRISPR-activation screen, allelic HMGN1 deletion/rescue\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CROP-seq causal gene screen + isogenic rescue with defined transcriptional and structural cardiac phenotype\",\n      \"pmids\": [\"41125893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HMGN1 (and HMGN2) function in activation of transcription initiation at over a thousand specific promoters and enhancers; they have shared and unique target genes; HMGN null cells generated by simultaneous deletion of multiple HMGN genes show preferential downregulation of target genes.\",\n      \"method\": \"HMGN null human cell line generation, isogenic rescue lines, genome-wide RNA-seq\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean HMGN null cell line with genome-wide transcriptomics; preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HMGN1 and HMGN2 preferentially bind nucleosomes containing acetylated H3 tail residues and the histone variant H2A.Z; in vitro, HMGN1 and HMGN2 binding to nucleosomes reduces p300-mediated acetylation of H3K18, H3K23, and H3K27; Hmgn1/Hmgn2 double KO mESCs show increased H3K27me2 and H3K27me3.\",\n      \"method\": \"Nucleosome binding assays with modified and variant nucleosomes, in vitro p300 acetylation assay, epiproteomic mass spectrometry, Hmgn1-/-, Hmgn2-/-, and double KO mESCs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted acetylation assay + nucleosome binding preference assay + KO epiproteomic validation\",\n      \"pmids\": [\"41325801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HMGN1 binds HBV cccDNA in the nucleus; silencing HMGN1 increases CLK2 kinase-mediated H3 phosphorylation and reduces cccDNA accessibility; HMGN1 promotes HBV transcription and replication through its nucleosomal binding domain.\",\n      \"method\": \"Biotin-avidin enrichment, ChIP, fluorescent in situ hybridization, HMGN1 knockdown and mutant transfection in HBV-infected cells, in vivo HBV mouse model\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + FISH + mutant rescue; single lab, specific functional domain identified\",\n      \"pmids\": [\"38181856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In human cells, HMGN1 (alone or combined with HMGN2 knockout) is not required for transcription-coupled nucleotide excision repair (TC-NER); HMGN1 is not recruited to UV-induced DNA damage sites and does not associate with the TC-NER complex; this contrasts with findings in mouse cells.\",\n      \"method\": \"HMGN1/HMGN2 KO and knockdown human cells, UV/Illudin S survival, transcription restart assay, GFP-HMGN1 live-cell recruitment at UV damage, co-IP with TC-NER factors\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO + live imaging + co-IP with multiple negative-result controls; establishes species-specific mechanistic difference\",\n      \"pmids\": [\"32152397\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HMGN1 is a nucleosome-binding architectural protein that binds specifically to nucleosome core particles (2 molecules per core) via its nucleosomal binding domain (NBD), localizes preferentially to active promoters, enhancers, and DNase I hypersensitive sites, and modulates the chromatin modification landscape by (i) hindering kinase access to nucleosomal H3-S10 and H2A-S1, thereby reducing their phosphorylation; (ii) enhancing HAT (PCAF/p300) access to nucleosomal H3-K14, promoting its acetylation and stimulating H3K27 acetylation globally; (iii) antagonizing PRC2 to reduce H3K27 trimethylation; (iv) unfolding higher-order chromatin structure through its acidic C-terminal domain targeting the H3 N-terminal tail; (v) facilitating DNA repair by increasing chromatin accessibility to NER factors and stimulating PARP-1 auto-PARylation; and (vi) cycling on and off chromatin in a cell-cycle-dependent manner regulated by mitotic phosphorylation of the NBD (which promotes 14-3-3 binding and blocks nuclear re-import) and by p300-mediated acetylation of the NBD (which weakens nucleosome affinity).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HMGN1 is a nucleosome-binding architectural protein that modulates chromatin accessibility, histone modification landscapes, and transcriptional output across diverse cellular contexts including DNA repair, cell-cycle progression, and differentiation. It binds specifically to nucleosome core particles (two molecules per core) via its nucleosomal binding domain (NBD), which contacts the nucleosome acidic patch and histone H2B, while its acidic C-terminal domain contacts the histone H3 N-terminal tail to counteract linker histone H1-mediated chromatin compaction without displacing H1 [PMID:6449690, PMID:9576905, PMID:28973435]. HMGN1 shapes the histone modification landscape by hindering kinase access to nucleosomal H3-S10 and H2A-S1 (reducing their phosphorylation), enhancing HAT-mediated acetylation of H3K14, stimulating global H3K27 acetylation, and antagonizing PRC2-dependent H3K27 trimethylation—activities that preferentially target active promoters, CpG island-containing promoters, enhancers, and DNase I hypersensitive sites [PMID:15327773, PMID:16096646, PMID:24747640, PMID:30428356, PMID:21173166]. Its chromatin association is dynamically regulated: mitotic phosphorylation of the NBD by MSK1/MSK2 reduces helical propensity, disrupts the acidic-patch interface, promotes 14-3-3 binding to block nuclear re-import, and p300-mediated acetylation of the NBD independently weakens nucleosome affinity; overexpression of HMGN1 from chromosome 21 trisomy drives B-cell acute lymphoblastic leukemia in mouse models and causes valvuloseptal heart defects in Down syndrome by shifting cardiomyocyte transcriptional identity [PMID:12215538, PMID:34458797, PMID:24747640, PMID:41125893].\",\n  \"teleology\": [\n    {\n      \"year\": 1980,\n      \"claim\": \"Establishing that HMGN1 is a specific nucleosome-binding protein—rather than a general DNA-binding factor—answered whether its chromatin association is structural and selective, showing two molecules bind cooperatively per core particle with preference for transcriptionally active sequences.\",\n      \"evidence\": \"Thermal denaturation, nuclease digestion, and nucleosome reconstitution with gene-sequence enrichment; NMR/CD showing intrinsic disorder and N-terminal DNA contact\",\n      \"pmids\": [\"6449690\", \"6257511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise residues mediating nucleosome specificity not yet mapped\", \"In vivo stoichiometry not confirmed\", \"Mechanism of preference for active chromatin unknown\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Mapping HMGN1 footprints on nucleosomes and demonstrating that it enhances RNA Pol II elongation on chromatin templates (not naked DNA) established the structural basis and functional consequence of nucleosome binding, while mutagenesis of the NBD proved this domain is essential for cooperative binding.\",\n      \"evidence\": \"Hydroxyl radical footprinting on cores/chromatosomes; in vitro transcription on chromatin vs DNA templates; site-directed mutagenesis with mobility-shift assays\",\n      \"pmids\": [\"8107104\", \"8047885\", \"7971283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NBD conformation enables cooperative binding at atomic level not resolved\", \"Whether elongation enhancement operates in vivo unclear\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Discovery that mitogen-stimulated serine phosphorylation of HMGN1 occurs in its N-terminal region, catalyzed by a nucleosome-associated kinase, revealed that post-translational modification regulates HMGN1–chromatin dynamics.\",\n      \"evidence\": \"In vivo metabolic labeling with mononucleosome fractionation and in vitro kinase assay\",\n      \"pmids\": [\"7925294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the kinase not yet determined\", \"Functional consequence of phosphorylation for chromatin structure unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showing that the acidic C-terminal domain alleviates H1-mediated transcriptional repression and disrupts chromatin compaction—with function maintained when replaced by heterologous acidic domains—established a modular architecture: NBD for nucleosome targeting, C-terminal domain for chromatin unfolding.\",\n      \"evidence\": \"In vitro transcription on SV40 minichromosomes, chromatin compaction assay, domain-swap mutagenesis\",\n      \"pmids\": [\"9315642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct histone contacts of C-terminal domain not mapped\", \"Whether H1 is displaced or merely antagonized in cis unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Photocrosslinking identified specific histone contacts—N-terminal domain to H2B and C-terminal chromatin-unfolding domain to the H3 N-terminal tail—providing the first molecular map of how HMGN1 domains interact with distinct histone surfaces.\",\n      \"evidence\": \"Protein photocrosslinking in reconstituted nucleosome cores\",\n      \"pmids\": [\"9576905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of full complex not available\", \"Whether contacts differ in dinucleosome/chromatin fiber context unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrating that HMGN1 dissociates from chromosomes during mitosis and re-enters nuclei via an importin-α-dependent NLS pathway established that chromatin binding is cell-cycle regulated.\",\n      \"evidence\": \"Immunofluorescence cell-cycle staging, reconstituted nuclei import assay with energy/importin depletion\",\n      \"pmids\": [\"9852141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What triggers mitotic release not identified\", \"Whether re-association is random or targeted to specific loci unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of p300-mediated acetylation of HMGN1 at seven sites including three in the NBD, with acetylation weakening nucleosome binding, revealed a second PTM axis (alongside phosphorylation) that tunes HMGN1–chromatin affinity.\",\n      \"evidence\": \"In vitro p300 acetylation, site identification, nucleosome binding assay comparing acetylated and unacetylated protein\",\n      \"pmids\": [\"10753971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo acetylation dynamics not characterized\", \"Whether acetylation and phosphorylation act combinatorially unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing that mitotic NBD phosphorylation prevents nuclear re-entry via phosphorylation-dependent 14-3-3 binding (not charge effects) explained how HMGN1 is excluded from reforming nuclei until dephosphorylation occurs.\",\n      \"evidence\": \"In vitro nuclear import with phosphomimetic mutants, affinity chromatography with mitotic vs logarithmic extracts\",\n      \"pmids\": [\"12215538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the phosphatase that restores import competence unknown\", \"Which 14-3-3 isotype is physiologically relevant in vivo not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"MSK1 and MSK2 were identified as the major kinases for HMGN1 phosphorylation upon mitogenic and stress stimulation, resolving the kinase identity question; separately, HMGN1 was shown to enhance nucleotide excision repair by reducing chromatin compaction, with Hmgn1-/- cells UV-hypersensitive.\",\n      \"evidence\": \"MSK1/MSK2 double-KO mouse fibroblasts with in vivo phosphorylation assay; Hmgn1-/- MEFs with UV survival and photoproduct removal assays, rescue with WT vs NBD-mutant\",\n      \"pmids\": [\"12773393\", \"12660172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MSK1/2 phosphorylation of HMGN1 directly enables NER factor access not tested\", \"Species specificity of NER role not yet apparent\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that HMGN1 reduces H3-S10 phosphorylation by sterically impeding kinase access to nucleosomal (but not free) H3, and that stress-induced HMGN1 phosphorylation transiently relieves this block, established a dynamic gating mechanism for histone modification.\",\n      \"evidence\": \"Hmgn1-/- MEFs, in vitro kinase assay on nucleosomal vs free H3, anisomycin kinetics, chromatin fractionation\",\n      \"pmids\": [\"15327773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this gating applies genome-wide or at specific loci unknown\", \"Which kinases are gated in vivo not fully defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"HMGN1 was shown to enhance PCAF-mediated H3K14 acetylation on nucleosomes (not free H3), increase ionizing radiation sensitivity with impaired G2/M checkpoint activation, and negatively regulate N-cadherin expression—broadening its functional scope to HAT facilitation, DNA damage checkpoints, and cell adhesion.\",\n      \"evidence\": \"Hmgn1-/- MEFs with in vitro PCAF acetylation on nucleosomes, IR survival and checkpoint assay, microarray and RT-PCR for N-cadherin, rescue with WT vs mutant HMGN1\",\n      \"pmids\": [\"16096646\", \"16061652\", \"16279949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HAT facilitation and kinase gating are mechanistically linked not tested\", \"Checkpoint phenotype not connected to specific histone modifications\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extension of the kinase-gating model to H2A-S1 phosphorylation (elevated in Hmgn1-/- cells) and the discovery that HMGN1 occupies Sox9 chromatin during embryogenesis to restrain chondrogenic differentiation established HMGN1 as a lineage-specific chromatin modulator.\",\n      \"evidence\": \"In vitro Rsk2/Msk1 kinase assay on nucleosomal vs free H2A; Hmgn1-/- limb bud micromass cultures with ChIP at Sox9 locus, rescue with WT vs mutant\",\n      \"pmids\": [\"17154547\", \"16382150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HMGN1 directly competes with HMGN2 at Sox9 in a zero-sum manner not resolved\", \"How HMGN1 is targeted to Sox9 versus other loci unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Physical interaction of HMGN1 with ERα and SRF, with estrogen-dependent recruitment to the TFF1 promoter where HMGN1 limits gene activation and H3K9 acetylation, established that transcription factors can recruit HMGN1 to act as a context-dependent transcriptional modulator.\",\n      \"evidence\": \"Reciprocal co-IP, in vitro pulldown, ChIP for HMGN1 and H3K9ac, knockdown/overexpression, phosphomimetic mutant\",\n      \"pmids\": [\"17938209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HMGN1 simultaneously enhances some acetylation marks and limits others at different promoters not reconciled\", \"Genome-wide scope of TF-mediated HMGN1 recruitment unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genome-wide ChIP-seq revealed that HMGN1 is not randomly distributed but preferentially localizes to DNase I hypersensitive sites, promoters, and functional enhancers, establishing that its chromatin occupancy is targeted to regulatory regions.\",\n      \"evidence\": \"Genome-wide ChIP-seq for HMGN1 compared to regulatory chromatin marks\",\n      \"pmids\": [\"21173166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of preferential targeting (sequence vs chromatin features) not resolved\", \"Dynamic redistribution upon stimulation not captured\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that HMGN1 directly stimulates PARP-1 auto-PARylation and interacts with PCNA to enhance its chromatin recruitment at damage sites extended the DNA repair role beyond chromatin accessibility to direct protein–protein facilitation of repair factors.\",\n      \"evidence\": \"In vitro PARylation with purified proteins, co-IP, laser micro-irradiation imaging of PARP-1 PARylation and PCNA recruitment in Hmgn1-/- cells, deletion mutagenesis\",\n      \"pmids\": [\"22736760\", \"22393258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PARP-1 stimulation and PCNA recruitment are independent or sequential not determined\", \"Crystal structure of HMGN1–PCNA complex lacking\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Multi-omic analysis in Hmgn1-/- ESCs showed that HMGN1 preferentially binds CpG island-containing promoters and affects nucleosome positioning at TSSs, DNase I hypersensitivity, and transcription in stem and progenitor cells, linking it to epigenetic regulation of cell identity.\",\n      \"evidence\": \"Hmgn1-/- ESCs with ChIP-seq, MNase-seq, DNase-seq, RNA-seq\",\n      \"pmids\": [\"23775126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether nucleosome positioning changes are a direct structural consequence of HMGN1 binding or indirect unknown\", \"Functional consequence for differentiation potential quantitatively undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"HMGN1 overexpression (modeling chr21 trisomy) was shown to suppress H3K27me3 at bivalent genes and promote B-ALL, establishing HMGN1 as a dosage-sensitive oncogene whose overexpression derepresses PRC2 targets.\",\n      \"evidence\": \"Mouse trisomy model, HMGN1 overexpression in B cells, ChIP for H3K27me3, B-ALL transplantation\",\n      \"pmids\": [\"24747640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HMGN1 directly antagonizes PRC2 binding or acts indirectly through acetylation not resolved\", \"Relevance to human B-ALL beyond Down syndrome not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"In vitro reconstitution showed HMGN1/HMGN2 counteract H1-dependent higher-order chromatin folding without displacing H1, by altering H1 C-terminal domain condensation and redirecting core histone tails inward, clarifying the non-competitive mechanism of chromatin decompaction.\",\n      \"evidence\": \"Sedimentation assay, hydroxyl radical footprinting, histone tail accessibility assays on reconstituted chromatin\",\n      \"pmids\": [\"28973435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this mechanism operates at all genomic loci or preferentially at regulatory elements not tested in vivo\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Spike-in normalized ChIP-seq demonstrated that HMGN1 overexpression causes a global (not locus-specific) increase in H3K27 acetylation, resolving whether the transcriptional amplification effect is quantitative and genome-wide.\",\n      \"evidence\": \"ChIP-Rx for H3K27ac with exogenous spike-in, HMGN1 overexpression and knockdown in DS B cell models\",\n      \"pmids\": [\"30428356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which HATs mediate the global H3K27ac increase not identified\", \"Whether global acetylation increase is direct or secondary to H3K27me3 loss unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Human HMGN1/HMGN2 KO cells showed no defect in transcription-coupled NER, and HMGN1 was not recruited to UV damage sites in human cells, establishing a species-specific difference from the mouse NER phenotype.\",\n      \"evidence\": \"HMGN1/HMGN2 KO human cells, UV/Illudin S survival, transcription restart, GFP-HMGN1 live imaging, co-IP with TC-NER factors\",\n      \"pmids\": [\"32152397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether global NER (as opposed to TC-NER) is affected in human cells not fully tested\", \"Molecular basis for species difference not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"NMR of semi-synthesized HMGN1 with site-specific PTMs revealed that NBD phosphorylation reduces helical propensity and disrupts the nucleosome acidic patch interface, providing the first atomic-level explanation for how phosphorylation abolishes nucleosome binding.\",\n      \"evidence\": \"Protein semi-synthesis, segmental isotope labeling, NMR, CD, nucleosome binding assays\",\n      \"pmids\": [\"34458797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full high-resolution structure of HMGN1 bound to nucleosome not available\", \"How long-range conformational effects of terminal PTMs propagate structurally is incompletely understood\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CRISPR-activation screening identified HMGN1 as the causal chr21 gene for atrioventricular canal defects in Down syndrome; reducing HMGN1 dosage from trisomic levels rescued valvuloseptal defects and restored cardiomyocyte transcriptional identity, establishing HMGN1 as a dosage-sensitive driver of congenital heart disease.\",\n      \"evidence\": \"Human iPSC and mouse trisomy 21 models, scRNA-seq, CROP-seq CRISPRa screen, allelic HMGN1 deletion/rescue\",\n      \"pmids\": [\"41125893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream chromatin targets mediating the cardiac phenotype not fully defined\", \"Whether HMGN1 dosage sensitivity operates through H3K27me3 or H3K27ac changes in cardiomyocytes not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"HMGN1 and HMGN2 preferentially bind nucleosomes containing acetylated H3 tails and H2A.Z, yet reduce p300-mediated acetylation of H3K18/K23/K27 on nucleosomes in vitro; double KO mESCs show elevated H3K27me2/me3, revealing a nuanced dual role in both reading and constraining acetylation.\",\n      \"evidence\": \"Nucleosome binding assays with modified/variant nucleosomes, in vitro p300 acetylation, epiproteomic MS, Hmgn1/Hmgn2 DKO mESCs\",\n      \"pmids\": [\"41325801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HMGN1 simultaneously enhances PCAF-mediated H3K14ac but reduces p300-mediated H3K18/K23/K27ac is mechanistically unresolved\", \"Whether preferential binding to acetylated nucleosomes is cause or consequence of acetylation state unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) the full atomic structure of HMGN1 bound to a nucleosome, (2) how HMGN1 is targeted to specific regulatory regions rather than binding all nucleosomes, (3) reconciliation of its apparently opposing effects on different histone acetylation marks (enhancing H3K14ac via PCAF while reducing H3K18/K23/K27ac via p300), and (4) the molecular basis for species-specific differences in its DNA repair functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution cryo-EM or crystal structure of HMGN1–nucleosome complex\", \"Targeting mechanism to specific loci unresolved\", \"Opposing acetylation effects for different HATs mechanistically unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 2, 5, 7, 27, 29, 30, 33]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 14, 17, 26, 28, 33]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [6, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 2, 21, 25]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [21, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6, 13, 14, 17, 26, 27, 28, 33]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 19, 22, 25]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [12, 23, 24]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [18, 31]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 10, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [26, 31]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PARP1\", \"PCNA\", \"ESR1\", \"SRF\", \"PCAF\", \"EP300\", \"YWHAB\"],\n    \"other_free_text\": []\n  }\n}\n```"}