{"gene":"HMGN5","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2009,"finding":"HMGN5/NSBP1 is specifically targeted by its C-terminal domain to nucleosomes in euchromatin, and its negatively charged C-terminal domain directly interacts with the positively charged C-terminal domain of linker histone H5, counteracting linker histone-mediated compaction of nucleosomal arrays. In living cells, HMGN5 interacts with linker histones and alters chromatin compaction, and dysregulation of cellular HMGN5 levels alters the transcription of numerous genes.","method":"FRAP in living cells, in vitro nucleosomal array compaction assay, domain-deletion mutagenesis, transcriptome analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution of nucleosomal array compaction, domain mutagenesis, and live-cell FRAP, multiple orthogonal methods in one study","pmids":["19748358"],"is_preprint":false},{"year":2011,"finding":"Both mouse and human HMGN5 proteins interact with histone H1, reduce H1 chromatin residence time (measured by FRAP), and induce large-scale chromatin decompaction in living cells. The C-terminal domain is the main determinant of chromatin interaction properties. Human and mouse HMGN5 differ in intranuclear organization and nucleosome interactions despite functional conservation.","method":"FRAP, chromatin binding assays, domain-deletion/mutant analysis, transcriptome analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — FRAP with mutagenesis, multiple orthogonal methods, replicates findings from PMID:19748358","pmids":["21518955"],"is_preprint":false},{"year":2013,"finding":"The N-terminal domain of HMGN5 interacts with the C-terminal domain of the lamin-binding protein LAP2α. Loss of either HMGN5 or LAP2α reciprocally affects the genome-wide chromatin distribution of the partner protein, identifying a functional link between chromatin-binding and lamin-binding proteins.","method":"Co-immunoprecipitation, domain-mapping pulldown, chromatin immunoprecipitation (ChIP) in knockout/knockdown cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, genome-wide ChIP in loss-of-function cells, two orthogonal methods in one study","pmids":["23673662"],"is_preprint":false},{"year":2015,"finding":"HMGN5-driven chromatin decompaction decreases nuclear sturdiness, elasticity, and rigidity in cultured cells. In mice overexpressing HMGN5 (globally or heart-specifically), heterochromatin is lost from the nuclear periphery, the nuclear lamina is disrupted, and cardiomyocyte nuclei become misshapen, leading to hypertrophic cardiomyopathy and death — demonstrating that heterochromatin/HMGN5-regulated chromatin compaction is required for nuclear mechanical integrity against contractile forces.","method":"Atomic force microscopy (nuclear stiffness), transgenic mouse overexpression, electron microscopy of nuclear ultrastructure, live-cell imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (AFM, transgenic mouse, EM), in vivo and in vitro, clear mechanistic phenotype","pmids":["25609380"],"is_preprint":false},{"year":2014,"finding":"Mice with targeted disruption of the HMGN5 nucleosome-binding domain show elevated hepatic glutathione levels and altered expression of glutathione metabolism genes (Gpx6, Hk1), with corresponding changes in chromatin structure at these loci detected by DNase I hypersensitivity, linking HMGN5 chromatin-remodeling activity to regulation of glutathione metabolism.","method":"Metabolomics, microarray/qPCR, DNase I chromatin accessibility assay, knockout mouse model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with metabolomics and chromatin accessibility assay, single lab, multiple orthogonal methods","pmids":["24392144"],"is_preprint":false},{"year":2015,"finding":"HMGN5 mRNA localizes to growth cones of neuron-like cells and hippocampal neurons, where it can be locally translated, and HMGN5 protein undergoes retrograde transport into the nucleus along neurites. Loss of HMGN5 impairs neurite outgrowth and causes transcriptional changes; overexpression induces neurite outgrowth and chromatin decompaction. These effects are dependent on growth cone localization of Hmgn5 mRNA.","method":"Fluorescence in situ hybridization (FISH) in neurons, live-cell imaging of retrograde transport, siRNA loss-of-function, overexpression, neurite outgrowth assays, transcriptome analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct FISH localization tied to functional consequence, loss- and gain-of-function with phenotypic readout, single lab","pmids":["25825524"],"is_preprint":false},{"year":2019,"finding":"In an in vitro reconstituted chromatin system, HMGN5 counteracts histone H1-mediated inhibition of distant enhancer-promoter communication (EPC). H1 inhibits EPC in a manner dependent on its N- and C-terminal tails, and HMGN5, which is associated with active chromatin, relieves this inhibition, suggesting that chromatin fiber dynamics between enhancer and promoter regulate EPC efficiency.","method":"In vitro reconstituted nucleosomal array EPC assay, histone H1 tail mutants","journal":"Molekuliarnaia biologiia","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with defined chromatin system, single lab, single method","pmids":["31876282"],"is_preprint":false},{"year":2009,"finding":"NSBP1/HMGN5 is highly expressed in mouse placenta and modulates the expression of prolactin gene family members in Rcho-1 trophoblast cells during differentiation; both siRNA knockdown and overexpression alter prolactin family gene expression without affecting transcription factor levels, implicating chromatin structural changes as the mechanism.","method":"siRNA knockdown, overexpression, RT-PCR/Western blot in Rcho-1 differentiation model","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — bidirectional manipulation (KD and OE) with defined gene expression readout, single lab","pmids":["19160411"],"is_preprint":false},{"year":2010,"finding":"NSBP1/HMGN5 knockdown in bladder cancer EJ cells decreases cell viability, causes G2/M cell cycle arrest with reduced cyclin B1 expression, and reduces MMP-9 activity without affecting MMP-2, demonstrating roles in cell cycle progression and invasion via MMP-9.","method":"RNAi knockdown, MTT assay, flow cytometry, zymography for MMP activity, Western blot","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — loss-of-function with multiple specific molecular readouts (cyclin B1, MMP-9 vs. MMP-2), single lab","pmids":["21695596"],"is_preprint":false},{"year":2012,"finding":"siRNA-mediated knockdown of HMGN5 in LNCaP prostate cancer cells induces apoptosis via the mitochondrial pathway: reduced mitochondrial membrane potential, increased Bax/Bcl-2 ratio, and activation of caspase-3.","method":"siRNA knockdown, Annexin V/TUNEL apoptosis assays, JC-1 mitochondrial membrane potential, caspase activity assay, Western blot","journal":"Asian journal of andrology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple orthogonal apoptosis assays with defined pathway readouts, single lab","pmids":["22504871"],"is_preprint":false},{"year":2020,"finding":"HMGN5 interacts with Hsp27 (confirmed by Co-IP) and promotes IL-6-induced EMT and invasion in bladder cancer cells by regulating STAT3 phosphorylation and STAT3-dependent transcription of the Twist promoter. This interaction promotes tumor growth in a xenograft model.","method":"Co-immunoprecipitation (PPI validation), siRNA knockdown, luciferase reporter (Twist promoter), Western blot for p-STAT3, in vivo xenograft","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP binding plus downstream pathway analysis with reporter assay, single lab, multiple methods","pmids":["32315283"],"is_preprint":false},{"year":2016,"finding":"Hmgn5 functions downstream of Hoxa10 in uterine stromal cells: cAMP/progesterone signaling upregulates Hmgn5 expression via Hoxa10, and Hmgn5 is required for decidualization-associated induction of differentiation markers (Prl8a2, Prl3c1) and expression of Cox-2, Vegf, and Mmp2. Epistasis experiments showed that HMGN5 overexpression rescued inhibition of decidualization markers caused by Hoxa10 siRNA.","method":"siRNA knockdown, overexpression, epistasis by double siRNA/rescue experiment, Western blot, RT-PCR","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (double KD rescue), multiple molecular readouts, single lab","pmids":["27579887"],"is_preprint":false},{"year":2014,"finding":"HMGN5 knockdown in prostate cancer cells sensitizes them to ionizing radiation by suppressing MnSOD induction, increasing mitochondrial ROS, and enhancing apoptosis via reduced Bcl-2/Bcl-xL and activated caspase-3/9. HMGN5 knockdown does not affect DNA double-strand break repair kinetics after radiation.","method":"Clonogenic survival assay, flow cytometry, comet assay, immunofluorescence (γH2AX foci), DHR123 ROS probe, Western blot, RT-PCR","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple orthogonal methods, specific negative result for DSB repair, single lab","pmids":["25307178"],"is_preprint":false},{"year":2022,"finding":"HMGN5 is transcriptionally activated by STAT3 and, in turn, escorts STAT3 to shape the oncogenic chromatin landscape and transcriptional program in breast cancer, forming a feed-forward circuit. Interference with HMGN5 via nanoparticle-delivered siRNA inhibits tumor growth in xenograft mice.","method":"ChIP-seq/ATAC-seq (chromatin landscape), siRNA knockdown, overexpression, transcriptome analysis, luciferase reporter, in vivo xenograft","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and chromatin accessibility assays showing mechanistic feed-forward, single lab, multiple orthogonal genomic methods","pmids":["36066963"],"is_preprint":false},{"year":2001,"finding":"Human NSBP1 (HMGN5) is a nuclear protein homologous to mouse Nsbp1, with conserved nucleosomal binding domains. The gene maps to chromosome Xq13.3, is encoded by 6 exons with exon-intron boundaries identical to HMG-14/-17 genes, and produces three transcripts with alternate polyadenylation sites. The 3' UTR contains AU-rich elements (AREs) and retrotransposon sequences.","method":"cDNA cloning, Northern blot, RT-PCR, radiation hybrid mapping, genomic sequencing","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct nuclear localization confirmed, gene structure characterized, canonical paper for human HMGN5","pmids":["11161810"],"is_preprint":false},{"year":2019,"finding":"HIF1A upregulates HMGN5 in osteosarcoma cells under hypoxia by transcriptionally increasing GATA1, which then promotes HMGN5 expression. Elevated HMGN5 subsequently upregulates MMP2 and MMP9 via the c-jun pathway, promoting migration and invasion.","method":"Overexpression and knockdown experiments, Western blot, RT-PCR, migration/invasion assays","journal":"BioMed research international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway inferred from KD/OE without direct binding evidence for GATA1-HMGN5 promoter interaction","pmids":["31930127"],"is_preprint":false},{"year":2017,"finding":"HMGN5 positively regulates phospho-Akt in urothelial bladder cancer cells; HMGN5 knockdown decreases p-Akt, slug, E-cadherin, and VEGF-C, and increases cytochrome c, cleaved caspase-3, and cleaved PARP under cisplatin treatment. These effects are rescued by IGF-1 (PI3K/Akt activator), placing HMGN5 upstream of PI3K/Akt signaling in chemosensitivity.","method":"siRNA knockdown, IGF-1 rescue, Western blot, cell viability/apoptosis assays","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement by rescue with pharmacological activator, no direct binding evidence","pmids":["29163683"],"is_preprint":false}],"current_model":"HMGN5 (NSBP1) is a nucleosome-binding architectural protein that uses its nucleosome-binding domain (NBD) to bind nucleosome core particles and its negatively charged C-terminal domain to directly interact with the positively charged C-terminal tail of linker histone H1, thereby reducing H1 chromatin residence time, counteracting linker histone-mediated chromatin compaction, and facilitating enhancer-promoter communication; it is preferentially targeted to euchromatin, interacts with the lamin-binding protein LAP2α to coordinate nuclear architecture, and its depletion or overexpression broadly alters gene transcription — with overexpression causing loss of peripheral heterochromatin, nuclear lamina disruption, and mechanical failure of the nucleus under contractile stress in cardiomyocytes in vivo."},"narrative":{"mechanistic_narrative":"HMGN5 (NSBP1) is a nucleosome-binding architectural protein that regulates higher-order chromatin compaction and, through it, nuclear mechanics and gene transcription [PMID:19748358, PMID:25609380]. It is targeted by its nucleosome-binding domain to nucleosomes preferentially in euchromatin, while its negatively charged C-terminal domain directly engages the positively charged C-terminal tail of linker histones (H5/H1), reducing H1 chromatin residence time and counteracting linker histone-mediated compaction of nucleosomal arrays; the C-terminal domain is the principal determinant of these chromatin-binding properties [PMID:19748358, PMID:21518955]. In reconstituted chromatin, HMGN5 relieves H1-imposed inhibition of distant enhancer-promoter communication, linking its decompaction activity to transcriptional output [PMID:31876282], and dysregulation of HMGN5 levels broadly alters gene transcription [PMID:19748358, PMID:21518955]. Beyond chromatin binding, the N-terminal domain interacts with the lamin-binding protein LAP2α, and the two proteins reciprocally determine each other's genome-wide chromatin distribution, coupling chromatin organization to the nuclear lamina [PMID:23673662]. HMGN5-driven decompaction reduces nuclear stiffness, and its overexpression in mice strips heterochromatin from the nuclear periphery, disrupts the lamina, and causes mechanical failure of cardiomyocyte nuclei under contractile stress, producing hypertrophic cardiomyopathy [PMID:25609380]. In the nervous system, Hmgn5 mRNA localizes to neuronal growth cones for local translation with retrograde transport of protein to the nucleus, and HMGN5 levels control neurite outgrowth [PMID:25825524]. Across multiple cancers HMGN5 acts as a chromatin-level effector of oncogenic programs—escorting STAT3 to shape an oncogenic chromatin landscape in a feed-forward circuit in breast cancer [PMID:36066963] and cooperating with Hsp27 to drive STAT3-dependent Twist transcription and EMT in bladder cancer [PMID:32315283]—and its knockdown impairs proliferation, induces mitochondrial apoptosis, and sensitizes tumor cells to radiation and chemotherapy [PMID:21695596, PMID:22504871, PMID:25307178].","teleology":[{"year":2001,"claim":"Established the human gene: was human NSBP1/HMGN5 a real nuclear protein and how is it organized relative to the HMGN family?","evidence":"cDNA cloning, Northern blot, radiation hybrid mapping, and genomic sequencing of human NSBP1","pmids":["11161810"],"confidence":"Medium","gaps":["Function of the conserved nucleosomal binding domain not tested","Role of 3' UTR AU-rich elements in regulation not addressed"]},{"year":2009,"claim":"Defined the core molecular mechanism: how does HMGN5 act on chromatin, resolving that it targets euchromatic nucleosomes and antagonizes linker histone via a direct domain-domain charge interaction.","evidence":"FRAP in living cells, in vitro nucleosomal array compaction assay, domain-deletion mutagenesis, and transcriptome analysis","pmids":["19748358"],"confidence":"High","gaps":["Structural basis of the C-terminal/H1 tail interaction not resolved","Genome-wide rules determining euchromatin targeting not defined"]},{"year":2009,"claim":"Connected the chromatin mechanism to a physiological output by showing HMGN5 modulates prolactin-family gene expression during trophoblast differentiation through chromatin rather than transcription-factor abundance.","evidence":"siRNA knockdown and overexpression with RT-PCR/Western readout in Rcho-1 trophoblast differentiation model","pmids":["19160411"],"confidence":"Medium","gaps":["Direct chromatin occupancy at prolactin loci not shown","Mechanism distinguishing chromatin change from indirect effects not established"]},{"year":2011,"claim":"Generalized and tested species conservation of the H1-antagonism mechanism, confirming H1 residence-time reduction and large-scale decompaction map to the C-terminal domain.","evidence":"FRAP, chromatin binding assays, and domain-deletion/mutant analysis in mouse and human cells","pmids":["21518955"],"confidence":"High","gaps":["Basis for human/mouse differences in intranuclear organization unexplained","Quantitative stoichiometry of HMGN5 vs H1 in vivo unknown"]},{"year":2013,"claim":"Linked chromatin binding to the nuclear lamina by identifying LAP2α as an N-terminal-domain partner whose distribution is reciprocally coupled to HMGN5.","evidence":"Reciprocal Co-IP with domain mapping and genome-wide ChIP in knockout/knockdown cells","pmids":["23673662"],"confidence":"High","gaps":["Whether the interaction is direct or bridged by chromatin not fully resolved","Functional consequence of the LAP2α link for transcription not quantified"]},{"year":2014,"claim":"Provided in vivo loss-of-function evidence linking HMGN5 chromatin-remodeling activity to a metabolic program (hepatic glutathione metabolism) at specific accessible loci.","evidence":"Nucleosome-binding-domain disruption mouse with metabolomics, expression profiling, and DNase I hypersensitivity","pmids":["24392144"],"confidence":"Medium","gaps":["Direct HMGN5 binding at Gpx6/Hk1 not demonstrated","Tissue specificity of metabolic effect not explained"]},{"year":2015,"claim":"Demonstrated the physiological stakes of chromatin compaction: HMGN5 decompaction reduces nuclear mechanical integrity, and its overexpression causes lamina disruption and lethal cardiomyopathy.","evidence":"Atomic force microscopy, transgenic mouse overexpression, electron microscopy, and live-cell imaging","pmids":["25609380"],"confidence":"High","gaps":["Endogenous HMGN5 contribution to nuclear mechanics at physiological levels not isolated","Direct causal chain from heterochromatin loss to lamina disruption not fully dissected"]},{"year":2015,"claim":"Revealed a non-canonical spatial regulation: Hmgn5 mRNA is locally translated in neuronal growth cones with retrograde nuclear transport, coupling subcellular localization to neurite outgrowth.","evidence":"FISH, live-cell imaging of retrograde transport, siRNA loss-of-function, overexpression, and neurite outgrowth assays","pmids":["25825524"],"confidence":"Medium","gaps":["Signal triggering retrograde transport unknown","Transcriptional targets mediating outgrowth not identified"]},{"year":2019,"claim":"Mechanistically tied HMGN5 decompaction to enhancer-promoter communication, showing it relieves H1-tail-dependent inhibition of long-range contacts in defined chromatin.","evidence":"In vitro reconstituted nucleosomal array enhancer-promoter communication assay with H1 tail mutants","pmids":["31876282"],"confidence":"Medium","gaps":["Not validated at endogenous loci in cells","Single in vitro system"]},{"year":2020,"claim":"Established a cancer signaling role: HMGN5 binds Hsp27 and drives STAT3-dependent Twist transcription to promote EMT and tumor growth.","evidence":"Co-IP, siRNA knockdown, Twist luciferase reporter, p-STAT3 Western blot, and xenograft","pmids":["32315283"],"confidence":"Medium","gaps":["Direct vs indirect basis of HMGN5-STAT3 regulation unclear","Chromatin mechanism connecting HMGN5 to STAT3 targets not mapped"]},{"year":2022,"claim":"Defined a feed-forward chromatin circuit in which STAT3 transcriptionally activates HMGN5 and HMGN5 escorts STAT3 to shape the oncogenic chromatin landscape.","evidence":"ChIP-seq/ATAC-seq, knockdown/overexpression, transcriptome analysis, reporter, and nanoparticle-siRNA xenograft","pmids":["36066963"],"confidence":"Medium","gaps":["Whether HMGN5-STAT3 association is direct not shown","Generality of the circuit beyond breast cancer untested"]},{"year":null,"claim":"How HMGN5's single chromatin-decompaction mechanism is selectively deployed across such diverse contexts (cardiac mechanics, neurite outgrowth, metabolism, and multiple oncogenic programs) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of HMGN5 on the nucleosome or bound to H1","Determinants of locus- and tissue-specific targeting unknown","Whether cancer phenotypes derive from the same H1-antagonism mechanism or distinct protein interactions unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,6,13]}],"complexes":[],"partners":["H1","LAP2A","HSP27","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P82970","full_name":"High mobility group nucleosome-binding domain-containing protein 5","aliases":["Nucleosome-binding protein 1"],"length_aa":282,"mass_kda":31.5,"function":"Preferentially binds to euchromatin and modulates cellular transcription by counteracting linker histone-mediated chromatin compaction","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P82970/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HMGN5","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000198157","cell_line_id":"CID001538","localizations":[{"compartment":"chromatin","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"H1F0","stoichiometry":10.0},{"gene":"PARP1","stoichiometry":10.0},{"gene":"BANF1","stoichiometry":4.0},{"gene":"WHSC1","stoichiometry":4.0},{"gene":"SMARCA5","stoichiometry":4.0},{"gene":"TOP2A","stoichiometry":4.0},{"gene":"NEDD8;NEDD8-MDP1","stoichiometry":4.0},{"gene":"H1FX","stoichiometry":4.0},{"gene":"BAZ1B","stoichiometry":4.0},{"gene":"H2AFY2","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001538","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":100.2}],"url":"https://www.proteinatlas.org/search/HMGN5"},"hgnc":{"alias_symbol":[],"prev_symbol":["NSBP1"]},"alphafold":{"accession":"P82970","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P82970","model_url":"https://alphafold.ebi.ac.uk/files/AF-P82970-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P82970-F1-predicted_aligned_error_v6.png","plddt_mean":52.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HMGN5","jax_strain_url":"https://www.jax.org/strain/search?query=HMGN5"},"sequence":{"accession":"P82970","fasta_url":"https://rest.uniprot.org/uniprotkb/P82970.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P82970/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P82970"}},"corpus_meta":[{"pmid":"22109888","id":"PMC_22109888","title":"Neonatal exposure to estradiol/bisphenol A alters promoter 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andrology","url":"https://pubmed.ncbi.nlm.nih.gov/22504871","citation_count":12,"is_preprint":false},{"pmid":"26315299","id":"PMC_26315299","title":"HMGN5 blockade by siRNA enhances apoptosis, suppresses invasion and increases chemosensitivity to temozolomide in meningiomas.","date":"2015","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26315299","citation_count":11,"is_preprint":false},{"pmid":"30128022","id":"PMC_30128022","title":"HMGN5 promotes proliferation and invasion via the activation of Wnt/β-catenin signaling pathway in pancreatic ductal adenocarcinoma.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30128022","citation_count":11,"is_preprint":false},{"pmid":"21518955","id":"PMC_21518955","title":"Distinct properties of human HMGN5 reveal a rapidly evolving but functionally conserved nucleosome binding protein.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21518955","citation_count":11,"is_preprint":false},{"pmid":"28914995","id":"PMC_28914995","title":"Silencing HMGN5 suppresses cell growth and promotes chemosensitivity in esophageal squamous cell carcinoma.","date":"2017","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/28914995","citation_count":10,"is_preprint":false},{"pmid":"31930127","id":"PMC_31930127","title":"Hypoxia-Inducible Factor 1A Upregulates HMGN5 by Increasing the Expression of GATA1 and Plays a Role in Osteosarcoma Metastasis.","date":"2019","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/31930127","citation_count":10,"is_preprint":false},{"pmid":"25572120","id":"PMC_25572120","title":"Expression of oncogenic HMGN5 increases the sensitivity of prostate cancer cells to gemcitabine.","date":"2014","source":"Oncology 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RNA interference induces cell cycle arrest in human lung cancer cells.","date":"2012","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/22994738","citation_count":7,"is_preprint":false},{"pmid":"32596388","id":"PMC_32596388","title":"HMGN5 Silencing Suppresses Cell Biological Progression via AKT/MAPK Pathway in Human Glioblastoma Cells.","date":"2020","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/32596388","citation_count":6,"is_preprint":false},{"pmid":"35261900","id":"PMC_35261900","title":"Circular RNA circTADA2A promotes the proliferation, invasion, and migration of non-small cell lung cancer cells via the miR-450b-3p/HMGN5 signaling pathway.","date":"2022","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35261900","citation_count":6,"is_preprint":false},{"pmid":"33629303","id":"PMC_33629303","title":"HMGN5 promotes invasion and migration of colorectal cancer through activating FGF/FGFR pathway.","date":"2021","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33629303","citation_count":5,"is_preprint":false},{"pmid":"40348637","id":"PMC_40348637","title":"Novel IgG and IgA autoantibodies validated in two independent cohorts are associated with disease activity and determine organ manifestations in systemic lupus erythematosus: implications for anti-LIN28A, anti-HMGN5, anti-IRF5, and anti-TGIF1.","date":"2025","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/40348637","citation_count":4,"is_preprint":false},{"pmid":"31876282","id":"PMC_31876282","title":"[Opposite Effects of Histone H1 and HMGN5 Protein on Distant Interactions in Chromatin].","date":"2019","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/31876282","citation_count":4,"is_preprint":false},{"pmid":"41198629","id":"PMC_41198629","title":"The MYC-dependent lncRNA MB3 inhibits apoptosis in Group 3 Medulloblastoma by regulating the TGF-β pathway via HMGN5.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41198629","citation_count":1,"is_preprint":false},{"pmid":"40487959","id":"PMC_40487959","title":"Circular RNA hsa_circRNA_101996 modulates gastric cancer cell proliferation and apoptosis through the miR-577/HMGN5 axis.","date":"2025","source":"World journal of gastrointestinal oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40487959","citation_count":1,"is_preprint":false},{"pmid":"34045871","id":"PMC_34045871","title":"miR-488 Inhibits Cell Growth and Metastasis in Renal Cell Carcinoma by Targeting HMGN5 [Retraction].","date":"2021","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34045871","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.23.650160","title":"A New Serological Autoantibody Signature Associated with Multiple Sclerosis","date":"2025-04-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.23.650160","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.21.619459","title":"A circuit involving the lncRNA MB3 and the driver genes MYC and OTX2 inhibits apoptosis in Group 3 Medulloblastoma by regulating the TGF-β pathway via HMGN5","date":"2024-10-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.21.619459","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22364,"output_tokens":4285,"usd":0.065684,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12316,"output_tokens":3892,"usd":0.07944,"stage2_stop_reason":"end_turn"},"total_usd":0.145124,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"HMGN5/NSBP1 is specifically targeted by its C-terminal domain to nucleosomes in euchromatin, and its negatively charged C-terminal domain directly interacts with the positively charged C-terminal domain of linker histone H5, counteracting linker histone-mediated compaction of nucleosomal arrays. In living cells, HMGN5 interacts with linker histones and alters chromatin compaction, and dysregulation of cellular HMGN5 levels alters the transcription of numerous genes.\",\n      \"method\": \"FRAP in living cells, in vitro nucleosomal array compaction assay, domain-deletion mutagenesis, transcriptome analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution of nucleosomal array compaction, domain mutagenesis, and live-cell FRAP, multiple orthogonal methods in one study\",\n      \"pmids\": [\"19748358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Both mouse and human HMGN5 proteins interact with histone H1, reduce H1 chromatin residence time (measured by FRAP), and induce large-scale chromatin decompaction in living cells. The C-terminal domain is the main determinant of chromatin interaction properties. Human and mouse HMGN5 differ in intranuclear organization and nucleosome interactions despite functional conservation.\",\n      \"method\": \"FRAP, chromatin binding assays, domain-deletion/mutant analysis, transcriptome analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — FRAP with mutagenesis, multiple orthogonal methods, replicates findings from PMID:19748358\",\n      \"pmids\": [\"21518955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The N-terminal domain of HMGN5 interacts with the C-terminal domain of the lamin-binding protein LAP2α. Loss of either HMGN5 or LAP2α reciprocally affects the genome-wide chromatin distribution of the partner protein, identifying a functional link between chromatin-binding and lamin-binding proteins.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping pulldown, chromatin immunoprecipitation (ChIP) in knockout/knockdown cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, genome-wide ChIP in loss-of-function cells, two orthogonal methods in one study\",\n      \"pmids\": [\"23673662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HMGN5-driven chromatin decompaction decreases nuclear sturdiness, elasticity, and rigidity in cultured cells. In mice overexpressing HMGN5 (globally or heart-specifically), heterochromatin is lost from the nuclear periphery, the nuclear lamina is disrupted, and cardiomyocyte nuclei become misshapen, leading to hypertrophic cardiomyopathy and death — demonstrating that heterochromatin/HMGN5-regulated chromatin compaction is required for nuclear mechanical integrity against contractile forces.\",\n      \"method\": \"Atomic force microscopy (nuclear stiffness), transgenic mouse overexpression, electron microscopy of nuclear ultrastructure, live-cell imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (AFM, transgenic mouse, EM), in vivo and in vitro, clear mechanistic phenotype\",\n      \"pmids\": [\"25609380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mice with targeted disruption of the HMGN5 nucleosome-binding domain show elevated hepatic glutathione levels and altered expression of glutathione metabolism genes (Gpx6, Hk1), with corresponding changes in chromatin structure at these loci detected by DNase I hypersensitivity, linking HMGN5 chromatin-remodeling activity to regulation of glutathione metabolism.\",\n      \"method\": \"Metabolomics, microarray/qPCR, DNase I chromatin accessibility assay, knockout mouse model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with metabolomics and chromatin accessibility assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24392144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HMGN5 mRNA localizes to growth cones of neuron-like cells and hippocampal neurons, where it can be locally translated, and HMGN5 protein undergoes retrograde transport into the nucleus along neurites. Loss of HMGN5 impairs neurite outgrowth and causes transcriptional changes; overexpression induces neurite outgrowth and chromatin decompaction. These effects are dependent on growth cone localization of Hmgn5 mRNA.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH) in neurons, live-cell imaging of retrograde transport, siRNA loss-of-function, overexpression, neurite outgrowth assays, transcriptome analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct FISH localization tied to functional consequence, loss- and gain-of-function with phenotypic readout, single lab\",\n      \"pmids\": [\"25825524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In an in vitro reconstituted chromatin system, HMGN5 counteracts histone H1-mediated inhibition of distant enhancer-promoter communication (EPC). H1 inhibits EPC in a manner dependent on its N- and C-terminal tails, and HMGN5, which is associated with active chromatin, relieves this inhibition, suggesting that chromatin fiber dynamics between enhancer and promoter regulate EPC efficiency.\",\n      \"method\": \"In vitro reconstituted nucleosomal array EPC assay, histone H1 tail mutants\",\n      \"journal\": \"Molekuliarnaia biologiia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with defined chromatin system, single lab, single method\",\n      \"pmids\": [\"31876282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NSBP1/HMGN5 is highly expressed in mouse placenta and modulates the expression of prolactin gene family members in Rcho-1 trophoblast cells during differentiation; both siRNA knockdown and overexpression alter prolactin family gene expression without affecting transcription factor levels, implicating chromatin structural changes as the mechanism.\",\n      \"method\": \"siRNA knockdown, overexpression, RT-PCR/Western blot in Rcho-1 differentiation model\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — bidirectional manipulation (KD and OE) with defined gene expression readout, single lab\",\n      \"pmids\": [\"19160411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NSBP1/HMGN5 knockdown in bladder cancer EJ cells decreases cell viability, causes G2/M cell cycle arrest with reduced cyclin B1 expression, and reduces MMP-9 activity without affecting MMP-2, demonstrating roles in cell cycle progression and invasion via MMP-9.\",\n      \"method\": \"RNAi knockdown, MTT assay, flow cytometry, zymography for MMP activity, Western blot\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — loss-of-function with multiple specific molecular readouts (cyclin B1, MMP-9 vs. MMP-2), single lab\",\n      \"pmids\": [\"21695596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"siRNA-mediated knockdown of HMGN5 in LNCaP prostate cancer cells induces apoptosis via the mitochondrial pathway: reduced mitochondrial membrane potential, increased Bax/Bcl-2 ratio, and activation of caspase-3.\",\n      \"method\": \"siRNA knockdown, Annexin V/TUNEL apoptosis assays, JC-1 mitochondrial membrane potential, caspase activity assay, Western blot\",\n      \"journal\": \"Asian journal of andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple orthogonal apoptosis assays with defined pathway readouts, single lab\",\n      \"pmids\": [\"22504871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HMGN5 interacts with Hsp27 (confirmed by Co-IP) and promotes IL-6-induced EMT and invasion in bladder cancer cells by regulating STAT3 phosphorylation and STAT3-dependent transcription of the Twist promoter. This interaction promotes tumor growth in a xenograft model.\",\n      \"method\": \"Co-immunoprecipitation (PPI validation), siRNA knockdown, luciferase reporter (Twist promoter), Western blot for p-STAT3, in vivo xenograft\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP binding plus downstream pathway analysis with reporter assay, single lab, multiple methods\",\n      \"pmids\": [\"32315283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Hmgn5 functions downstream of Hoxa10 in uterine stromal cells: cAMP/progesterone signaling upregulates Hmgn5 expression via Hoxa10, and Hmgn5 is required for decidualization-associated induction of differentiation markers (Prl8a2, Prl3c1) and expression of Cox-2, Vegf, and Mmp2. Epistasis experiments showed that HMGN5 overexpression rescued inhibition of decidualization markers caused by Hoxa10 siRNA.\",\n      \"method\": \"siRNA knockdown, overexpression, epistasis by double siRNA/rescue experiment, Western blot, RT-PCR\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (double KD rescue), multiple molecular readouts, single lab\",\n      \"pmids\": [\"27579887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HMGN5 knockdown in prostate cancer cells sensitizes them to ionizing radiation by suppressing MnSOD induction, increasing mitochondrial ROS, and enhancing apoptosis via reduced Bcl-2/Bcl-xL and activated caspase-3/9. HMGN5 knockdown does not affect DNA double-strand break repair kinetics after radiation.\",\n      \"method\": \"Clonogenic survival assay, flow cytometry, comet assay, immunofluorescence (γH2AX foci), DHR123 ROS probe, Western blot, RT-PCR\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple orthogonal methods, specific negative result for DSB repair, single lab\",\n      \"pmids\": [\"25307178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HMGN5 is transcriptionally activated by STAT3 and, in turn, escorts STAT3 to shape the oncogenic chromatin landscape and transcriptional program in breast cancer, forming a feed-forward circuit. Interference with HMGN5 via nanoparticle-delivered siRNA inhibits tumor growth in xenograft mice.\",\n      \"method\": \"ChIP-seq/ATAC-seq (chromatin landscape), siRNA knockdown, overexpression, transcriptome analysis, luciferase reporter, in vivo xenograft\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and chromatin accessibility assays showing mechanistic feed-forward, single lab, multiple orthogonal genomic methods\",\n      \"pmids\": [\"36066963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human NSBP1 (HMGN5) is a nuclear protein homologous to mouse Nsbp1, with conserved nucleosomal binding domains. The gene maps to chromosome Xq13.3, is encoded by 6 exons with exon-intron boundaries identical to HMG-14/-17 genes, and produces three transcripts with alternate polyadenylation sites. The 3' UTR contains AU-rich elements (AREs) and retrotransposon sequences.\",\n      \"method\": \"cDNA cloning, Northern blot, RT-PCR, radiation hybrid mapping, genomic sequencing\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct nuclear localization confirmed, gene structure characterized, canonical paper for human HMGN5\",\n      \"pmids\": [\"11161810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HIF1A upregulates HMGN5 in osteosarcoma cells under hypoxia by transcriptionally increasing GATA1, which then promotes HMGN5 expression. Elevated HMGN5 subsequently upregulates MMP2 and MMP9 via the c-jun pathway, promoting migration and invasion.\",\n      \"method\": \"Overexpression and knockdown experiments, Western blot, RT-PCR, migration/invasion assays\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway inferred from KD/OE without direct binding evidence for GATA1-HMGN5 promoter interaction\",\n      \"pmids\": [\"31930127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HMGN5 positively regulates phospho-Akt in urothelial bladder cancer cells; HMGN5 knockdown decreases p-Akt, slug, E-cadherin, and VEGF-C, and increases cytochrome c, cleaved caspase-3, and cleaved PARP under cisplatin treatment. These effects are rescued by IGF-1 (PI3K/Akt activator), placing HMGN5 upstream of PI3K/Akt signaling in chemosensitivity.\",\n      \"method\": \"siRNA knockdown, IGF-1 rescue, Western blot, cell viability/apoptosis assays\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement by rescue with pharmacological activator, no direct binding evidence\",\n      \"pmids\": [\"29163683\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HMGN5 (NSBP1) is a nucleosome-binding architectural protein that uses its nucleosome-binding domain (NBD) to bind nucleosome core particles and its negatively charged C-terminal domain to directly interact with the positively charged C-terminal tail of linker histone H1, thereby reducing H1 chromatin residence time, counteracting linker histone-mediated chromatin compaction, and facilitating enhancer-promoter communication; it is preferentially targeted to euchromatin, interacts with the lamin-binding protein LAP2α to coordinate nuclear architecture, and its depletion or overexpression broadly alters gene transcription — with overexpression causing loss of peripheral heterochromatin, nuclear lamina disruption, and mechanical failure of the nucleus under contractile stress in cardiomyocytes in vivo.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HMGN5 (NSBP1) is a nucleosome-binding architectural protein that regulates higher-order chromatin compaction and, through it, nuclear mechanics and gene transcription [#0, #3]. It is targeted by its nucleosome-binding domain to nucleosomes preferentially in euchromatin, while its negatively charged C-terminal domain directly engages the positively charged C-terminal tail of linker histones (H5/H1), reducing H1 chromatin residence time and counteracting linker histone-mediated compaction of nucleosomal arrays; the C-terminal domain is the principal determinant of these chromatin-binding properties [#0, #1]. In reconstituted chromatin, HMGN5 relieves H1-imposed inhibition of distant enhancer-promoter communication, linking its decompaction activity to transcriptional output [#6], and dysregulation of HMGN5 levels broadly alters gene transcription [#0, #1]. Beyond chromatin binding, the N-terminal domain interacts with the lamin-binding protein LAP2\\u03b1, and the two proteins reciprocally determine each other's genome-wide chromatin distribution, coupling chromatin organization to the nuclear lamina [#2]. HMGN5-driven decompaction reduces nuclear stiffness, and its overexpression in mice strips heterochromatin from the nuclear periphery, disrupts the lamina, and causes mechanical failure of cardiomyocyte nuclei under contractile stress, producing hypertrophic cardiomyopathy [#3]. In the nervous system, Hmgn5 mRNA localizes to neuronal growth cones for local translation with retrograde transport of protein to the nucleus, and HMGN5 levels control neurite outgrowth [#5]. Across multiple cancers HMGN5 acts as a chromatin-level effector of oncogenic programs\\u2014escorting STAT3 to shape an oncogenic chromatin landscape in a feed-forward circuit in breast cancer [#13] and cooperating with Hsp27 to drive STAT3-dependent Twist transcription and EMT in bladder cancer [#10]\\u2014and its knockdown impairs proliferation, induces mitochondrial apoptosis, and sensitizes tumor cells to radiation and chemotherapy [#8, #9, #12].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the human gene: was human NSBP1/HMGN5 a real nuclear protein and how is it organized relative to the HMGN family?\",\n      \"evidence\": \"cDNA cloning, Northern blot, radiation hybrid mapping, and genomic sequencing of human NSBP1\",\n      \"pmids\": [\"11161810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of the conserved nucleosomal binding domain not tested\", \"Role of 3' UTR AU-rich elements in regulation not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the core molecular mechanism: how does HMGN5 act on chromatin, resolving that it targets euchromatic nucleosomes and antagonizes linker histone via a direct domain-domain charge interaction.\",\n      \"evidence\": \"FRAP in living cells, in vitro nucleosomal array compaction assay, domain-deletion mutagenesis, and transcriptome analysis\",\n      \"pmids\": [\"19748358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the C-terminal/H1 tail interaction not resolved\", \"Genome-wide rules determining euchromatin targeting not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected the chromatin mechanism to a physiological output by showing HMGN5 modulates prolactin-family gene expression during trophoblast differentiation through chromatin rather than transcription-factor abundance.\",\n      \"evidence\": \"siRNA knockdown and overexpression with RT-PCR/Western readout in Rcho-1 trophoblast differentiation model\",\n      \"pmids\": [\"19160411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin occupancy at prolactin loci not shown\", \"Mechanism distinguishing chromatin change from indirect effects not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Generalized and tested species conservation of the H1-antagonism mechanism, confirming H1 residence-time reduction and large-scale decompaction map to the C-terminal domain.\",\n      \"evidence\": \"FRAP, chromatin binding assays, and domain-deletion/mutant analysis in mouse and human cells\",\n      \"pmids\": [\"21518955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis for human/mouse differences in intranuclear organization unexplained\", \"Quantitative stoichiometry of HMGN5 vs H1 in vivo unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked chromatin binding to the nuclear lamina by identifying LAP2\\u03b1 as an N-terminal-domain partner whose distribution is reciprocally coupled to HMGN5.\",\n      \"evidence\": \"Reciprocal Co-IP with domain mapping and genome-wide ChIP in knockout/knockdown cells\",\n      \"pmids\": [\"23673662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the interaction is direct or bridged by chromatin not fully resolved\", \"Functional consequence of the LAP2\\u03b1 link for transcription not quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided in vivo loss-of-function evidence linking HMGN5 chromatin-remodeling activity to a metabolic program (hepatic glutathione metabolism) at specific accessible loci.\",\n      \"evidence\": \"Nucleosome-binding-domain disruption mouse with metabolomics, expression profiling, and DNase I hypersensitivity\",\n      \"pmids\": [\"24392144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HMGN5 binding at Gpx6/Hk1 not demonstrated\", \"Tissue specificity of metabolic effect not explained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated the physiological stakes of chromatin compaction: HMGN5 decompaction reduces nuclear mechanical integrity, and its overexpression causes lamina disruption and lethal cardiomyopathy.\",\n      \"evidence\": \"Atomic force microscopy, transgenic mouse overexpression, electron microscopy, and live-cell imaging\",\n      \"pmids\": [\"25609380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous HMGN5 contribution to nuclear mechanics at physiological levels not isolated\", \"Direct causal chain from heterochromatin loss to lamina disruption not fully dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a non-canonical spatial regulation: Hmgn5 mRNA is locally translated in neuronal growth cones with retrograde nuclear transport, coupling subcellular localization to neurite outgrowth.\",\n      \"evidence\": \"FISH, live-cell imaging of retrograde transport, siRNA loss-of-function, overexpression, and neurite outgrowth assays\",\n      \"pmids\": [\"25825524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signal triggering retrograde transport unknown\", \"Transcriptional targets mediating outgrowth not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mechanistically tied HMGN5 decompaction to enhancer-promoter communication, showing it relieves H1-tail-dependent inhibition of long-range contacts in defined chromatin.\",\n      \"evidence\": \"In vitro reconstituted nucleosomal array enhancer-promoter communication assay with H1 tail mutants\",\n      \"pmids\": [\"31876282\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not validated at endogenous loci in cells\", \"Single in vitro system\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a cancer signaling role: HMGN5 binds Hsp27 and drives STAT3-dependent Twist transcription to promote EMT and tumor growth.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, Twist luciferase reporter, p-STAT3 Western blot, and xenograft\",\n      \"pmids\": [\"32315283\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect basis of HMGN5-STAT3 regulation unclear\", \"Chromatin mechanism connecting HMGN5 to STAT3 targets not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a feed-forward chromatin circuit in which STAT3 transcriptionally activates HMGN5 and HMGN5 escorts STAT3 to shape the oncogenic chromatin landscape.\",\n      \"evidence\": \"ChIP-seq/ATAC-seq, knockdown/overexpression, transcriptome analysis, reporter, and nanoparticle-siRNA xenograft\",\n      \"pmids\": [\"36066963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HMGN5-STAT3 association is direct not shown\", \"Generality of the circuit beyond breast cancer untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HMGN5's single chromatin-decompaction mechanism is selectively deployed across such diverse contexts (cardiac mechanics, neurite outgrowth, metabolism, and multiple oncogenic programs) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of HMGN5 on the nucleosome or bound to H1\", \"Determinants of locus- and tissue-specific targeting unknown\", \"Whether cancer phenotypes derive from the same H1-antagonism mechanism or distinct protein interactions unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 6, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"H1\", \"LAP2A\", \"HSP27\", \"STAT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}