{"gene":"SP140","run_date":"2026-06-10T07:46:38","timeline":{"discoveries":[{"year":2025,"finding":"SP140 does not directly repress Ifnb1 transcription; instead, SP140 negatively regulates Ifnb1 mRNA stability by directly repressing expression of a previously uncharacterized regulator called RESIST (annexin 2 receptor). RESIST promotes Ifnb1 mRNA stability by counteracting destabilization mediated by the tristetraprolin (TTP) family of RNA-binding proteins and the CCR4-NOT deadenylase complex.","method":"Genetic epistasis (Sp140-/- mice), identification of RESIST as SP140 target gene, mRNA stability assays, functional rescue experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mice, mRNA stability assays, identification of novel regulatory node), peer-reviewed, mechanistically comprehensive","pmids":["40500448"],"is_preprint":false},{"year":2025,"finding":"SP140 localizes within nuclear bodies and inhibits replication of the gammaherpesvirus MHV68 through a mechanism independent of its ability to regulate Ifnb1 mRNA levels, establishing dual antiviral and interferon regulatory functions.","method":"Sp140-/- mouse infections with MHV68, epistasis with Ifnb1 regulation","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined phenotype and functional independence demonstrated, single lab","pmids":["40500448"],"is_preprint":false},{"year":2021,"finding":"SP140 represses type I IFN transcription during bacterial infection, acting as a negative regulator of type I IFNs. Sp140-/- mice are susceptible to Legionella pneumophila and Mycobacterium tuberculosis infection, and this susceptibility is rescued by genetic deletion of the type I IFN receptor (Ifnar-/-).","method":"Sp140-/- mouse generation, bacterial infection models, genetic epistasis cross to Ifnar-/- mice","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mice, epistasis rescue with Ifnar-/-, replicated across two bacterial infection models","pmids":["34151776"],"is_preprint":false},{"year":2017,"finding":"SP140 preferentially occupies promoters of silenced, lineage-inappropriate genes bearing the histone modification H3K27me3 (e.g., HOXA cluster) in human macrophages and ensures their repression. Depletion of SP140 in macrophages results in severely compromised microbe-induced activation.","method":"ChIP-seq/chromatin occupancy analysis, SP140 knockdown in mouse and human macrophages, functional macrophage activation assays","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq plus functional KD in both mouse and human macrophages, multiple orthogonal readouts","pmids":["28783698"],"is_preprint":false},{"year":2022,"finding":"SP140 acts as a repressor of topoisomerases (TOP1 and TOP2), maintaining heterochromatin and macrophage fate. Loss of SP140 results in unleashed topoisomerase activity, de-repression of developmentally silenced genes, and defective microbe-inducible macrophage transcriptional programs and bacterial killing. Pharmacological inhibition of TOP1/2 rescues these defects in Sp140-/- mice.","method":"Global proteomic strategy to identify SP140 interactors, Sp140-/- mice, pharmacological TOP1/2 inhibitor rescue experiments in vivo and in vitro","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — proteomic identification plus genetic KO plus pharmacological rescue in vivo, multiple orthogonal methods in a single rigorous study","pmids":["35952671"],"is_preprint":false},{"year":2022,"finding":"SP140 negatively regulates STAT1 transcription by directly binding to the STAT1 promoter (shown by chromatin immunoprecipitation), and SP140 overexpression in macrophages induces a proinflammatory phenotype with increased IFN-γ production.","method":"ChIP, ATAC-seq, SP140 overexpression and knockdown in macrophages and tumor-associated macrophages, cytokine ELISAs","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus ATAC-seq plus functional OE/KD, single lab","pmids":["36600652"],"is_preprint":false},{"year":2022,"finding":"Loss of SP140 in hematopoietic cells leads to blooms of Proteobacteria (Helicobacter in mice; Enterobacteriaceae in humans with SP140 loss-of-function variant), and phagocytes from Sp140-/- mice or patients show altered antimicrobial defense programs; colitis driven by altered microbiota is transmissible by cohousing and ameliorated with antibiotics.","method":"Sp140-/- mouse model (hematopoietic-specific), cohousing and antibiotic experiments, microbiome sequencing, phagocytic function assays","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic model, multiple orthogonal approaches (cohousing, antibiotics, phagocyte assays), validated in human patient cells","pmids":["36130593"],"is_preprint":false},{"year":2013,"finding":"The PHD finger of Sp140 adopts an atypical fold that does not bind histone H3 tails but is recognized by the peptidylprolyl isomerase Pin1. Pin1 specifically binds a phosphopeptide corresponding to the L3 loop of Sp140-PHD and catalyzes cis-trans isomerization of a pThr-Pro bond. Co-immunoprecipitation confirmed FLAG-Sp140 interaction with endogenous Pin1 in vivo.","method":"NMR solution structure, in vitro binding assays, co-immunoprecipitation (FLAG-Sp140 with endogenous Pin1)","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure plus in vitro binding plus co-IP in cells, single lab but multiple orthogonal methods","pmids":["24267382"],"is_preprint":false},{"year":2018,"finding":"Sp140 is a multi-SUMO-1 target with at least 13 SUMOylation sites including the bromodomain. The PHD finger directly binds the SUMO E2 ligase Ubc9 and SUMO-1 (by NMR), and acts as a SUMO E3 ligase promoting intramolecular SUMOylation of the adjacent bromodomain in vitro.","method":"Mass spectrometry identification of SUMOylation sites, NMR binding experiments, in vitro SUMOylation reactions, biochemical experiments in Burkitt's lymphoma cells and HEK293T cells","journal":"Biochimica et biophysica acta. General subjects","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR, mass spectrometry, and in vitro reconstitution of SUMO E3 ligase activity, multiple orthogonal methods, single lab","pmids":["30465816"],"is_preprint":false},{"year":2018,"finding":"SP140 silencing in lymphoblastoid cell lines leads to upregulation of NF-κB transcriptional activity and NF-κB-driven inflammatory genes, including those involved in cytokine production and cell-cell adhesion, identifying SP140 as a repressor of NF-κB-driven transcription in B cells.","method":"SP140 siRNA knockdown, RNA-seq, luciferase NF-κB reporter assay, promoter enrichment analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq plus functional NF-κB reporter assay, two orthogonal methods, single lab","pmids":["30102396"],"is_preprint":false},{"year":2025,"finding":"SP140 represses specific loci by recruiting the Polycomb Repressive Complex 2 (PRC2) and NuRD complex. SP140 interaction with PRC2 and NuRD is functional, directing H3K27me3 deposition and NuRD binding at target genes implicated in cellular growth and leukemia progression.","method":"Interactomics (proteomics), ChIP-seq, multi-omics in Burkitt lymphoma cell lines","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — proteomic interactomics plus ChIP-seq demonstrating functional H3K27me3 deposition, multiple orthogonal methods, single lab","pmids":["39718989"],"is_preprint":false},{"year":2002,"finding":"Sp140, identified by yeast two-hybrid screen as a potential HIV-1 Vif binding partner, is found specifically in all non-permissive (NP) cells tested, and HIV-1 infection induces partial dispersal of Sp140 from nuclear bodies into cytosolic colocalization with Vif, implicating Sp140 in an innate antiviral response.","method":"Yeast two-hybrid screen, indirect immunofluorescence colocalization, cell line panel comparison","journal":"Journal of virology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid plus colocalization, single lab, no direct functional validation of Sp140-Vif interaction consequence","pmids":["12368356"],"is_preprint":false},{"year":2009,"finding":"Sp140 is a component of PML nuclear bodies (NBs). Anti-Sp140 antibodies in PBC patients were identified using a neuroblastoma cell line expressing Sp140, confirming its nuclear body localization and identifying the NB as a multiantigenic complex.","method":"Indirect immunofluorescence, neuroblastoma cell line expressing Sp140, clinical serology in PBC patients","journal":"The American journal of gastroenterology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by immunofluorescence, no direct functional consequence tested, single approach","pmids":["19861957"],"is_preprint":false},{"year":2022,"finding":"SP140 inhibition by small molecule GSK761 reduces SP140 chromatin binding at transcriptional start sites of pro-inflammatory cytokine/chemokine genes in inflammatory macrophages, reducing LPS-induced cytokine expression and monocyte-to-inflammatory macrophage differentiation, while inducing CD206+ regulatory macrophages.","method":"Small molecule SP140 inhibitor (GSK761) development, ChIP-seq in inflammatory macrophages, LPS stimulation assays, flow cytometry","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus functional pharmacological inhibition, first selective inhibitor with orthogonal readouts, single lab","pmids":["35986286"],"is_preprint":false},{"year":2024,"finding":"SP140 expression in tumors can be driven by an alternative intronic promoter derived from an intronic endogenous retrovirus (LTR8B family), regulated by oncogenic MAPK signaling. Silencing this ERV promoter in a fibrosarcoma cell line increased sensitivity to interferon-mediated cytotoxicity and dysregulated multiple immune genes.","method":"Transcriptomic analysis, ERV promoter silencing (CRISPR or siRNA), interferon cytotoxicity assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter silencing plus cytotoxicity assays, mechanistic link to MAPK regulation, single lab","pmids":["38751339"],"is_preprint":false},{"year":2021,"finding":"siRNA-mediated knockdown of Sp140 in bone marrow-derived cultured mast cells (BMCMCs) decreased IgE-dependent histamine release and cytokine production, establishing a role for Sp140 in IgE-dependent mast cell activation.","method":"siRNA knockdown in BMCMCs, IgE-dependent activation assays (histamine release, cytokine ELISA)","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined functional readout, but single lab and no mechanistic pathway placement","pmids":["34156030"],"is_preprint":false},{"year":2026,"finding":"SP140 acts as an epigenetic gatekeeper suppressing hematopoiesis. Transient SP140 inhibition unlocks transcription at endothelial-to-hematopoietic transition (EHT) loci through topoisomerase 1-dependent chromatin remodeling, and this effect is blocked by topoisomerase 1 inhibition. SP140 binding at EHT and HSC-specification gene loci was confirmed by CUT&TAG profiling.","method":"CRISPR/Cas9 screen, transient SP140 KO or GSK761 pharmacological inhibition, CUT&TAG chromatin profiling, topoisomerase 1 inhibitor epistasis, transplantation assays in immunodeficient mice","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&TAG plus epistasis with TOP1 inhibitor plus functional rescue in transplantation, single lab","pmids":["41397285"],"is_preprint":false}],"current_model":"SP140 is an immune-restricted, nuclear body-localized epigenetic 'reader' containing PHD, bromodomain, and SAND domains that functions as a transcriptional co-repressor: it occupies promoters of silenced, H3K27me3-marked lineage-inappropriate genes by recruiting PRC2 and NuRD complexes, represses topoisomerase (TOP1/2) activity to maintain heterochromatin and macrophage identity, and indirectly restrains type I interferon (IFNβ) production not by directly repressing Ifnb1 transcription but by repressing RESIST—a novel stabilizer of Ifnb1 mRNA that acts against TTP/CCR4-NOT-mediated destabilization; SP140 is itself regulated post-translationally by multi-site SUMO-1 modification (with its PHD finger acting as an intramolecular SUMO E3 ligase for the adjacent bromodomain) and by interaction with the prolyl isomerase Pin1, and loss-of-function of SP140 in macrophages leads to unleashed topoisomerase activity, de-repression of developmentally silenced genes, impaired bacterial killing, altered gut microbiota, and exacerbated intestinal inflammation—phenotypes genetically linked to Crohn's disease, multiple sclerosis, and chronic lymphocytic leukemia."},"narrative":{"mechanistic_narrative":"SP140 is an immune-restricted, nuclear body-localized epigenetic reader that acts as a transcriptional co-repressor enforcing macrophage and hematopoietic cell identity by silencing lineage-inappropriate genes [PMID:28783698]. It preferentially occupies promoters bearing H3K27me3 (e.g., the HOXA cluster) in macrophages and ensures their repression, and its loss severely compromises microbe-induced macrophage activation [PMID:28783698]. Repression is executed through recruitment of the PRC2 and NuRD complexes, directing H3K27me3 deposition and NuRD binding at target loci [PMID:39718989], and through restraint of topoisomerase TOP1/TOP2 activity to maintain heterochromatin; loss of SP140 unleashes topoisomerase activity, de-represses silenced genes, and impairs bacterial killing, defects rescued by pharmacological TOP1/2 inhibition [PMID:35952671]. SP140 also gatekeeps the endothelial-to-hematopoietic transition through TOP1-dependent chromatin remodeling [PMID:41397285]. As a negative regulator of innate immunity, SP140 restrains type I interferon: it represses Ifnb1 not directly but by repressing RESIST, a stabilizer of Ifnb1 mRNA that counteracts TTP/CCR4-NOT-mediated destabilization [PMID:40500448], and Sp140-deficient mice are susceptible to Legionella and Mycobacterium tuberculosis in an IFNAR-dependent manner [PMID:34151776]. SP140 loss in hematopoietic cells drives Proteobacteria blooms, altered antimicrobial programs, and transmissible colitis [PMID:36130593]. The protein is regulated post-translationally: its atypical PHD finger does not bind histone H3 but is recognized by the prolyl isomerase Pin1, which isomerizes a phosphorylated pThr-Pro bond in the PHD L3 loop [PMID:24267382], and the PHD finger also binds Ubc9/SUMO-1 and acts as an intramolecular SUMO E3 ligase for the adjacent multi-SUMOylated bromodomain [PMID:30465816]. These activities link SP140 genetically and functionally to intestinal inflammation, Crohn's disease, and lymphoma biology [PMID:36130593, PMID:39718989].","teleology":[{"year":2002,"claim":"Established SP140 as a nuclear body protein with a possible innate antiviral role, the first functional context for the gene.","evidence":"Yeast two-hybrid screen for HIV-1 Vif partners plus immunofluorescence colocalization in non-permissive cell lines","pmids":["12368356"],"confidence":"Low","gaps":["Vif interaction consequence never functionally validated","no direct antiviral mechanism defined","single low-confidence approach"]},{"year":2009,"claim":"Confirmed SP140 as a constituent of PML nuclear bodies, defining its subcellular compartment.","evidence":"Indirect immunofluorescence and clinical serology in PBC patients using Sp140-expressing neuroblastoma cells","pmids":["19861957"],"confidence":"Low","gaps":["no functional consequence of NB localization tested","localization only by single approach"]},{"year":2013,"claim":"Determined that the SP140 PHD finger is an atypical non-histone-binding fold regulated by Pin1, revealing post-translational control of the reader.","evidence":"NMR solution structure, in vitro phosphopeptide binding, and co-IP of FLAG-Sp140 with endogenous Pin1","pmids":["24267382"],"confidence":"High","gaps":["functional outcome of Pin1-catalyzed isomerization on SP140 activity not defined","kinase generating the phospho-Thr unknown"]},{"year":2017,"claim":"Defined SP140 as a chromatin reader occupying H3K27me3-marked silenced promoters to maintain macrophage identity, establishing its core transcriptional repressor role.","evidence":"ChIP-seq chromatin occupancy plus SP140 knockdown and macrophage activation assays in mouse and human cells","pmids":["28783698"],"confidence":"High","gaps":["effector complexes mediating repression not yet identified at this stage","mechanism of H3K27me3-locus targeting unresolved"]},{"year":2018,"claim":"Showed SP140 is itself SUMO-regulated and that its PHD finger is an intramolecular SUMO E3 ligase, adding a layer of self-modification control.","evidence":"Mass spectrometry SUMO-site mapping, NMR binding to Ubc9/SUMO-1, and in vitro SUMOylation reconstitution","pmids":["30465816"],"confidence":"High","gaps":["functional consequence of bromodomain SUMOylation on chromatin activity not established in cells","regulation of SUMOylation in vivo unknown"]},{"year":2018,"claim":"Extended SP140's repressor role to NF-κB-driven inflammatory transcription in B cells.","evidence":"siRNA knockdown with RNA-seq and NF-κB luciferase reporter assays in lymphoblastoid lines","pmids":["30102396"],"confidence":"Medium","gaps":["direct vs indirect repression of NF-κB targets not distinguished","single cell-type context"]},{"year":2021,"claim":"Placed SP140 as a negative regulator of type I IFN whose loss causes IFNAR-dependent susceptibility to intracellular bacteria, linking the gene to infection outcome.","evidence":"Sp140-/- mice in Legionella and M. tuberculosis models with genetic Ifnar-/- epistasis rescue","pmids":["34151776"],"confidence":"High","gaps":["molecular mechanism of IFN repression not yet defined at this stage","did not distinguish transcriptional vs post-transcriptional control"]},{"year":2021,"claim":"Identified a role for SP140 in IgE-dependent mast cell activation, broadening its immune-cell functions.","evidence":"siRNA knockdown in bone marrow-derived mast cells with histamine release and cytokine assays","pmids":["34156030"],"confidence":"Medium","gaps":["no mechanistic pathway placement","single lab, single readout"]},{"year":2022,"claim":"Revealed that SP140 represses topoisomerases TOP1/TOP2 to maintain heterochromatin and macrophage fate, providing a mechanistic basis for gene silencing.","evidence":"Proteomic interactor identification, Sp140-/- mice, and pharmacological TOP1/2 inhibitor rescue in vivo and in vitro","pmids":["35952671"],"confidence":"High","gaps":["biochemical mode of topoisomerase inhibition not detailed","link between topoisomerase restraint and specific H3K27me3 loci incomplete"]},{"year":2022,"claim":"Connected SP140 loss to gut dysbiosis and transmissible colitis, tying the molecular phenotype to intestinal inflammatory disease.","evidence":"Hematopoietic-specific Sp140-/- mice, cohousing/antibiotic experiments, microbiome sequencing, and human patient phagocyte analysis","pmids":["36130593"],"confidence":"High","gaps":["causal microbial species not pinned to a single mechanism","phagocyte program defects not fully resolved at the molecular level"]},{"year":2022,"claim":"Showed SP140 directly represses STAT1 transcription, with overexpression driving a proinflammatory macrophage phenotype.","evidence":"ChIP, ATAC-seq, and SP140 overexpression/knockdown in macrophages with cytokine ELISAs","pmids":["36600652"],"confidence":"Medium","gaps":["direct STAT1 promoter occupancy effect on downstream signaling not fully traced","single lab"]},{"year":2022,"claim":"Provided a selective small-molecule tool (GSK761) demonstrating SP140 chromatin binding is druggable and reprograms inflammatory macrophages.","evidence":"GSK761 inhibitor with ChIP-seq, LPS stimulation, and flow cytometry in macrophages","pmids":["35986286"],"confidence":"Medium","gaps":["on-target specificity beyond reported readouts not exhaustively defined","single lab"]},{"year":2024,"claim":"Showed SP140 tumor expression can be driven by an LTR8B ERV-derived intronic promoter under MAPK control, affecting interferon sensitivity.","evidence":"Transcriptomics, ERV promoter silencing, and interferon cytotoxicity assays in fibrosarcoma cells","pmids":["38751339"],"confidence":"Medium","gaps":["generality across tumor types unknown","link between ERV-driven isoform and canonical repressor function unclear"]},{"year":2025,"claim":"Resolved the mechanism of IFN regulation: SP140 represses RESIST, an Ifnb1 mRNA stabilizer, rather than repressing Ifnb1 transcription directly, defining a post-transcriptional axis.","evidence":"Sp140-/- genetic epistasis, RESIST target identification, mRNA stability assays, and rescue experiments","pmids":["40500448"],"confidence":"High","gaps":["direct chromatin mechanism of RESIST repression not fully detailed","RESIST molecular function on Ifnb1 mRNA not structurally resolved"]},{"year":2025,"claim":"Demonstrated SP140 inhibits gammaherpesvirus MHV68 independently of its Ifnb1 mRNA regulatory function, establishing separable antiviral and IFN functions.","evidence":"Sp140-/- mouse MHV68 infection with epistasis against Ifnb1 regulation","pmids":["40500448"],"confidence":"Medium","gaps":["antiviral effector mechanism not defined","single lab"]},{"year":2025,"claim":"Identified PRC2 and NuRD as the effector complexes SP140 recruits to deposit H3K27me3 and silence growth/leukemia loci, completing the repression mechanism.","evidence":"Interactomics, ChIP-seq, and multi-omics in Burkitt lymphoma cells","pmids":["39718989"],"confidence":"High","gaps":["recruitment determinants and locus selectivity not fully mapped","relationship to topoisomerase repression not integrated"]},{"year":2026,"claim":"Showed SP140 gatekeeps the endothelial-to-hematopoietic transition via TOP1-dependent chromatin remodeling, extending its repressor role to HSC specification.","evidence":"CRISPR screen, transient SP140 KO/GSK761, CUT&TAG, TOP1-inhibitor epistasis, and transplantation in immunodeficient mice","pmids":["41397285"],"confidence":"Medium","gaps":["durability and therapeutic window of transient inhibition unresolved","single lab"]},{"year":null,"claim":"How SP140 integrates topoisomerase restraint, PRC2/NuRD recruitment, and SUMO/Pin1 self-regulation into locus-specific targeting, and whether one effector axis predominates in each disease context, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no unified model linking topoisomerase repression to H3K27me3 deposition","how SUMOylation and Pin1 isomerization tune chromatin activity in vivo is unknown","determinants of SP140 locus selectivity unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,5,9,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,5]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11,12]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,3,6]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,4,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,5,9,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[16]}],"complexes":["PML nuclear body"],"partners":["PIN1","UBC9","EZH2","SP140"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13342","full_name":"Nuclear body protein SP140","aliases":["Lymphoid-restricted homolog of Sp100","LYSp100","Nuclear autoantigen Sp-140","Speckled 140 kDa"],"length_aa":867,"mass_kda":98.2,"function":"Component of the nuclear body, also known as nuclear domain 10, PML oncogenic domain, and KR body (PubMed:8910577). May be involved in the pathogenesis of acute promyelocytic leukemia and viral infection (PubMed:8910577). May play a role in chromatin-mediated regulation of gene expression although it does not bind to histone H3 tails (PubMed:24267382)","subcellular_location":"Nucleus; Nucleus, PML body; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q13342/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SP140","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SP140","total_profiled":1310},"omim":[{"mim_id":"617747","title":"NUCLEAR BODY PROTEIN SP140-LIKE; SP140L","url":"https://www.omim.org/entry/617747"},{"mim_id":"611296","title":"ANNEXIN A2 RECEPTOR; ANXA2R","url":"https://www.omim.org/entry/611296"},{"mim_id":"608602","title":"NUCLEAR BODY PROTEIN SP140; SP140","url":"https://www.omim.org/entry/608602"},{"mim_id":"608448","title":"INFLAMMATORY BOWEL DISEASE 9; IBD9","url":"https://www.omim.org/entry/608448"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli fibrillar center","reliability":"Approved"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":14.5},{"tissue":"lymphoid tissue","ntpm":52.3}],"url":"https://www.proteinatlas.org/search/SP140"},"hgnc":{"alias_symbol":["LYSP100-B","LYSP100-A"],"prev_symbol":[]},"alphafold":{"accession":"Q13342","domains":[{"cath_id":"3.10.390.10","chopping":"590-658","consensus_level":"high","plddt":86.8561,"start":590,"end":658},{"cath_id":"1.20.920.10","chopping":"739-859","consensus_level":"high","plddt":84.6211,"start":739,"end":859},{"cath_id":"1.10.533","chopping":"38-134","consensus_level":"high","plddt":87.8923,"start":38,"end":134}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13342","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13342-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13342-F1-predicted_aligned_error_v6.png","plddt_mean":57.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SP140","jax_strain_url":"https://www.jax.org/strain/search?query=SP140"},"sequence":{"accession":"Q13342","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13342.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13342/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13342"}},"corpus_meta":[{"pmid":"34151776","id":"PMC_34151776","title":"Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34151776","citation_count":79,"is_preprint":false},{"pmid":"19861957","id":"PMC_19861957","title":"PML nuclear body component Sp140 is a novel autoantigen in primary biliary cirrhosis.","date":"2009","source":"The American journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/19861957","citation_count":68,"is_preprint":false},{"pmid":"28783698","id":"PMC_28783698","title":"Maintenance of macrophage transcriptional programs and intestinal homeostasis by epigenetic reader SP140.","date":"2017","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28783698","citation_count":62,"is_preprint":false},{"pmid":"12368356","id":"PMC_12368356","title":"Implication of the lymphocyte-specific nuclear body protein Sp140 in an innate response to human immunodeficiency virus type 1.","date":"2002","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12368356","citation_count":54,"is_preprint":false},{"pmid":"26888452","id":"PMC_26888452","title":"Whole Genome DNA Methylation Analysis of Obstructive Sleep Apnea: IL1R2, NPR2, AR, SP140 Methylation and Clinical Phenotype.","date":"2016","source":"Sleep","url":"https://pubmed.ncbi.nlm.nih.gov/26888452","citation_count":43,"is_preprint":false},{"pmid":"35952671","id":"PMC_35952671","title":"Epigenetic reader SP140 loss of function drives Crohn's disease due to uncontrolled macrophage topoisomerases.","date":"2022","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/35952671","citation_count":30,"is_preprint":false},{"pmid":"27070736","id":"PMC_27070736","title":"Highly Efficient Delivery of Functional Cargoes by a Novel Cell-Penetrating Peptide Derived from SP140-Like Protein.","date":"2016","source":"Bioconjugate chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27070736","citation_count":28,"is_preprint":false},{"pmid":"30102396","id":"PMC_30102396","title":"SP140 regulates the expression of immune-related genes associated with multiple sclerosis and other autoimmune diseases by NF-κB inhibition.","date":"2018","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30102396","citation_count":26,"is_preprint":false},{"pmid":"36600652","id":"PMC_36600652","title":"SP140 inhibits STAT1 signaling, induces IFN-γ in tumor-associated macrophages, and is a predictive biomarker of immunotherapy response.","date":"2022","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36600652","citation_count":24,"is_preprint":false},{"pmid":"35986286","id":"PMC_35986286","title":"Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140.","date":"2022","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/35986286","citation_count":21,"is_preprint":false},{"pmid":"40500448","id":"PMC_40500448","title":"SP140-RESIST pathway regulates interferon mRNA stability and antiviral immunity.","date":"2025","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/40500448","citation_count":15,"is_preprint":false},{"pmid":"36130593","id":"PMC_36130593","title":"Immune chromatin reader SP140 regulates microbiota and risk for inflammatory bowel disease.","date":"2022","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/36130593","citation_count":15,"is_preprint":false},{"pmid":"24267382","id":"PMC_24267382","title":"Structure of human Sp140 PHD finger: an atypical fold interacting with Pin1.","date":"2013","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/24267382","citation_count":15,"is_preprint":false},{"pmid":"30465816","id":"PMC_30465816","title":"Sp140 is a multi-SUMO-1 target and its PHD finger promotes SUMOylation of the adjacent Bromodomain.","date":"2018","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/30465816","citation_count":11,"is_preprint":false},{"pmid":"34156030","id":"PMC_34156030","title":"The role of Sp140 revealed in IgE and mast cell responses in Collaborative Cross mice.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/34156030","citation_count":11,"is_preprint":false},{"pmid":"38468469","id":"PMC_38468469","title":"SP140 inhibitor suppressing TRIM22 expression regulates glioma progress through PI3K/AKT signaling pathway.","date":"2024","source":"Brain and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/38468469","citation_count":8,"is_preprint":false},{"pmid":"39162523","id":"PMC_39162523","title":"Transcriptional regulators SP110 and SP140 modulate inflammatory response genes in Mycobacterium tuberculosis-infected human macrophages.","date":"2024","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/39162523","citation_count":5,"is_preprint":false},{"pmid":"39974928","id":"PMC_39974928","title":"The SP140-RESIST pathway regulates interferon mRNA stability and antiviral immunity.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39974928","citation_count":4,"is_preprint":false},{"pmid":"38751339","id":"PMC_38751339","title":"An endogenous retrovirus regulates tumor-specific expression of the immune transcriptional regulator SP140.","date":"2024","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38751339","citation_count":3,"is_preprint":false},{"pmid":"39718989","id":"PMC_39718989","title":"SP140 represses specific loci by recruiting polycomb repressive complex 2 and NuRD complex.","date":"2025","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/39718989","citation_count":2,"is_preprint":false},{"pmid":"37232738","id":"PMC_37232738","title":"The Epigenetic Reader Protein SP140 Regulates Dendritic Cell Activation, Maturation and Tolerogenic Potential.","date":"2023","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/37232738","citation_count":2,"is_preprint":false},{"pmid":"41397285","id":"PMC_41397285","title":"Transient SP140 inhibition unlocks hematopoietic stem cell fate from human pluripotent stem cells.","date":"2026","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/41397285","citation_count":1,"is_preprint":false},{"pmid":"41415425","id":"PMC_41415425","title":"SP140 limits type I interferon-driven pathology, preserving T cell motility and promoting resistance in tuberculosis.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41415425","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.01.668220","title":"A  <i>Mycobacterium tuberculosis</i>  rare variable antigen vaccine reduces lung pathology without affecting bacterial burdens","date":"2025-08-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.01.668220","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.19.677270","title":"The C3HeB/FeJ Kramnik mouse as a model to investigate the efficacy of therapeutic tuberculosis interventions","date":"2025-09-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.19.677270","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.13.648563","title":"Sustained Antigen Stimulation to Evoke and Study Negative feedback Systems responsible for Self-Tolerance/Tumor Immune Escape and transition to the M2 macrophage","date":"2025-04-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.13.648563","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.02.673674","title":"<i>Mycobacterium tuberculosis, Mycobacterium kansasii</i>  and  <i>Rhodococcus equi</i>  induce macrophage necroptosis in the presence of a caspase inhibitor acting on a non-canonical target(s)","date":"2025-09-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.02.673674","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16954,"output_tokens":4235,"usd":0.057194,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12252,"output_tokens":4944,"usd":0.09243,"stage2_stop_reason":"end_turn"},"total_usd":0.149624,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"SP140 does not directly repress Ifnb1 transcription; instead, SP140 negatively regulates Ifnb1 mRNA stability by directly repressing expression of a previously uncharacterized regulator called RESIST (annexin 2 receptor). RESIST promotes Ifnb1 mRNA stability by counteracting destabilization mediated by the tristetraprolin (TTP) family of RNA-binding proteins and the CCR4-NOT deadenylase complex.\",\n      \"method\": \"Genetic epistasis (Sp140-/- mice), identification of RESIST as SP140 target gene, mRNA stability assays, functional rescue experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO mice, mRNA stability assays, identification of novel regulatory node), peer-reviewed, mechanistically comprehensive\",\n      \"pmids\": [\"40500448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SP140 localizes within nuclear bodies and inhibits replication of the gammaherpesvirus MHV68 through a mechanism independent of its ability to regulate Ifnb1 mRNA levels, establishing dual antiviral and interferon regulatory functions.\",\n      \"method\": \"Sp140-/- mouse infections with MHV68, epistasis with Ifnb1 regulation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined phenotype and functional independence demonstrated, single lab\",\n      \"pmids\": [\"40500448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SP140 represses type I IFN transcription during bacterial infection, acting as a negative regulator of type I IFNs. Sp140-/- mice are susceptible to Legionella pneumophila and Mycobacterium tuberculosis infection, and this susceptibility is rescued by genetic deletion of the type I IFN receptor (Ifnar-/-).\",\n      \"method\": \"Sp140-/- mouse generation, bacterial infection models, genetic epistasis cross to Ifnar-/- mice\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mice, epistasis rescue with Ifnar-/-, replicated across two bacterial infection models\",\n      \"pmids\": [\"34151776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SP140 preferentially occupies promoters of silenced, lineage-inappropriate genes bearing the histone modification H3K27me3 (e.g., HOXA cluster) in human macrophages and ensures their repression. Depletion of SP140 in macrophages results in severely compromised microbe-induced activation.\",\n      \"method\": \"ChIP-seq/chromatin occupancy analysis, SP140 knockdown in mouse and human macrophages, functional macrophage activation assays\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq plus functional KD in both mouse and human macrophages, multiple orthogonal readouts\",\n      \"pmids\": [\"28783698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SP140 acts as a repressor of topoisomerases (TOP1 and TOP2), maintaining heterochromatin and macrophage fate. Loss of SP140 results in unleashed topoisomerase activity, de-repression of developmentally silenced genes, and defective microbe-inducible macrophage transcriptional programs and bacterial killing. Pharmacological inhibition of TOP1/2 rescues these defects in Sp140-/- mice.\",\n      \"method\": \"Global proteomic strategy to identify SP140 interactors, Sp140-/- mice, pharmacological TOP1/2 inhibitor rescue experiments in vivo and in vitro\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — proteomic identification plus genetic KO plus pharmacological rescue in vivo, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"35952671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SP140 negatively regulates STAT1 transcription by directly binding to the STAT1 promoter (shown by chromatin immunoprecipitation), and SP140 overexpression in macrophages induces a proinflammatory phenotype with increased IFN-γ production.\",\n      \"method\": \"ChIP, ATAC-seq, SP140 overexpression and knockdown in macrophages and tumor-associated macrophages, cytokine ELISAs\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus ATAC-seq plus functional OE/KD, single lab\",\n      \"pmids\": [\"36600652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of SP140 in hematopoietic cells leads to blooms of Proteobacteria (Helicobacter in mice; Enterobacteriaceae in humans with SP140 loss-of-function variant), and phagocytes from Sp140-/- mice or patients show altered antimicrobial defense programs; colitis driven by altered microbiota is transmissible by cohousing and ameliorated with antibiotics.\",\n      \"method\": \"Sp140-/- mouse model (hematopoietic-specific), cohousing and antibiotic experiments, microbiome sequencing, phagocytic function assays\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic model, multiple orthogonal approaches (cohousing, antibiotics, phagocyte assays), validated in human patient cells\",\n      \"pmids\": [\"36130593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The PHD finger of Sp140 adopts an atypical fold that does not bind histone H3 tails but is recognized by the peptidylprolyl isomerase Pin1. Pin1 specifically binds a phosphopeptide corresponding to the L3 loop of Sp140-PHD and catalyzes cis-trans isomerization of a pThr-Pro bond. Co-immunoprecipitation confirmed FLAG-Sp140 interaction with endogenous Pin1 in vivo.\",\n      \"method\": \"NMR solution structure, in vitro binding assays, co-immunoprecipitation (FLAG-Sp140 with endogenous Pin1)\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure plus in vitro binding plus co-IP in cells, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24267382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sp140 is a multi-SUMO-1 target with at least 13 SUMOylation sites including the bromodomain. The PHD finger directly binds the SUMO E2 ligase Ubc9 and SUMO-1 (by NMR), and acts as a SUMO E3 ligase promoting intramolecular SUMOylation of the adjacent bromodomain in vitro.\",\n      \"method\": \"Mass spectrometry identification of SUMOylation sites, NMR binding experiments, in vitro SUMOylation reactions, biochemical experiments in Burkitt's lymphoma cells and HEK293T cells\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR, mass spectrometry, and in vitro reconstitution of SUMO E3 ligase activity, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30465816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SP140 silencing in lymphoblastoid cell lines leads to upregulation of NF-κB transcriptional activity and NF-κB-driven inflammatory genes, including those involved in cytokine production and cell-cell adhesion, identifying SP140 as a repressor of NF-κB-driven transcription in B cells.\",\n      \"method\": \"SP140 siRNA knockdown, RNA-seq, luciferase NF-κB reporter assay, promoter enrichment analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq plus functional NF-κB reporter assay, two orthogonal methods, single lab\",\n      \"pmids\": [\"30102396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SP140 represses specific loci by recruiting the Polycomb Repressive Complex 2 (PRC2) and NuRD complex. SP140 interaction with PRC2 and NuRD is functional, directing H3K27me3 deposition and NuRD binding at target genes implicated in cellular growth and leukemia progression.\",\n      \"method\": \"Interactomics (proteomics), ChIP-seq, multi-omics in Burkitt lymphoma cell lines\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — proteomic interactomics plus ChIP-seq demonstrating functional H3K27me3 deposition, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"39718989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Sp140, identified by yeast two-hybrid screen as a potential HIV-1 Vif binding partner, is found specifically in all non-permissive (NP) cells tested, and HIV-1 infection induces partial dispersal of Sp140 from nuclear bodies into cytosolic colocalization with Vif, implicating Sp140 in an innate antiviral response.\",\n      \"method\": \"Yeast two-hybrid screen, indirect immunofluorescence colocalization, cell line panel comparison\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid plus colocalization, single lab, no direct functional validation of Sp140-Vif interaction consequence\",\n      \"pmids\": [\"12368356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sp140 is a component of PML nuclear bodies (NBs). Anti-Sp140 antibodies in PBC patients were identified using a neuroblastoma cell line expressing Sp140, confirming its nuclear body localization and identifying the NB as a multiantigenic complex.\",\n      \"method\": \"Indirect immunofluorescence, neuroblastoma cell line expressing Sp140, clinical serology in PBC patients\",\n      \"journal\": \"The American journal of gastroenterology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by immunofluorescence, no direct functional consequence tested, single approach\",\n      \"pmids\": [\"19861957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SP140 inhibition by small molecule GSK761 reduces SP140 chromatin binding at transcriptional start sites of pro-inflammatory cytokine/chemokine genes in inflammatory macrophages, reducing LPS-induced cytokine expression and monocyte-to-inflammatory macrophage differentiation, while inducing CD206+ regulatory macrophages.\",\n      \"method\": \"Small molecule SP140 inhibitor (GSK761) development, ChIP-seq in inflammatory macrophages, LPS stimulation assays, flow cytometry\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus functional pharmacological inhibition, first selective inhibitor with orthogonal readouts, single lab\",\n      \"pmids\": [\"35986286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SP140 expression in tumors can be driven by an alternative intronic promoter derived from an intronic endogenous retrovirus (LTR8B family), regulated by oncogenic MAPK signaling. Silencing this ERV promoter in a fibrosarcoma cell line increased sensitivity to interferon-mediated cytotoxicity and dysregulated multiple immune genes.\",\n      \"method\": \"Transcriptomic analysis, ERV promoter silencing (CRISPR or siRNA), interferon cytotoxicity assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter silencing plus cytotoxicity assays, mechanistic link to MAPK regulation, single lab\",\n      \"pmids\": [\"38751339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"siRNA-mediated knockdown of Sp140 in bone marrow-derived cultured mast cells (BMCMCs) decreased IgE-dependent histamine release and cytokine production, establishing a role for Sp140 in IgE-dependent mast cell activation.\",\n      \"method\": \"siRNA knockdown in BMCMCs, IgE-dependent activation assays (histamine release, cytokine ELISA)\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined functional readout, but single lab and no mechanistic pathway placement\",\n      \"pmids\": [\"34156030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SP140 acts as an epigenetic gatekeeper suppressing hematopoiesis. Transient SP140 inhibition unlocks transcription at endothelial-to-hematopoietic transition (EHT) loci through topoisomerase 1-dependent chromatin remodeling, and this effect is blocked by topoisomerase 1 inhibition. SP140 binding at EHT and HSC-specification gene loci was confirmed by CUT&TAG profiling.\",\n      \"method\": \"CRISPR/Cas9 screen, transient SP140 KO or GSK761 pharmacological inhibition, CUT&TAG chromatin profiling, topoisomerase 1 inhibitor epistasis, transplantation assays in immunodeficient mice\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&TAG plus epistasis with TOP1 inhibitor plus functional rescue in transplantation, single lab\",\n      \"pmids\": [\"41397285\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SP140 is an immune-restricted, nuclear body-localized epigenetic 'reader' containing PHD, bromodomain, and SAND domains that functions as a transcriptional co-repressor: it occupies promoters of silenced, H3K27me3-marked lineage-inappropriate genes by recruiting PRC2 and NuRD complexes, represses topoisomerase (TOP1/2) activity to maintain heterochromatin and macrophage identity, and indirectly restrains type I interferon (IFNβ) production not by directly repressing Ifnb1 transcription but by repressing RESIST—a novel stabilizer of Ifnb1 mRNA that acts against TTP/CCR4-NOT-mediated destabilization; SP140 is itself regulated post-translationally by multi-site SUMO-1 modification (with its PHD finger acting as an intramolecular SUMO E3 ligase for the adjacent bromodomain) and by interaction with the prolyl isomerase Pin1, and loss-of-function of SP140 in macrophages leads to unleashed topoisomerase activity, de-repression of developmentally silenced genes, impaired bacterial killing, altered gut microbiota, and exacerbated intestinal inflammation—phenotypes genetically linked to Crohn's disease, multiple sclerosis, and chronic lymphocytic leukemia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SP140 is an immune-restricted, nuclear body-localized epigenetic reader that acts as a transcriptional co-repressor enforcing macrophage and hematopoietic cell identity by silencing lineage-inappropriate genes [#3]. It preferentially occupies promoters bearing H3K27me3 (e.g., the HOXA cluster) in macrophages and ensures their repression, and its loss severely compromises microbe-induced macrophage activation [#3]. Repression is executed through recruitment of the PRC2 and NuRD complexes, directing H3K27me3 deposition and NuRD binding at target loci [#10], and through restraint of topoisomerase TOP1/TOP2 activity to maintain heterochromatin; loss of SP140 unleashes topoisomerase activity, de-represses silenced genes, and impairs bacterial killing, defects rescued by pharmacological TOP1/2 inhibition [#4]. SP140 also gatekeeps the endothelial-to-hematopoietic transition through TOP1-dependent chromatin remodeling [#16]. As a negative regulator of innate immunity, SP140 restrains type I interferon: it represses Ifnb1 not directly but by repressing RESIST, a stabilizer of Ifnb1 mRNA that counteracts TTP/CCR4-NOT-mediated destabilization [#0], and Sp140-deficient mice are susceptible to Legionella and Mycobacterium tuberculosis in an IFNAR-dependent manner [#2]. SP140 loss in hematopoietic cells drives Proteobacteria blooms, altered antimicrobial programs, and transmissible colitis [#6]. The protein is regulated post-translationally: its atypical PHD finger does not bind histone H3 but is recognized by the prolyl isomerase Pin1, which isomerizes a phosphorylated pThr-Pro bond in the PHD L3 loop [#7], and the PHD finger also binds Ubc9/SUMO-1 and acts as an intramolecular SUMO E3 ligase for the adjacent multi-SUMOylated bromodomain [#8]. These activities link SP140 genetically and functionally to intestinal inflammation, Crohn's disease, and lymphoma biology [#6, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established SP140 as a nuclear body protein with a possible innate antiviral role, the first functional context for the gene.\",\n      \"evidence\": \"Yeast two-hybrid screen for HIV-1 Vif partners plus immunofluorescence colocalization in non-permissive cell lines\",\n      \"pmids\": [\"12368356\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Vif interaction consequence never functionally validated\", \"no direct antiviral mechanism defined\", \"single low-confidence approach\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Confirmed SP140 as a constituent of PML nuclear bodies, defining its subcellular compartment.\",\n      \"evidence\": \"Indirect immunofluorescence and clinical serology in PBC patients using Sp140-expressing neuroblastoma cells\",\n      \"pmids\": [\"19861957\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no functional consequence of NB localization tested\", \"localization only by single approach\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Determined that the SP140 PHD finger is an atypical non-histone-binding fold regulated by Pin1, revealing post-translational control of the reader.\",\n      \"evidence\": \"NMR solution structure, in vitro phosphopeptide binding, and co-IP of FLAG-Sp140 with endogenous Pin1\",\n      \"pmids\": [\"24267382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"functional outcome of Pin1-catalyzed isomerization on SP140 activity not defined\", \"kinase generating the phospho-Thr unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined SP140 as a chromatin reader occupying H3K27me3-marked silenced promoters to maintain macrophage identity, establishing its core transcriptional repressor role.\",\n      \"evidence\": \"ChIP-seq chromatin occupancy plus SP140 knockdown and macrophage activation assays in mouse and human cells\",\n      \"pmids\": [\"28783698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"effector complexes mediating repression not yet identified at this stage\", \"mechanism of H3K27me3-locus targeting unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed SP140 is itself SUMO-regulated and that its PHD finger is an intramolecular SUMO E3 ligase, adding a layer of self-modification control.\",\n      \"evidence\": \"Mass spectrometry SUMO-site mapping, NMR binding to Ubc9/SUMO-1, and in vitro SUMOylation reconstitution\",\n      \"pmids\": [\"30465816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"functional consequence of bromodomain SUMOylation on chromatin activity not established in cells\", \"regulation of SUMOylation in vivo unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended SP140's repressor role to NF-\\u03baB-driven inflammatory transcription in B cells.\",\n      \"evidence\": \"siRNA knockdown with RNA-seq and NF-\\u03baB luciferase reporter assays in lymphoblastoid lines\",\n      \"pmids\": [\"30102396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct vs indirect repression of NF-\\u03baB targets not distinguished\", \"single cell-type context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed SP140 as a negative regulator of type I IFN whose loss causes IFNAR-dependent susceptibility to intracellular bacteria, linking the gene to infection outcome.\",\n      \"evidence\": \"Sp140-/- mice in Legionella and M. tuberculosis models with genetic Ifnar-/- epistasis rescue\",\n      \"pmids\": [\"34151776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular mechanism of IFN repression not yet defined at this stage\", \"did not distinguish transcriptional vs post-transcriptional control\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a role for SP140 in IgE-dependent mast cell activation, broadening its immune-cell functions.\",\n      \"evidence\": \"siRNA knockdown in bone marrow-derived mast cells with histamine release and cytokine assays\",\n      \"pmids\": [\"34156030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no mechanistic pathway placement\", \"single lab, single readout\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed that SP140 represses topoisomerases TOP1/TOP2 to maintain heterochromatin and macrophage fate, providing a mechanistic basis for gene silencing.\",\n      \"evidence\": \"Proteomic interactor identification, Sp140-/- mice, and pharmacological TOP1/2 inhibitor rescue in vivo and in vitro\",\n      \"pmids\": [\"35952671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"biochemical mode of topoisomerase inhibition not detailed\", \"link between topoisomerase restraint and specific H3K27me3 loci incomplete\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected SP140 loss to gut dysbiosis and transmissible colitis, tying the molecular phenotype to intestinal inflammatory disease.\",\n      \"evidence\": \"Hematopoietic-specific Sp140-/- mice, cohousing/antibiotic experiments, microbiome sequencing, and human patient phagocyte analysis\",\n      \"pmids\": [\"36130593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"causal microbial species not pinned to a single mechanism\", \"phagocyte program defects not fully resolved at the molecular level\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed SP140 directly represses STAT1 transcription, with overexpression driving a proinflammatory macrophage phenotype.\",\n      \"evidence\": \"ChIP, ATAC-seq, and SP140 overexpression/knockdown in macrophages with cytokine ELISAs\",\n      \"pmids\": [\"36600652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct STAT1 promoter occupancy effect on downstream signaling not fully traced\", \"single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided a selective small-molecule tool (GSK761) demonstrating SP140 chromatin binding is druggable and reprograms inflammatory macrophages.\",\n      \"evidence\": \"GSK761 inhibitor with ChIP-seq, LPS stimulation, and flow cytometry in macrophages\",\n      \"pmids\": [\"35986286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"on-target specificity beyond reported readouts not exhaustively defined\", \"single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed SP140 tumor expression can be driven by an LTR8B ERV-derived intronic promoter under MAPK control, affecting interferon sensitivity.\",\n      \"evidence\": \"Transcriptomics, ERV promoter silencing, and interferon cytotoxicity assays in fibrosarcoma cells\",\n      \"pmids\": [\"38751339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"generality across tumor types unknown\", \"link between ERV-driven isoform and canonical repressor function unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the mechanism of IFN regulation: SP140 represses RESIST, an Ifnb1 mRNA stabilizer, rather than repressing Ifnb1 transcription directly, defining a post-transcriptional axis.\",\n      \"evidence\": \"Sp140-/- genetic epistasis, RESIST target identification, mRNA stability assays, and rescue experiments\",\n      \"pmids\": [\"40500448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"direct chromatin mechanism of RESIST repression not fully detailed\", \"RESIST molecular function on Ifnb1 mRNA not structurally resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated SP140 inhibits gammaherpesvirus MHV68 independently of its Ifnb1 mRNA regulatory function, establishing separable antiviral and IFN functions.\",\n      \"evidence\": \"Sp140-/- mouse MHV68 infection with epistasis against Ifnb1 regulation\",\n      \"pmids\": [\"40500448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"antiviral effector mechanism not defined\", \"single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified PRC2 and NuRD as the effector complexes SP140 recruits to deposit H3K27me3 and silence growth/leukemia loci, completing the repression mechanism.\",\n      \"evidence\": \"Interactomics, ChIP-seq, and multi-omics in Burkitt lymphoma cells\",\n      \"pmids\": [\"39718989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"recruitment determinants and locus selectivity not fully mapped\", \"relationship to topoisomerase repression not integrated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed SP140 gatekeeps the endothelial-to-hematopoietic transition via TOP1-dependent chromatin remodeling, extending its repressor role to HSC specification.\",\n      \"evidence\": \"CRISPR screen, transient SP140 KO/GSK761, CUT&TAG, TOP1-inhibitor epistasis, and transplantation in immunodeficient mice\",\n      \"pmids\": [\"41397285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"durability and therapeutic window of transient inhibition unresolved\", \"single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SP140 integrates topoisomerase restraint, PRC2/NuRD recruitment, and SUMO/Pin1 self-regulation into locus-specific targeting, and whether one effector axis predominates in each disease context, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no unified model linking topoisomerase repression to H3K27me3 deposition\", \"how SUMOylation and Pin1 isomerization tune chromatin activity in vivo is unknown\", \"determinants of SP140 locus selectivity unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 5, 9, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 3, 6]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 4, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 5, 9, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [\"PML nuclear body\"],\n    \"partners\": [\"PIN1\", \"UBC9\", \"EZH2\", \"SP140\"]\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}