Affinage

GSE1

Genetic suppressor element 1 · UniProt Q14687

Round 2 corrected
Length
1217 aa
Mass
136.2 kDa
Annotated
2026-04-28
39 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GSE1 is a chromatin-associated scaffolding protein that functions within the HDAC1/CoREST/BHC (LSD1-containing) co-repressor complex to mediate transcriptional silencing and coordinate the DNA damage response. GSE1 anchors the deubiquitinase USP22 to the CoREST complex, enabling H2B-K120 deubiquitination upon DNA damage without affecting the complex's histone deacetylase activity, and cooperates with HDAC1 to repress target genes including the tumor suppressor KLF6 and immune/cytokine-signaling loci (PMID:37878419, PMID:34862459, PMID:38886911). GSE1 is required for placental development in mice, where its loss causes embryonic lethality due to deficient syncytiotrophoblast-II differentiation in a placenta-autonomous manner (PMID:37019373). Overexpression of GSE1 in multiple cancer types promotes proliferation, invasion, and therapy resistance through transcriptional repression of tumor suppressors and modulation of apoptotic gene expression (PMID:26828271, PMID:34439112, PMID:33623790).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 High

    Establishing GSE1 as a subunit of a novel HDAC1/2-containing co-repressor complex (BHC/CoREST) resolved its molecular context and linked it to chromatin-mediated gene silencing.

    Evidence Biochemical purification and mass spectrometry of native HDAC-containing complexes, with reciprocal co-immunoprecipitation

    PMID:12493763

    Open questions at the time
    • Direct contribution of GSE1 to complex activity was not tested
    • Whether GSE1 contacts DNA or histones directly was unknown
  2. 2005 High

    Demonstrating that CoREST is required for LSD1-mediated nucleosomal H3K4 demethylation placed the BHC complex — and GSE1 within it — in a defined enzymatic pathway of transcriptional repression on chromatin substrates.

    Evidence In vitro reconstitution of BHC complex with recombinant subunits and nucleosomal demethylation assays

    PMID:16079794

    Open questions at the time
    • GSE1's specific role within the complex during demethylation was not dissected
    • Genomic targets of the complex in vivo were not identified
  3. 2011 Medium

    Chemoproteomic profiling confirmed GSE1 as a scaffolding subunit specifically of the BHC/BRAF-HDAC complex, distinguishing it from Sin3 and NCoR complexes, and revealed that certain HDAC inhibitors selectively target this complex.

    Evidence Affinity capture of HDAC complexes combined with quantitative mass spectrometry

    PMID:21258344

    Open questions at the time
    • Whether GSE1 mediates pharmacological selectivity was not tested
    • No functional assay for GSE1 loss was performed
  4. 2016 Medium

    Loss-of-function studies in breast cancer cells established GSE1 as an oncogenic effector, showing that its silencing suppresses proliferation, migration, and invasion, and identifying GSE1 as a direct target of the tumor-suppressive miR-489-5p.

    Evidence siRNA knockdown, miRNA overexpression/depletion, luciferase reporter assay for direct target validation, cell proliferation/migration/invasion assays

    PMID:26828271

    Open questions at the time
    • Mechanism by which GSE1 drives pro-invasive transcription was not defined
    • In vivo validation was not performed
  5. 2021 Medium

    ChIP and pharmacological studies in AML cells showed that GSE1 co-localizes with LSD1 at promoters of immune-response and cytokine-signaling genes to enforce their silencing; LSD1 inhibition reduces GSE1 promoter occupancy and triggers myeloid differentiation, linking GSE1 to differentiation blockade in leukemia.

    Evidence ChIP, gene expression profiling, shRNA/siRNA knockdown, in vivo xenograft, pharmacological LSD1 inhibition with MC2580/DDP-38003

    PMID:34862459

    Open questions at the time
    • Whether GSE1 recruitment depends on LSD1 catalytic activity or protein–protein interaction was not resolved
    • Direct DNA-binding capacity of GSE1 was not addressed
  6. 2021 Medium

    Studies in prostate and gastric cancer extended GSE1's pro-tumorigenic role by showing that its depletion suppresses EMT markers, BCL2, and tumorsphere formation while upregulating pro-apoptotic and epithelial genes, implicating GSE1 in therapy resistance and metastatic progression.

    Evidence shRNA knockdown, in vitro proliferation/migration/tumorsphere assays, in vivo xenograft, western blot, multi-omics cohort analysis

    PMID:33623790 PMID:34439112

    Open questions at the time
    • Trastuzumab resistance mechanism via BCL-2 relied on a single knockdown approach without chromatin-level data
    • Whether GSE1 directly regulates BCL2 transcription or acts indirectly was not determined
  7. 2023 High

    Defining GSE1 as the anchor that recruits USP22 to the CoREST complex resolved its unique mechanistic contribution: GSE1 is dispensable for HDAC activity but essential for H2B-K120 deubiquitination and a functional DNA damage response, establishing a multi-enzymatic eraser subcomplex (USP22–GSE1–CoREST).

    Evidence AP-MS, CRISPR knockout, phosphoproteomics, γH2AX and ATR-SQ motif analysis, in vitro deubiquitination assays

    PMID:37878419

    Open questions at the time
    • Structural basis for GSE1–USP22 interaction is unknown
    • Whether GSE1's DDR role is relevant in vivo (animal models) has not been tested
    • Contribution of USP22 anchoring versus other GSE1 functions to cancer phenotypes is not disentangled
  8. 2023 High

    Genetic deletion in mice revealed that Gse1 is essential for placental development, specifically for syncytiotrophoblast-II differentiation, demonstrating a physiological developmental role beyond cancer contexts.

    Evidence Conditional and germline knockout mice, placenta-specific Cre-mediated deletion, single-cell gene expression profiling, immunofluorescence

    PMID:37019373

    Open questions at the time
    • Downstream transcriptional targets mediating syncytiotrophoblast-II failure are not fully characterized
    • Whether the placental phenotype depends on CoREST complex function or a GSE1-autonomous mechanism is unclear
  9. 2024 Medium

    Transcriptomic analysis of GSE1-depleted lung adenocarcinoma cells identified KLF6 as a key tumor-suppressor target co-repressed by GSE1 and HDAC1, providing a specific gene-level mechanism for GSE1-driven proliferation.

    Evidence Co-immunoprecipitation, RNA-seq, qRT-PCR, western blot, siRNA knockdown in NSCLC cells

    PMID:38886911

    Open questions at the time
    • Direct binding of GSE1/HDAC1 to the KLF6 promoter was not shown by ChIP
    • Whether KLF6 re-expression fully rescues the GSE1 depletion phenotype was not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for GSE1's scaffolding within the CoREST complex, how GSE1's USP22-anchoring and HDAC1-cooperating functions are partitioned across different biological contexts (DDR, development, oncogenesis), and whether GSE1 has functions independent of the CoREST complex.
  • No high-resolution structure of GSE1 or the GSE1–USP22 interface exists
  • Relative importance of USP22-anchoring versus transcriptional repression in cancer phenotypes is unknown
  • Whether GSE1 operates outside the CoREST complex has not been addressed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 2
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-73894 DNA Repair 1
Partners
GTF2IHDAC1HDAC2KDM1ARCOR1USP22
Complex memberships
BHC/BRAF-HDAC/CoREST complexUSP22-GSE1-CoREST subcomplex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 GSE1 (then described as a candidate X-linked mental retardation gene product) was identified as a component of a novel multiprotein corepressor complex containing HDAC1/2 and BHC110 (LSD1), along with TFII-I; this complex functions to keep genes silent through chromatin structure modification. Biochemical purification of native complexes, mass spectrometry, co-immunoprecipitation The Journal of biological chemistry High 12493763
2005 GSE1 is a component of the BHC (BRAF-HDAC/CoREST) complex; the CoREST subunit of this complex is essential for LSD1/BHC110-mediated H3K4 demethylation on nucleosomal substrates, placing GSE1 within a multi-subunit chromatin-remodeling and transcriptional repression machinery. In vitro reconstitution of BHC complex from recombinant subunits, nucleosomal demethylation assay, CoREST depletion in cell culture Nature High 16079794
2011 GSE1 was identified as a scaffolding subunit of the BHC/BRAF-HDAC complex (an ELM-SANT domain-containing HDAC complex), which is selectively targeted by certain HDAC inhibitors (aminobenzamides) with distinct profiles relative to Sin3 and NCoR complexes. Affinity capture of HDAC complexes combined with quantitative mass spectrometry (chemoproteomics) Nature biotechnology Medium 21258344
2013 GSE1 was confirmed as a component of the HDAC1-containing BHC/CoREST complex in T cells; HDAC1 interactions within chromatin-remodeling complexes including this one are largely stable as measured by quantitative proteomics. Immunoaffinity purification, quantitative mass spectrometry (label-free and SILAC), fluorescence microscopy Molecular systems biology Medium 23752268
2016 GSE1 silencing in breast cancer cells significantly suppressed proliferation, migration, and invasion; GSE1 was identified as a direct target of miR-489-5p, and restoration of miR-489-5p phenocopied GSE1 knockdown. Depletion of GSE1 by siRNA abrogated enhanced proliferation and invasion caused by miR-489-5p depletion. siRNA knockdown, miRNA overexpression/depletion, luciferase reporter assay (direct target validation), cell proliferation/migration/invasion assays Biochemical and biophysical research communications Medium 26828271
2021 GSE1 depletion in AML (NB4) cells caused decreased cell viability in vitro and tumor growth in vivo; LSD1 inhibitors (MC2580, DDP-38003) downregulate GSE1 protein and trigger myeloid differentiation. LSD1 and GSE1 co-localize at promoters of immune response and cytokine-signaling genes, enforcing their transcriptional silencing; LSD1 inhibition reduces GSE1 binding to these promoters, activating transcriptional programs. shRNA/siRNA knockdown, in vivo xenograft, ChIP, gene expression profiling, pharmacological LSD1 inhibition Oncogene Medium 34862459
2021 GSE1 overexpression promotes trastuzumab resistance in HER2-positive gastric cancer cells; BCL-2 was identified as a downstream gene positively regulated by GSE1, and GSE1 depletion decreased trastuzumab resistance. siRNA knockdown, acquired resistance cell line model, western blot, cell viability assays BioMed research international Low 33623790
2021 shRNA-mediated GSE1 knockdown in metastatic prostate cancer cells inhibited proliferation, migration, and tumorsphere formation, with suppression of VIM, SNAI2, and BCL2 and upregulation of TACSTD2 and BAX; GSE1 and TACSTD2 show a direct inverse expression relationship driving metastatic disease and castration resistance. shRNA knockdown, in vitro cell assays (proliferation, migration, tumorsphere), in vivo xenograft, multi-omics cohort analysis Cancers Medium 34439112
2023 GSE1 forms a complex with the HDAC1/CoREST co-repressor complex (identified by AP-MS); loss of GSE1 impairs DNA damage response (DDR), ATR signaling, and γH2AX formation. GSE1 is essential for binding of deubiquitinase USP22 to CoREST and for H2B K120 deubiquitination in response to DNA damage; loss of GSE1 does not affect CoREST histone deacetylation activity. Thus GSE1 anchors a USP22-GSE1-CoREST multi-enzymatic eraser subcomplex. Affinity purification mass spectrometry (AP-MS), phosphoproteomics/phosphorylome analysis, CRISPR knockout, in vivo DNA damage assays (γH2AX, ATR-SQ motif analysis), deubiquitination assay Nucleic acids research High 37878419
2023 Gse1 is required for mouse placental development; zygotic deletion causes embryonic lethality from E12.5 and maternal deletion increases prenatal death. Gse1 mutant placentas are deficient in MCT4+ syncytiotrophoblast II from E14.5, and placenta-specific deletion recapitulates embryonic defects, demonstrating a placenta-autonomous role for Gse1. Conditional and germline knockout mice, placenta-specific Cre-mediated deletion, histological analysis, gene expression profiling (single-cell level), immunofluorescence Developmental biology High 37019373
2024 GSE1 interacts with HDAC1 and other BHC (BRAF-HDAC) complex components in lung adenocarcinoma cells; GSE1 cooperates with HDAC1 to suppress transcription of the tumor suppressor KLF6, thereby promoting proliferation and migration of non-small cell lung cancer cells. Co-immunoprecipitation, RNA-seq (transcriptome of GSE1-knockdown cells), qRT-PCR, western blot, bioinformatics (HDAC1 binding site analysis), siRNA knockdown Cell biology international Medium 38886911

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2008 An empirical framework for binary interactome mapping. Nature methods 652 19060904
2005 An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 648 16079794
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2011 Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nature biotechnology 531 21258344
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2006 Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Molecular psychiatry 345 17043677
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2020 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature 292 32322062
2013 The functional interactome landscape of the human histone deacetylase family. Molecular systems biology 235 23752268
2016 A High-Density Map for Navigating the Human Polycomb Complexome. Cell reports 216 27705803
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2002 A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. The Journal of biological chemistry 156 12493763
2018 MYC Protein Interactome Profiling Reveals Functionally Distinct Regions that Cooperate to Drive Tumorigenesis. Molecular cell 152 30415952
2020 Comparative Application of BioID and TurboID for Protein-Proximity Biotinylation. Cells 146 32344865
2009 Ubiquitin-mediated proteolysis of HuR by heat shock. The EMBO journal 142 19322201
2017 RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC biology 135 29117863
2016 GSE1 negative regulation by miR-489-5p promotes breast cancer cell proliferation and invasion. Biochemical and biophysical research communications 36 26828271
2021 Pharmacological inhibition of LSD1 triggers myeloid differentiation by targeting GSE1 oncogenic functions in AML. Oncogene 27 34862459
2021 Overexpression of GSE1 Related to Trastuzumab Resistance in Gastric Cancer Cells. BioMed research international 11 33623790
2021 Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2). Cancers 11 34439112
2023 CDK5R1, GSE1, HSPG2 and WDFY3 as indirect epigenetic-sensitive genes in atrial fibrillation. European journal of clinical investigation 7 37991085
2023 Gse1, a component of the CoREST complex, is required for placenta development in the mouse. Developmental biology 6 37019373
2023 GSE1 links the HDAC1/CoREST co-repressor complex to DNA damage. Nucleic acids research 6 37878419
2024 GSE1 promotes the proliferation and migration of lung adenocarcinoma cells by downregulating KLF6 expression. Cell biology international 2 38886911
2023 Circ_0001982 aggravates breast cancer development through the circ_0001982-miR-144-3p-GSE1 axis. Journal of biochemical and molecular toxicology 1 37867456