{"gene":"QSER1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2021,"finding":"QSER1 is a key guardian of bivalent promoters and poised enhancers of developmental genes, especially those in DNA methylation valleys (canyons), protecting them from DNMT3-mediated de novo methylation. A genome-wide CRISPR-Cas9 screen in human embryonic stem cells identified QSER1 as the top hit for DNA methylation regulation. Genetic and biochemical interactions between QSER1 and TET1 were demonstrated, supporting their cooperation to safeguard transcriptional and developmental programs.","method":"Genome-wide CRISPR-Cas9 screen with knockin DNA methylation reporter in hESCs; genetic epistasis; biochemical interaction assays (Co-IP/pulldown implied by 'biochemical interactions')","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide functional screen plus genetic and biochemical interaction data in a single rigorous study; published in high-impact peer-reviewed journal","pmids":["33833093"],"is_preprint":false},{"year":2022,"finding":"QSER1 functions together with SIN3A to suppress pro-apoptotic gene PUMA (and other pro-apoptotic genes) in a p53-dependent and p53-independent manner, preventing apoptosis. QSER1 and p53 occupy distinct cis-regulatory regions of a common subset of pro-apoptotic genes and function antagonistically. A specific regulatory DNA element (QSER1 binding site in PUMA, QBP) was identified; deletion of QBP de-represses PUMA and induces apoptosis.","method":"ChIP-seq (occupancy mapping of QSER1 and p53 at cis-regulatory elements); CRISPR deletion of QBP regulatory element; siRNA knockdown with apoptosis assays; Co-IP/interaction assays with SIN3A","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP-seq, CRISPR deletion, knockdown + phenotypic readout, interaction assay) in a single study","pmids":["36371602"],"is_preprint":false},{"year":2023,"finding":"TET1 and QSER1 together protect transcriptionally competent chromatin regions (CCRs) — distal regulatory regions distinct from canonical enhancers — from excessive DNA methylation in human embryonic stem cells, while HDAC1 family members prevent their premature activation.","method":"Multiple CRISPR-activation screens; loss-of-function (TET1/QSER1 depletion) with DNA methylation and chromatin accessibility readouts in hESCs","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — CRISPR screens with functional chromatin readout in a preprint, single lab, not yet peer-reviewed as full article","pmids":["37398096"],"is_preprint":true},{"year":2023,"finding":"QSER1 is a phase-specific chromatin-associated factor enriched in the ground and formative pluripotency states, identified by quantitative chromatin proteomics (ChAC-DIA-MS) as a component of the chromatome during pluripotency transitions.","method":"Chromatin Aggregation Capture (ChAC) followed by Data-Independent Acquisition mass spectrometry (DIA-MS) across ground, formative, and primed pluripotency states","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — rigorous proteomics method but single lab, single method, no functional validation of QSER1 specifically beyond detection","pmids":["36806742"],"is_preprint":false},{"year":2025,"finding":"YAP1 cooperates with QSER1 in human pluripotent stem cells to regulate lineage genes; YAP1:TEAD4 enhancers recruit QSER1, which prevents RNA Polymerase II recruitment at target loci. QSER1 depletion, like YAP1 depletion, increases NODAL gene expression and leads to hyperactive NODAL signaling in human 2D-gastruloids.","method":"Proximity labeling assay (BioID or similar) in human pluripotent stem cells; biochemical assays (Co-IP); molecular modeling; QSER1 depletion with scRNAseq and NODAL signaling readout; ChIP/CUT&RUN for TEAD4 and Pol II occupancy","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling plus biochemical assays plus loss-of-function with defined signaling phenotype, single lab, multiple orthogonal methods","pmids":["41888256"],"is_preprint":false},{"year":2025,"finding":"Heterozygous loss-of-function variants in QSER1 (de novo frameshift and splice-site variants) are associated with neurodevelopmental phenotypes in humans. In zebrafish, qser1 is dynamically and broadly expressed during embryogenesis with strong presence in the developing brain, consistent with a role in vertebrate neural development.","method":"Human genetics (trio sequencing identifying de novo variants); minigene splice assay; in situ hybridization in zebrafish embryos","journal":"HGG advances","confidence":"Low","confidence_rationale":"Tier 3 / Weak — human variant identification with minigene and ISH in zebrafish, no direct mechanistic rescue experiment; single study","pmids":["41139957"],"is_preprint":false}],"current_model":"QSER1 is a chromatin-associated epigenetic regulator that cooperates with TET1 to protect DNA methylation valleys, bivalent promoters, and poised enhancers of developmental genes from DNMT3-mediated de novo methylation in embryonic stem cells; it is recruited by YAP1:TEAD4 enhancers to block RNA Polymerase II at lineage-specific loci (including NODAL), and it suppresses pro-apoptotic genes (e.g., PUMA) by partnering with SIN3A at distinct cis-regulatory elements, antagonizing p53-driven transcription."},"narrative":{"mechanistic_narrative":"QSER1 is a chromatin-associated epigenetic regulator that safeguards the transcriptional and developmental programs of pluripotent stem cells by protecting key cis-regulatory regions from aberrant de novo DNA methylation [PMID:33833093]. A genome-wide CRISPR screen in human embryonic stem cells identified QSER1 as the top regulator of DNA methylation, where it cooperates genetically and biochemically with TET1 to protect bivalent promoters, poised enhancers, and DNA methylation valleys from DNMT3-mediated methylation [PMID:33833093], and extends this protection to a distinct class of distal transcriptionally competent chromatin regions [PMID:37398096]. At lineage-specific loci QSER1 acts as a transcriptional brake: it is recruited to YAP1:TEAD4 enhancers and blocks RNA Polymerase II recruitment, so that its loss—like YAP1 loss—derepresses NODAL and produces hyperactive NODAL signaling in human gastruloids [PMID:41888256]. QSER1 additionally partners with SIN3A to occupy cis-regulatory elements of pro-apoptotic genes such as PUMA, where it antagonizes p53-driven transcription and restrains apoptosis [PMID:36371602]. Consistent with these developmental roles, QSER1 is enriched in the chromatome of ground and formative pluripotency states [PMID:36806742], and heterozygous loss-of-function variants in humans are associated with neurodevelopmental phenotypes [PMID:41139957].","teleology":[{"year":2021,"claim":"Established QSER1 as a principal guardian of the DNA methylation landscape in pluripotent cells, answering whether a dedicated factor protects developmental regulatory regions from de novo methylation.","evidence":"Genome-wide CRISPR-Cas9 screen with a knockin methylation reporter in hESCs, plus genetic epistasis and biochemical interaction with TET1","pmids":["33833093"],"confidence":"High","gaps":["Molecular basis by which QSER1 recognizes or is recruited to methylation valleys not resolved","Direct enzymatic activity, if any, of QSER1 undefined","Structural basis of the QSER1-TET1 interaction not determined"]},{"year":2022,"claim":"Showed QSER1 actively restrains apoptosis by silencing pro-apoptotic genes, revealing a transcriptional repressive role distinct from methylation protection.","evidence":"ChIP-seq mapping of QSER1 and p53 occupancy, CRISPR deletion of the QBP element at PUMA, siRNA knockdown with apoptosis readout, and Co-IP with SIN3A","pmids":["36371602"],"confidence":"High","gaps":["How QSER1 selects pro-apoptotic target loci is unknown","Mechanism linking SIN3A recruitment to p53 antagonism not defined","Whether the PUMA QBP behavior generalizes across all pro-apoptotic targets unestablished"]},{"year":2023,"claim":"Extended QSER1/TET1 methylation protection to a previously uncharacterized class of distal transcriptionally competent chromatin regions, and placed QSER1 in the pluripotency chromatome.","evidence":"CRISPR-activation screens with methylation and chromatin accessibility readouts (preprint); ChAC-DIA-MS chromatin proteomics across pluripotency states","pmids":["37398096","36806742"],"confidence":"Medium","gaps":["CCR findings derive from a single-lab preprint","Functional consequence of QSER1 enrichment in ground/formative states not directly tested","Relationship between CCRs and previously defined bivalent/valley regions unclear"]},{"year":2025,"claim":"Defined a mechanistic link between Hippo/YAP signaling and QSER1-mediated repression, showing QSER1 enforces a Pol II block at lineage enhancers to restrain NODAL signaling.","evidence":"Proximity labeling and Co-IP in human pluripotent stem cells, QSER1 depletion with scRNA-seq, and CUT&RUN/ChIP for TEAD4 and Pol II occupancy in 2D-gastruloids","pmids":["41888256"],"confidence":"Medium","gaps":["Direct physical contact between QSER1 and the YAP1:TEAD4 complex versus indirect recruitment not fully resolved","How QSER1 mechanistically blocks Pol II recruitment unknown","Single-lab study"]},{"year":2025,"claim":"Connected QSER1 dosage to human neurodevelopment, addressing whether its molecular functions have an organismal phenotype.","evidence":"Trio sequencing identifying de novo loss-of-function variants, minigene splice assay, and in situ hybridization of qser1 in zebrafish embryos","pmids":["41139957"],"confidence":"Low","gaps":["No direct mechanistic rescue experiment linking variants to QSER1 chromatin function","Causality from association alone is limited","Neural phenotype inferred from expression pattern, not functional perturbation"]},{"year":null,"claim":"The molecular mechanism by which QSER1 senses unmethylated chromatin and physically excludes DNMT3, blocks Pol II, or recruits its partners remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of QSER1 or its chromatin-binding mode","No defined catalytic or domain-level activity","Recruitment logic distinguishing protective versus repressive targets unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,4]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1]}],"complexes":[],"partners":["TET1","SIN3A","YAP1","TEAD4","TP53"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q2KHR3","full_name":"Glutamine and serine-rich protein 1","aliases":[],"length_aa":1735,"mass_kda":190.0,"function":"Plays an essential role in the protection and maintenance of transcriptional and developmental programs. Protects many bivalent promoters and poised enhancers from hypermethylation, showing a marked preference for these regulatory elements over other types of promoters or enhancers. Mechanistically, cooperates with TET1 and binds to DNA in a common complex to inhibit the binding of DNMT3A/3B and therefore de novo methylation","subcellular_location":"Chromosome","url":"https://www.uniprot.org/uniprotkb/Q2KHR3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/QSER1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"BRD2","stoichiometry":4.0},{"gene":"DNAJB6","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/QSER1","total_profiled":1310},"omim":[{"mim_id":"619440","title":"GLUTAMINE- AND SERINE-RICH PROTEIN 1; QSER1","url":"https://www.omim.org/entry/619440"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/QSER1"},"hgnc":{"alias_symbol":["FLJ21924"],"prev_symbol":[]},"alphafold":{"accession":"Q2KHR3","domains":[{"cath_id":"-","chopping":"1327-1442","consensus_level":"high","plddt":82.3652,"start":1327,"end":1442},{"cath_id":"-","chopping":"1535-1735","consensus_level":"high","plddt":87.0092,"start":1535,"end":1735}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2KHR3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q2KHR3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q2KHR3-F1-predicted_aligned_error_v6.png","plddt_mean":43.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=QSER1","jax_strain_url":"https://www.jax.org/strain/search?query=QSER1"},"sequence":{"accession":"Q2KHR3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q2KHR3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q2KHR3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2KHR3"}},"corpus_meta":[{"pmid":"19772629","id":"PMC_19772629","title":"Genomewide association study for onset age in Parkinson disease.","date":"2009","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19772629","citation_count":101,"is_preprint":false},{"pmid":"33833093","id":"PMC_33833093","title":"QSER1 protects DNA methylation valleys from de novo methylation.","date":"2021","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/33833093","citation_count":92,"is_preprint":false},{"pmid":"30598658","id":"PMC_30598658","title":"The plasma peptides of ovarian cancer.","date":"2018","source":"Clinical proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/30598658","citation_count":43,"is_preprint":false},{"pmid":"31889940","id":"PMC_31889940","title":"The plasma peptides of breast versus ovarian cancer.","date":"2019","source":"Clinical proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/31889940","citation_count":27,"is_preprint":false},{"pmid":"30126146","id":"PMC_30126146","title":"Identification of Novel Candidate Markers of Type 2 Diabetes and Obesity in Russia by Exome Sequencing with a Limited Sample Size.","date":"2018","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/30126146","citation_count":22,"is_preprint":false},{"pmid":"24912414","id":"PMC_24912414","title":"A novel Alu-mediated microdeletion at 11p13 removes WT1 in a patient with cryptorchidism and azoospermia.","date":"2014","source":"Reproductive biomedicine online","url":"https://pubmed.ncbi.nlm.nih.gov/24912414","citation_count":18,"is_preprint":false},{"pmid":"36371602","id":"PMC_36371602","title":"QSER1 preserves the suppressive status of the pro-apoptotic genes to prevent apoptosis.","date":"2022","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/36371602","citation_count":17,"is_preprint":false},{"pmid":"38385532","id":"PMC_38385532","title":"Bivalent chromatin: a developmental balancing act tipped in cancer.","date":"2024","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/38385532","citation_count":13,"is_preprint":false},{"pmid":"37759801","id":"PMC_37759801","title":"Presenilin-1-Derived Circular RNAs: Neglected Epigenetic Regulators with Various Functions in Alzheimer's Disease.","date":"2023","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37759801","citation_count":12,"is_preprint":false},{"pmid":"34385509","id":"PMC_34385509","title":"Mapping gene and gene pathways associated with coronary artery disease: a CARDIoGRAM exome and multi-ancestry UK biobank analysis.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34385509","citation_count":8,"is_preprint":false},{"pmid":"37169822","id":"PMC_37169822","title":"Prioritization of genes associated with type 2 diabetes mellitus for functional studies.","date":"2023","source":"Nature reviews. Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/37169822","citation_count":7,"is_preprint":false},{"pmid":"36806742","id":"PMC_36806742","title":"Comprehensive chromatin proteomics resolves functional phases of pluripotency and identifies changes in regulatory components.","date":"2023","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/36806742","citation_count":6,"is_preprint":false},{"pmid":"37398096","id":"PMC_37398096","title":"Discovery of Competent Chromatin Regions in Human Embryonic Stem Cells.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37398096","citation_count":5,"is_preprint":false},{"pmid":"35210841","id":"PMC_35210841","title":"Insights into the Association Between QSER1 and M2 Macrophages and Remarkable Malignancy Characteristics in Hepatocellular Carcinoma.","date":"2022","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35210841","citation_count":2,"is_preprint":false},{"pmid":"37823896","id":"PMC_37823896","title":"RNAseq-based transcriptomics of treatment-naïve multi-inflammatory syndrome in children (MIS-C) demonstrates predominant activation of matrisome, innate and humoral immune pathways.","date":"2023","source":"Rheumatology international","url":"https://pubmed.ncbi.nlm.nih.gov/37823896","citation_count":2,"is_preprint":false},{"pmid":"39557769","id":"PMC_39557769","title":"Identification of Novel Genomic Variants in COVID-19 Patients Using Whole-Exome Sequencing: Exploring the Plausible Targets of Functional Genomics.","date":"2024","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39557769","citation_count":1,"is_preprint":false},{"pmid":"40667326","id":"PMC_40667326","title":"YAP1 and QSER1 are Key Modulators of Embryonic Signaling Pathways in the Mammalian Epiblast.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40667326","citation_count":0,"is_preprint":false},{"pmid":"41139957","id":"PMC_41139957","title":"Splicing and frameshift variants in QSER1 may be involved in developmental phenotypes.","date":"2025","source":"HGG advances","url":"https://pubmed.ncbi.nlm.nih.gov/41139957","citation_count":0,"is_preprint":false},{"pmid":"41888256","id":"PMC_41888256","title":"YAP1 and QSER1 are key modulators of embryonic signaling pathways in the mammalian epiblast.","date":"2026","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/41888256","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12627,"output_tokens":1725,"usd":0.031878,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8553,"output_tokens":2422,"usd":0.051658,"stage2_stop_reason":"end_turn"},"total_usd":0.083536,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"QSER1 is a key guardian of bivalent promoters and poised enhancers of developmental genes, especially those in DNA methylation valleys (canyons), protecting them from DNMT3-mediated de novo methylation. A genome-wide CRISPR-Cas9 screen in human embryonic stem cells identified QSER1 as the top hit for DNA methylation regulation. Genetic and biochemical interactions between QSER1 and TET1 were demonstrated, supporting their cooperation to safeguard transcriptional and developmental programs.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen with knockin DNA methylation reporter in hESCs; genetic epistasis; biochemical interaction assays (Co-IP/pulldown implied by 'biochemical interactions')\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide functional screen plus genetic and biochemical interaction data in a single rigorous study; published in high-impact peer-reviewed journal\",\n      \"pmids\": [\"33833093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"QSER1 functions together with SIN3A to suppress pro-apoptotic gene PUMA (and other pro-apoptotic genes) in a p53-dependent and p53-independent manner, preventing apoptosis. QSER1 and p53 occupy distinct cis-regulatory regions of a common subset of pro-apoptotic genes and function antagonistically. A specific regulatory DNA element (QSER1 binding site in PUMA, QBP) was identified; deletion of QBP de-represses PUMA and induces apoptosis.\",\n      \"method\": \"ChIP-seq (occupancy mapping of QSER1 and p53 at cis-regulatory elements); CRISPR deletion of QBP regulatory element; siRNA knockdown with apoptosis assays; Co-IP/interaction assays with SIN3A\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP-seq, CRISPR deletion, knockdown + phenotypic readout, interaction assay) in a single study\",\n      \"pmids\": [\"36371602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TET1 and QSER1 together protect transcriptionally competent chromatin regions (CCRs) — distal regulatory regions distinct from canonical enhancers — from excessive DNA methylation in human embryonic stem cells, while HDAC1 family members prevent their premature activation.\",\n      \"method\": \"Multiple CRISPR-activation screens; loss-of-function (TET1/QSER1 depletion) with DNA methylation and chromatin accessibility readouts in hESCs\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — CRISPR screens with functional chromatin readout in a preprint, single lab, not yet peer-reviewed as full article\",\n      \"pmids\": [\"37398096\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"QSER1 is a phase-specific chromatin-associated factor enriched in the ground and formative pluripotency states, identified by quantitative chromatin proteomics (ChAC-DIA-MS) as a component of the chromatome during pluripotency transitions.\",\n      \"method\": \"Chromatin Aggregation Capture (ChAC) followed by Data-Independent Acquisition mass spectrometry (DIA-MS) across ground, formative, and primed pluripotency states\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — rigorous proteomics method but single lab, single method, no functional validation of QSER1 specifically beyond detection\",\n      \"pmids\": [\"36806742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YAP1 cooperates with QSER1 in human pluripotent stem cells to regulate lineage genes; YAP1:TEAD4 enhancers recruit QSER1, which prevents RNA Polymerase II recruitment at target loci. QSER1 depletion, like YAP1 depletion, increases NODAL gene expression and leads to hyperactive NODAL signaling in human 2D-gastruloids.\",\n      \"method\": \"Proximity labeling assay (BioID or similar) in human pluripotent stem cells; biochemical assays (Co-IP); molecular modeling; QSER1 depletion with scRNAseq and NODAL signaling readout; ChIP/CUT&RUN for TEAD4 and Pol II occupancy\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling plus biochemical assays plus loss-of-function with defined signaling phenotype, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41888256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Heterozygous loss-of-function variants in QSER1 (de novo frameshift and splice-site variants) are associated with neurodevelopmental phenotypes in humans. In zebrafish, qser1 is dynamically and broadly expressed during embryogenesis with strong presence in the developing brain, consistent with a role in vertebrate neural development.\",\n      \"method\": \"Human genetics (trio sequencing identifying de novo variants); minigene splice assay; in situ hybridization in zebrafish embryos\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — human variant identification with minigene and ISH in zebrafish, no direct mechanistic rescue experiment; single study\",\n      \"pmids\": [\"41139957\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"QSER1 is a chromatin-associated epigenetic regulator that cooperates with TET1 to protect DNA methylation valleys, bivalent promoters, and poised enhancers of developmental genes from DNMT3-mediated de novo methylation in embryonic stem cells; it is recruited by YAP1:TEAD4 enhancers to block RNA Polymerase II at lineage-specific loci (including NODAL), and it suppresses pro-apoptotic genes (e.g., PUMA) by partnering with SIN3A at distinct cis-regulatory elements, antagonizing p53-driven transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"QSER1 is a chromatin-associated epigenetic regulator that safeguards the transcriptional and developmental programs of pluripotent stem cells by protecting key cis-regulatory regions from aberrant de novo DNA methylation [#0]. A genome-wide CRISPR screen in human embryonic stem cells identified QSER1 as the top regulator of DNA methylation, where it cooperates genetically and biochemically with TET1 to protect bivalent promoters, poised enhancers, and DNA methylation valleys from DNMT3-mediated methylation [#0], and extends this protection to a distinct class of distal transcriptionally competent chromatin regions [#2]. At lineage-specific loci QSER1 acts as a transcriptional brake: it is recruited to YAP1:TEAD4 enhancers and blocks RNA Polymerase II recruitment, so that its loss—like YAP1 loss—derepresses NODAL and produces hyperactive NODAL signaling in human gastruloids [#4]. QSER1 additionally partners with SIN3A to occupy cis-regulatory elements of pro-apoptotic genes such as PUMA, where it antagonizes p53-driven transcription and restrains apoptosis [#1]. Consistent with these developmental roles, QSER1 is enriched in the chromatome of ground and formative pluripotency states [#3], and heterozygous loss-of-function variants in humans are associated with neurodevelopmental phenotypes [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Established QSER1 as a principal guardian of the DNA methylation landscape in pluripotent cells, answering whether a dedicated factor protects developmental regulatory regions from de novo methylation.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 screen with a knockin methylation reporter in hESCs, plus genetic epistasis and biochemical interaction with TET1\",\n      \"pmids\": [\"33833093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis by which QSER1 recognizes or is recruited to methylation valleys not resolved\", \"Direct enzymatic activity, if any, of QSER1 undefined\", \"Structural basis of the QSER1-TET1 interaction not determined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed QSER1 actively restrains apoptosis by silencing pro-apoptotic genes, revealing a transcriptional repressive role distinct from methylation protection.\",\n      \"evidence\": \"ChIP-seq mapping of QSER1 and p53 occupancy, CRISPR deletion of the QBP element at PUMA, siRNA knockdown with apoptosis readout, and Co-IP with SIN3A\",\n      \"pmids\": [\"36371602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How QSER1 selects pro-apoptotic target loci is unknown\", \"Mechanism linking SIN3A recruitment to p53 antagonism not defined\", \"Whether the PUMA QBP behavior generalizes across all pro-apoptotic targets unestablished\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended QSER1/TET1 methylation protection to a previously uncharacterized class of distal transcriptionally competent chromatin regions, and placed QSER1 in the pluripotency chromatome.\",\n      \"evidence\": \"CRISPR-activation screens with methylation and chromatin accessibility readouts (preprint); ChAC-DIA-MS chromatin proteomics across pluripotency states\",\n      \"pmids\": [\"37398096\", \"36806742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CCR findings derive from a single-lab preprint\", \"Functional consequence of QSER1 enrichment in ground/formative states not directly tested\", \"Relationship between CCRs and previously defined bivalent/valley regions unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a mechanistic link between Hippo/YAP signaling and QSER1-mediated repression, showing QSER1 enforces a Pol II block at lineage enhancers to restrain NODAL signaling.\",\n      \"evidence\": \"Proximity labeling and Co-IP in human pluripotent stem cells, QSER1 depletion with scRNA-seq, and CUT&RUN/ChIP for TEAD4 and Pol II occupancy in 2D-gastruloids\",\n      \"pmids\": [\"41888256\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical contact between QSER1 and the YAP1:TEAD4 complex versus indirect recruitment not fully resolved\", \"How QSER1 mechanistically blocks Pol II recruitment unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected QSER1 dosage to human neurodevelopment, addressing whether its molecular functions have an organismal phenotype.\",\n      \"evidence\": \"Trio sequencing identifying de novo loss-of-function variants, minigene splice assay, and in situ hybridization of qser1 in zebrafish embryos\",\n      \"pmids\": [\"41139957\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct mechanistic rescue experiment linking variants to QSER1 chromatin function\", \"Causality from association alone is limited\", \"Neural phenotype inferred from expression pattern, not functional perturbation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which QSER1 senses unmethylated chromatin and physically excludes DNMT3, blocks Pol II, or recruits its partners remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of QSER1 or its chromatin-binding mode\", \"No defined catalytic or domain-level activity\", \"Recruitment logic distinguishing protective versus repressive targets unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TET1\", \"SIN3A\", \"YAP1\", \"TEAD4\", \"TP53\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":5,"faith_pct":80.0}}