{"gene":"L3MBTL2","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2024,"finding":"L3MBTL2, a member of the non-canonical polycomb repressive complex PRC1.6, co-localizes with the HUSH complex on chromatin primarily at active promoters and contributes to HUSH complex-mediated silencing of proviruses in a promoter-specific manner; PRC1.6 binding at a subset of HUSH-silenced genes depends on the core HUSH component MPP8.","method":"Proximity labeling (C-BERST/dCas9-APEX2), forward genetic screen, genome-wide chromatin profiling (co-localization), loss-of-function analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single preprint, proximity labeling and genetic screen without in vitro reconstitution or direct biochemical interaction assay between L3MBTL2 and HUSH components","pmids":["bio_10.1101_2024.07.12.603173"],"is_preprint":true}],"current_model":"L3MBTL2, as a component of the non-canonical PRC1.6 polycomb complex, co-localizes with the HUSH complex at active promoters on chromatin and contributes to promoter-specific transcriptional silencing, with its chromatin binding at a subset of target genes depending on the HUSH core component MPP8."},"narrative":{"mechanistic_narrative":"L3MBTL2 is a component of the non-canonical polycomb repressive complex PRC1.6 that participates in promoter-specific transcriptional silencing [PMID:bio_10.1101_2024.07.12.603173]. It co-localizes with the HUSH complex on chromatin, primarily at active promoters, and contributes to HUSH-mediated silencing of proviruses, with PRC1.6 recruitment at a subset of HUSH-silenced genes depending on the core HUSH component MPP8 [PMID:bio_10.1101_2024.07.12.603173]. Beyond this single preprint observation, no further mechanistic detail on L3MBTL2 has been characterized in the available corpus.","teleology":[{"year":2024,"claim":"It was unknown how the non-canonical PRC1.6 complex coordinates with the HUSH silencing machinery; proximity labeling and chromatin profiling established that L3MBTL2/PRC1.6 co-localizes with HUSH at active promoters and that its binding at a subset of targets requires the HUSH component MPP8.","evidence":"proximity labeling (C-BERST/dCas9-APEX2), forward genetic screen, genome-wide chromatin co-localization, and loss-of-function analysis in human cells (preprint)","pmids":["bio_10.1101_2024.07.12.603173"],"confidence":"Low","gaps":["Single preprint without in vitro reconstitution or direct biochemical interaction assay between L3MBTL2 and HUSH components","Mechanism by which MPP8 recruits PRC1.6 to chromatin is not defined","No direct demonstration that L3MBTL2 itself, rather than the broader PRC1.6 complex, mediates the silencing"]},{"year":null,"claim":"Whether L3MBTL2 directly contacts HUSH components and the molecular basis of its promoter-specific silencing activity remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstituted biochemistry defining L3MBTL2-HUSH contacts","No structural model of PRC1.6 engagement with HUSH-silenced promoters"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0]}],"pathway":[],"complexes":["PRC1.6"],"partners":["MPP8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969R5","full_name":"Lethal(3)malignant brain tumor-like protein 2","aliases":[],"length_aa":705,"mass_kda":79.1,"function":"Putative Polycomb group (PcG) protein. PcG proteins maintain the transcriptionally repressive state of genes, probably via a modification of chromatin, rendering it heritably changed in its expressibility. Its association with a chromatin-remodeling complex suggests that it may contribute to prevent expression of genes that trigger the cell into mitosis. Binds to monomethylated and dimethylated 'Lys-20' on histone H4. Binds histone H3 peptides that are monomethylated or dimethylated on 'Lys-4', 'Lys-9' or 'Lys-27'","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q969R5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/L3MBTL2","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":[],"url":"https://opencell.sf.czbiohub.org/search/L3MBTL2","total_profiled":1310},"omim":[{"mim_id":"611865","title":"L3MBTL HISTONE METHYL-LYSINE-BINDING PROTEIN 2; L3MBTL2","url":"https://www.omim.org/entry/611865"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/L3MBTL2"},"hgnc":{"alias_symbol":["H-l(3)mbt-l","DKFZP761I141","dJ756G23.3"],"prev_symbol":[]},"alphafold":{"accession":"Q969R5","domains":[{"cath_id":"2.30.30.140","chopping":"325-413","consensus_level":"medium","plddt":89.6816,"start":325,"end":413},{"cath_id":"2.30.30.140","chopping":"420-525","consensus_level":"high","plddt":93.0379,"start":420,"end":525}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969R5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969R5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969R5-F1-predicted_aligned_error_v6.png","plddt_mean":74.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=L3MBTL2","jax_strain_url":"https://www.jax.org/strain/search?query=L3MBTL2"},"sequence":{"accession":"Q969R5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969R5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969R5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969R5"}},"corpus_meta":[{"pmid":null,"id":"bio_10.1101_2024.07.12.603173","title":"PRC1.6 localizes on chromatin with the human silencing hub (HUSH) complex for promoter-specific silencing","date":"2024-07-12","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.12.603173","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":2971,"output_tokens":389,"usd":0.007374,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6608,"output_tokens":905,"usd":0.027832,"stage2_stop_reason":"end_turn"},"total_usd":0.035206,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"L3MBTL2, a member of the non-canonical polycomb repressive complex PRC1.6, co-localizes with the HUSH complex on chromatin primarily at active promoters and contributes to HUSH complex-mediated silencing of proviruses in a promoter-specific manner; PRC1.6 binding at a subset of HUSH-silenced genes depends on the core HUSH component MPP8.\",\n      \"method\": \"Proximity labeling (C-BERST/dCas9-APEX2), forward genetic screen, genome-wide chromatin profiling (co-localization), loss-of-function analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single preprint, proximity labeling and genetic screen without in vitro reconstitution or direct biochemical interaction assay between L3MBTL2 and HUSH components\",\n      \"pmids\": [\"bio_10.1101_2024.07.12.603173\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"L3MBTL2, as a component of the non-canonical PRC1.6 polycomb complex, co-localizes with the HUSH complex at active promoters on chromatin and contributes to promoter-specific transcriptional silencing, with its chromatin binding at a subset of target genes depending on the HUSH core component MPP8.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"L3MBTL2 is a component of the non-canonical polycomb repressive complex PRC1.6 that participates in promoter-specific transcriptional silencing [#0]. It co-localizes with the HUSH complex on chromatin, primarily at active promoters, and contributes to HUSH-mediated silencing of proviruses, with PRC1.6 recruitment at a subset of HUSH-silenced genes depending on the core HUSH component MPP8 [#0]. Beyond this single preprint observation, no further mechanistic detail on L3MBTL2 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2024,\n      \"claim\": \"It was unknown how the non-canonical PRC1.6 complex coordinates with the HUSH silencing machinery; proximity labeling and chromatin profiling established that L3MBTL2/PRC1.6 co-localizes with HUSH at active promoters and that its binding at a subset of targets requires the HUSH component MPP8.\",\n      \"evidence\": \"proximity labeling (C-BERST/dCas9-APEX2), forward genetic screen, genome-wide chromatin co-localization, and loss-of-function analysis in human cells (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.12.603173\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single preprint without in vitro reconstitution or direct biochemical interaction assay between L3MBTL2 and HUSH components\",\n        \"Mechanism by which MPP8 recruits PRC1.6 to chromatin is not defined\",\n        \"No direct demonstration that L3MBTL2 itself, rather than the broader PRC1.6 complex, mediates the silencing\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether L3MBTL2 directly contacts HUSH components and the molecular basis of its promoter-specific silencing activity remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No reconstituted biochemistry defining L3MBTL2-HUSH contacts\",\n        \"No structural model of PRC1.6 engagement with HUSH-silenced promoters\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [\"PRC1.6\"],\n    \"partners\": [\"MPP8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win"}}