SMARCAD1 ATPase activity is required to silence endogenous retroviruses in embryonic stem cells

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: March 22, 2019

Abstract Endogenous retroviruses (ERVs) can confer benefits to their host but present a threat genome integrity if not regulated correctly. Here we identify the SWI/SNF-like remodeler SMARCAD1 as key factor in control of ERVs embryonic stem cells. is enriched at ERV subfamilies class I and II, particularly active intracisternal A-type particles (IAPs), where it preserves repressive histone methylation marks. Depletion results de-repression IAPs adjacent genes. Recruitment dependent on KAP1, central component silencing machinery. KAP1 occupancy co-dependent requires ATPase function SMARCAD1. Our findings uncover role for enzymatic activity cooperating with silence ERVs. This reveals ATP-dependent chromatin remodeling an integral step retrotransposon regulation cells advances our understanding mechanisms driving heterochromatin establishment.

Language: Английский

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Long non-coding RNAs: definitions, functions, challenges and recommendations

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(6), P. 430 - 447

Published: Jan. 3, 2023

Language: Английский

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Organization and regulation of gene transcription

Nature, Journal Year: 2019, Volume and Issue: 573(7772), P. 45 - 54

Published: Aug. 28, 2019

Language: Английский

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Modular Organization and Assembly of SWI/SNF Family Chromatin Remodeling Complexes

Cell, Journal Year: 2018, Volume and Issue: 175(5), P. 1272 - 1288.e20

Published: Oct. 18, 2018

Language: Английский

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Modulation of cellular processes by histone and non-histone protein acetylation

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(5), P. 329 - 349

Published: Jan. 18, 2022

Language: Английский

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Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection

Cell, Journal Year: 2020, Volume and Issue: 184(1), P. 76 - 91.e13

Published: Oct. 20, 2020

Language: Английский

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The evolving metabolic landscape of chromatin biology and epigenetics

Nature Reviews Genetics, Journal Year: 2020, Volume and Issue: 21(12), P. 737 - 753

Published: Sept. 9, 2020

Language: Английский

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Mammalian SWI/SNF Chromatin Remodeling Complexes: Emerging Mechanisms and Therapeutic Strategies

Trends in Genetics, Journal Year: 2020, Volume and Issue: 36(12), P. 936 - 950

Published: Aug. 29, 2020

Over 20% of human cancers carry a mutation in mSWI/SNF complex subunit genes.Mistargeting activity by disease-relevant transcription factors contributes to oncogenic gene expression programs.Targetable synthetic lethal opportunities exist for harboring perturbations subunits.The presence alternate subtypes and variants enables complex-specific pharmacological targeting.Discovery development novel, subunit-specific small-molecule inhibitors degraders are ongoing. Small molecule-based targeting chromatin regulatory has emerged as promising therapeutic strategy recent years. The ongoing clinical evaluation novel agents range processes, including DNA or histone modifiers, readers, protein complexes, inspired the field identify act upon full compendium opportunities. Emerging studies highlight frequent involvement altered mammalian Switch/Sucrose-Nonfermentable (mSWI/SNF) chromatin-remodeling complexes (also called BAF complexes) both cancer neurological disorders, suggesting new mechanisms accompanying routes toward intervention. Here, we review current approaches direct structure function discuss settings which aberrant biology is implicated oncology other diseases. Gene regulation crucial proper execution all biological processes. >3.2 billion base-pairs every cell compacted into higher order structures, dynamic critical ensure timing, location, sequence events. A well-established processes govern topology, modifications, ATP-dependent remodeling. In this review, focus specifically on (BAF) family complexes. Recent advances proteomics, biochemical characterization strategies, genetic manipulation approaches, 3D structural insights, have significantly advanced our understanding modular organization assembly Notably, it now clear that products 29 genes encoding subunits assemble three distinct termed canonical (cBAF), polybromo-associated (PBAF), noncanonical (ncBAF), each comprises common well (Figure 1A , Key Figure, Table 1). All contain one two mutually exclusive catalytic subunits, SMARCA4 SMARCA2 referred BRG1 BRM, respectively), DNA-stimulated ATPase utilize energy provided ATP hydrolysis remodel through nucleosome sliding eviction [1.Chiba H. et al.Two homologues Saccharomyces cerevisiae SWI2/SNF2 Drosophila brahma transcriptional coactivators cooperating with estrogen receptor retinoic acid receptor.Nucleic Acids Res. 1994; 22: 1815-1820Crossref PubMed Scopus (274) Google Scholar, 2.Clapier C.R. al.Mechanisms action chromatin-remodelling complexes.Nat. Rev. Mol. Cell Biol. 2017; 18: 407-422Crossref (248) 3.Khavari P.A. al.BRG1 contains conserved domain SW'2 / SNF2 necessary normal mitotic growth transcription.Nature. 1993; 366: 170-174Crossref (0) 4.Kwon al.Nucleosome disruption enhancement activator binding SW1/SNF complex.Nature. 370: 477-481Crossref (608) 5.Wang W. al.Purification heterogeneity SWI-SNF complex.EMBO J. 1996; 15: 5370-5382Crossref (626) Scholar]. contribution noncatalytic remodeling remains be comprehensively understood. Recently, SMARCB1 was shown make contact acidic patch; interaction required potential [6.Valencia A.M. al.Recurrent mutations reveal patch site potentiates remodeling.Cell. 2019; 179: 1342-1356Abstract Full Text PDF (20) cBAF 12-member containing complex, distinguished incorporation AT-rich (ARID)-domain-containing proteins, ARID1A ARID1B, tandem PHD domain-containing DPF2 subunit. PBAF incorporates ARID protein, ARID2, place ARID1A/ARID1B, also uniquely includes bromodomain-containing PBRM1 BRD7, PHD-containing PHF10. ncBAF identified characterized does not incorporate an tandem-PHD PHF/DPF subunit, but instead GLTSCR1/GLSTCR1L BRD9 [7.Alpsoy A. Dykhuizen E.C. Glioma tumor suppressor candidate region 1 (GLTSCR1) its paralog GLTSCR1-like form SWI/SNF subcomplexes.J. Chem. 2018; 16: 3892-3903Abstract (35) Scholar,8.Michel B.C. al.A non-canonical target driven perturbation.Nat. 20: 1410-1420Crossref (75) These bind multitude genomic loci, distal enhancers, promoters CCCTC-binding factor (CTCF)-binding sites (see Glossary), at they facilitate maintain accessibility regulate transcription. often associated promoting activation, can to, position, nucleosomes enable repressive (TFs) establish state [9.Rafati al.Repressive LTR positioning HIV latency.PLoS 2011; 9e1001206Crossref (97) Scholar].Table 1mSWI/SNF Complexes FeaturesTable FeaturesaSummary their aliases, annotated domains from InterPro database. specific modules listed [24.Mashtalir N. al.Modular complexes.Cell. 175: 1272-1288Abstract (114) Scholar], along associations neurodevelopmental disorders interacting TFs. Biogrid version 3.5.180 database [96.Shu X. al.The epigenetic modifier restricts basal innate immune system repressing acid-inducible gene-I-like signalling prognostic biomarker colon cancer: represses RLR CRC.J. Pathol. 244: 36-48Crossref Scholar] queried literature-described interactions between components TFs sequence-specific properties. Rows shaded group paralogs.bN.O.S., otherwise specified.cPlease refer main text additional details references. aSummary paralogs. bN.O.S., specified. cPlease Multiple positions within occupied Lineage- disease-specific programs dictate expressed assembled complex. For example, PHF10 incorporated embryonic stem cell- neural progenitor-specific (esBAF npBAF, respectively) found most types, whereas DPF1 DPF3 exclusively postmitotic neuron-specific (previously 'nBAF') [10.Son E.Y. Crabtree G.R. role development.Am. Med. Genet. C: Semin. 2014; 166C: 333-349Crossref (68) Additionally, leukemia-specific (leukBAF) reported preferentially over paralogs ARID1B [11.Buscarlet M. al.Essential BRG, leukemia maintenance.Blood. 123: 1720-1728Crossref (59) Scholar]; however, these appear dominant adult types. Advances strategies single-cell RNA-seq technologies will further increase cell-, tissue-, could illuminate unique (Box 1).Box 1Strategies Discovering Novel Therapeutics Targeting ComplexesThe multimeric, combinatorically targeted multiple chemical achieve functional outcomes. First, use enzymatic and/or ATPase/helicase 'Targeting SMARCA4-mutant cancers' text). activators may applications diseases partial loss functions. Second, highly domains, particularly reader involved regulation. PBRM1, BRD9, SMARCA2, proteins; DPF1, DPF2, DPF3, PHF10, PHD-finger SMARCC1 SMARCC2 chromodomain-containing proteins. ligandable binders explored use. Furthermore, coupled, via linker, molecules E3 ubiquitin ligases, such Cereblon VHL, develop bifunctional degradation disease [8.Michel Scholar,45.Farnaby al.BAF vulnerabilities demonstrated structure-based PROTAC design.Nat. 672-680Crossref (81) Scholar,64.Brien G.L. al.Targeted reverses synovial sarcoma.Elife. 7e41305Crossref Third, recruit drive factors' Development selectively disrupt TF-mSWI/SNF attractive drug discovery approach reverse inhibit disease-driving states. Among many modifiers regulators been being mutated large-scale genome-sequencing [12.Bailey M.H. al.Comprehensive driver mutations.Cell. 173: 371-385Abstract (487) [The Cancer Genome Atlas (TCGA) Pan Atlas, MSK-IMPACT [13.Zehir al.Mutational landscape metastatic revealed prospective sequencing 10,000 patients.Nat. 23: 703-713Crossref (1063) Catalog Somatic Mutations (COSMIC) [14.Tate J.G. al.COSMIC: Catalogue Of Cancer.Nucleic 47: D941-D947Crossref (607) Scholar]], members >20% tumors collectively, making them frequently chromatin-related 1B) [15.Kadoch C. al.Proteomic bioinformatic analysis reveals extensive roles malignancy.Nat. 2013; 45: 592-601Crossref ARID1A, SMARCA4, ARID2 various currently included cancer-sequencing panels routine diagnostics. Interestingly, different 1C). malignant rhabdoid (MRT), atypical teratoid/rhabdoid tumors, >90% epitheliod sarcomas [16.Biegel J.A. al.Germ-line acquired INI1 teratoid tumors.Cancer 1999; 59: 74-79PubMed 17.Roberts C.W.M. al.Haploinsufficiency Snf5 (integrase interactor 1) predisposes mice.Proc. Natl. Acad. Sci. U. S. 2000; 97: 13796-13800Crossref (309) 18.Sullivan L.M. al.Epithelioid sarcoma high percentage deletions.Mod. 26: 385-392Crossref rarely observed malignancies. Large-scale screening lines dependencies essential [19.Meyers R.M. al.Computational correction copy number effect improves specificity CRISPR–Cas9 essentiality screens cells.Nat. 49: 1779-1784Crossref (341) Likely, biallelic only tolerated states lineages promote tumorigenesis, types leading loss. Mutation >40% renal carcinoma (ccRCC), few types; fusion SS18 SSX (SS18-SSX oncoprotein) hallmark event while paralogs, respectively, less underlying unexpected defined require Outstanding Questions). Nevertheless, observations suggested cancers. Given large harbor loss-of-function result absent level, there significant interest identifying generated mutational contexts. Genome-scale line dependency using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 hairpin (sh)RNA, coupled focused, hypothesis-directed experiments, and, some cases, probe compound evaluation, several relationships context-specific (Table 2).Table 2Cancer-Associated Mutant Complex Subunits Targeted Therapeutic ModalitiesMutant memberAssociated cancersTherapeutic modalitiesARID1ABladder, stomach, endometrial, solid tumorsbRefer Figure 1C text.ARID1B-selective degrader, EZH2 inhibitor, PI3K inhibitorSMARCA4Nonsmall lung carcinoma, text.SMARCA2-selective inhibitor CDK4/6 inhibitorSMARCA2aSMARCA2 epigenetically silenced low confers SMARCA4.EsophagealSMARCA4-selective degraderSS18-SSXSynovial sarcomaBRD9-selective SS18-SSX degraderSMARCB1Malignant tumor, epithelial inhibitorPBRM1Kidney cancersbRefer text.Immune checkpoint agentsa SMARCA4.b Refer text. Open table tab across shRNA CRISPR efforts 20.Cheung H.W. al.Systematic investigation lineage-specific ovarian cancer.Proc. 108: 12372-12377Crossref (288) 21.McDonald E.R. al.Project DRIVE: uncovered large-scale, deep RNAi screening.Cell. 170: 577-592Abstract (219) carrying homozygous rely closely related paralog, survival [21.McDonald Scholar,22.Helming K.C. al.ARID1B vulnerability ARID1A-mutant cancers.Nat. 251-254Crossref (198) 2A ). absence ARID1B-containing compensate accessibility, enhancers important proliferation survival, MET BCL2L1 [23.Kelso T.W.R. al.Chromatin underlies lethality cancers.eLife. 6e30506Crossref share ~60% identity addition shared N-terminal DNA-binding domain, proteins similar C-terminal recently contacts serving hub lack druggable date stifled selective inhibitor. However, if any ligand were demonstrate binding, lead degrader therapy EZH2, component Polycomb Repressive 2 (PRC2), [25.Bitler B.G. al.Synthetic methyltransferase ARID1A-mutated 2015; 21: 231-238Crossref (330) Pharmacological inhibition GSK126, knockdown shRNA, performed hundreds 2A) PRC2 opposing effects [26.Kennison Tamkun J.W. Dosage-dependent polycomb antennapedia Drosophila.Proc. 1988; 85: 8136-8140Crossref apoptosis derepression PI3K/AKT signaling, PIK3IP1 Activating PI3KCA commonly co-occur [27.Chandler R.L. al.Coexistent ARID1A-PIK3CA clear-cell tumorigenesis pro-tumorigenic inflammatory cytokine signaling.Nat. Commun. 66118Crossref (149) signaling setting. Human showed enhanced sensitivity AKT [28.Samartzis E.P. al.Loss sensitizes cells PI3K- AKT-inhibition.Oncotarget. 5: 5295-5303Crossref (82) impact complicated status because resistance switch [29.Wu al.SWI/SNF subunits' drives -mutated 94116Crossref (15) This upregulation antiapoptotic gene, BCL2; subsequently, overcome treatment ABT263, BCL2 antagonist results provide rationale combining mutant regulation, linked repair maintenance integrity [30.Brownlee P.M. remodelling complex: Its maintaining genome stability preventing tumourigenesis.DNA Repair. 32: 127-133Crossref (50) promoted double-strand breaks [31.Chai B. al.Distinct RSC Swi/Snf remodelers break repair.Genes Dev. 2005; 19: 1656-1661Crossref (233) Scholar,32.Park J.-H. al.Mammalian γ-H2AX induction.EMBO 2006; 25: 3986-3997Crossref renders more sensitive DNA-damaging [33.Shen al.ARID1A deficiency impairs damage PARP inhibitors.Cancer Discov. 752-767Crossref (177) 34.Watanabe R. cellular include show interdependent stability.Cancer 74: 2465-2475Crossref (85) 35.Park Y. combined ionizing radiation therapy.Clin. 5584-5594Crossref directly interact with, MSH2 mismatch [36.Shen promotes mutability antitumor immunity unleashed blockade.Nat. 24: 556-562Crossref (125) Inhibitors ATR PARP, reactive oxygen species (ROS)-inducing agent elesclomol Scholar,37.Kwan S.-Y. leads ROS-inducing gynecologic cells.Oncotarget. 2016; 7: 56933-56943Crossref (13) Scholar,38.Williamson C.T. al.ATR tumours deficient ARID1A.

Language: Английский

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Epigenetic regulation of the innate immune response to infection

Nature reviews. Immunology, Journal Year: 2019, Volume and Issue: 19(7), P. 417 - 432

Published: March 27, 2019

Language: Английский

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Structure of nucleosome-bound human BAF complex

Science, Journal Year: 2020, Volume and Issue: 367(6480), P. 875 - 881

Published: Jan. 31, 2020

Mammalian SWI/SNF family chromatin remodelers, BRG1/BRM-associated factor (BAF) and polybromo-associated BAF (PBAF), regulate structure transcription, their mutations are linked to cancers. The 3.7-angstrom-resolution cryo-electron microscopy of human bound the nucleosome reveals that is sandwiched by base adenosine triphosphatase (ATPase) modules, which bridged actin-related protein (ARP) module. ATPase motor positioned proximal nucleosomal DNA and, upon ATP hydrolysis, engages with pumps along nucleosome. C-terminal α helix SMARCB1, enriched in positively charged residues frequently mutated cancers, mediates interactions an acidic patch AT-rich interactive domain-containing 1A (ARID1A) complex subunit SMARCC serve as a structural core scaffold module organization, respectively. Our study provides insights into organization recognition complex.

Language: Английский

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