Abstract
Chromatin remodellers were once thought to be highly redundant and nonspecific in their actions. However, recent human genetic studies demonstrate remarkable biological specificity and dosage sensitivity of the thirty-two adenosine triphosphate (ATP)-dependent chromatin remodellers encoded in the human genome. Mutations in remodellers produce many human developmental disorders and cancers, motivating efforts to investigate their distinct functions in biologically relevant settings. Exquisitely specific biological functions seem to be an emergent property in mammals, and in many cases are based on the combinatorial assembly of subunits and the generation of stable, composite surfaces. Critical interactions between remodelling complex subunits, the nucleosome and other transcriptional regulators are now being defined from structural and biochemical studies. In addition, in vivo analyses of remodellers at relevant genetic loci have provided minute-by-minute insights into their dynamics. These studies are proposing new models for the determinants of remodeller localization and function on chromatin.
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References
Flaus, A. Identification of multiple distinct Snf2 subfamilies with conserved structural motifs. Nucleic Acids Res. 34, 2887–2905 (2006).
Centore, R. C., Sandoval, G. J., Soares, L. M. M., Kadoch, C. & Chan, H. M. Mammalian SWI/SNF chromatin remodeling complexes: emerging mechanisms and therapeutic strategies. Trends Genet. 36, 936–950 (2020).
Hodges, C., Kirkland, J. G. & Crabtree, G. R. The many roles of BAF (mSWI/SNF) and PBAF complexes in cancer. Cold Spring Harb. Perspect. Med. 6, a026930 (2016).
Pulice, J. L. & Kadoch, C. Composition and function of mammalian SWI/SNF chromatin remodeling complexes in human disease. Cold Spring Harb. Symp. Quant. Biol. 81, 53–60 (2016).
Bracken, A. P., Brien, G. L. & Verrijzer, C. P. Dangerous liaisons: interplay between SWI/SNF, NuRD, and Polycomb in chromatin regulation and cancer. Genes. Dev. 33, 936–959 (2019).
Ho, P. J., Lloyd, S. M. & Bao, X. Unwinding chromatin at the right places: how BAF is targeted to specific genomic locations during development. Development 146, dev178780 (2019).
Alendar, A. & Berns, A. Sentinels of chromatin: chromodomain helicase DNA-binding proteins in development and disease. Genes Dev. 35, 1403–1430 (2021).
Clapier, C. R. Sophisticated conversations between chromatin and chromatin remodelers, and dissonances in cancer. Int. J. Mol. Sci. 22, ijms22115578 (2021).
Hota, S. K. & Bruneau, B. G. ATP-dependent chromatin remodeling during mammalian development. Development 143, 2882–2897 (2016). Hota and Bruneau comprehensively review genetic and functional studies showing the unique roles of chromatin remodellers during mammalian development.
Sundaramoorthy, R. & Owen-Hughes, T. Chromatin remodelling comes into focus. F1000Res 9, https://doi.org/10.12688/f1000research.21933.1 (2020).
Hirschhorn, J. N., Brown, S. A., Clark, C. D. & Winston, F. Evidence that SNF2/SWI2 and SNF5 activate transcription in yeast by altering chromatin structure. Genes. Dev. 6, 2288–2298 (1992).
Sternberg, P. W., Stern, M. J., Clark, I. & Herskowitz, I. Activation of the yeast HO gene by release from multiple negative controls. Cell 48, 567–577 (1987).
Nasmyth, K., Stillman, D. & Kipling, D. Both positive and negative regulators of HO transcription are required for mother-cell-specific mating-type switching in yeast. Cell 48, 579–587 (1987).
Mizuguchi, G. et al. ATP-driven exchange of histone H2AZ variant catalyzed by SWR1 chromatin remodeling complex. Science 303, 343–348 (2004).
Hota, S. K. et al. Nucleosome mobilization by ISW2 requires the concerted action of the ATPase and SLIDE domains. Nat. Struct. Mol. Biol. 20, 222–229 (2013).
Hamiche, A., Sandaltzopoulos, R., Gdula, D. A. & Wu, C. ATP-dependent histone octamer sliding mediated by the chromatin remodeling complex NURF. Cell 97, 833–842 (1999).
Langst, G., Bonte, E. J., Corona, D. F. & Becker, P. B. Nucleosome movement by CHRAC and ISWI without disruption or trans-displacement of the histone octamer. Cell 97, 843–852 (1999).
Kwon, H., Imbalzano, A. N., Khavari, P. A., Kingston, R. E. & Green, M. R. Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex. Nature 370, 477–481 (1994).
Ayala, R. et al. Structure and regulation of the human INO80-nucleosome complex. Nature 556, 391–395 (2018).
Narlikar, G. J., Sundaramoorthy, R. & Owen-Hughes, T. Mechanisms and functions of ATP-dependent chromatin-remodeling enzymes. Cell 154, 490–503 (2013). This is a clear and concise review of the basic biochemical mechanisms of nucleosome remodelling.
Deuring, R. et al. The ISWI chromatin-remodeling protein is required for gene expression and the maintenance of higher order chromatin structure in vivo. Mol. Cell 5, 355–365 (2000).
Längst, G. & Becker, P. B. Nucleosome mobilization and positioning by ISWI-containing chromatin-remodeling factors. J. Cell Sci. 114, 2561–2568 (2001).
Drane, P., Ouararhni, K., Depaux, A., Shuaib, M. & Hamiche, A. The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Genes Dev. 24, 1253–1265 (2010).
Lewis, P. W., Elsaesser, S. J., Noh, K. M., Stadler, S. C. & Allis, C. D. Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc. Natl Acad. Sci. USA 107, 14075–14080 (2010).
Dyer, M. A., Qadeer, Z. A., Valle-Garcia, D. & Bernstein, E. ATRX and DAXX: mechanisms and mutations. Cold Spring Harb. Perspect. Med. 7, a026567 (2017).
Ni, K. et al. LSH mediates gene repression through macroH2A deposition. Nat. Commun. 11, 5647 (2020).
Kadoch, C. et al. Dynamics of BAF–Polycomb complex opposition on heterochromatin in normal and oncogenic states. Nat. Genet. 49, 213–222 (2017).
Stanton, B. Z. et al. Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin. Nat. Genet. 49, 282–288 (2017).
Clapier, C. R. & Cairns, B. R. Regulation of ISWI involves inhibitory modules antagonized by nucleosomal epitopes. Nature 492, 280–284 (2012).
Wu, J. I., Lessard, J. & Crabtree, G. R. Understanding the words of chromatin regulation. Cell 136, 200–206 (2009).
Mashtalir, N. et al. Modular organization and assembly of SWI/SNF family chromatin remodeling complexes. Cell 175, 1272–1288 e1220 (2018).
Erdel, F. & Rippe, K. Chromatin remodelling in mammalian cells by ISWI-type complexes—where, when and why? FEBS J. 278, 3608–3618 (2011).
Wang, W. et al. Diversity and specialization of mammalian SWI/SNF complexes. Genes. Dev. 10, 2117–2130 (1996).
Wang, W. et al. Purification and biochemical heterogeneity of the mammalian SWI–SNF complex. EMBO J. 15, 5370–5382 (1996).
Ren, J. et al. Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei. eLife 8, e49424 (2019).
Chang, C. Y. et al. Increased ACTL6A occupancy within mSWI/SNF chromatin remodelers drives human squamous cell carcinoma. Mol. Cell 81, 4964–4978 e4968 (2021).
Biggin, M. D. Animal transcription networks as highly connected, quantitative continua. Dev. Cell 21, 611–626 (2011).
Fulton, S. L. et al. Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome. Nat. Commun. 13, 6384 (2022).
Braun, S. M. G. et al. BAF subunit switching regulates chromatin accessibility to control cell cycle exit in the developing mammalian cortex. Genes. Dev. 35, 335–353 (2021).
Lessard, J. et al. An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 55, 201–215 (2007). Lessard and colleagues describe a neuron-specific remodelling complex (neuronal BAF or nBAF) with subunits expressed only in the nervous system.
Goodman, J. V. & Bonni, A. Regulation of neuronal connectivity in the mammalian brain by chromatin remodeling. Curr. Opin. Neurobiol. 59, 59–68 (2019).
Nitarska, J. et al. A functional switch of NuRD chromatin remodeling complex subunits regulates mouse cortical development. Cell Rep. 17, 1683–1698 (2016).
Yoo, A. S., Staahl, B. T., Chen, L. & Crabtree, G. R. MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature 460, 642–646 (2009).
Takeuchi, J. K. & Bruneau, B. G. Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 459, 708–711 (2009). These two studies defined switches in BAF complex subunit composition that are instructive for maturation of neurons (Yoo et al., 2009) or the cardiomyocytes (Takeuchi et al., 2009), and the groups have continued to study the cell-type-specific remodeller complexes.
Lim, H. Y. G. et al. Keratins are asymmetrically inherited fate determinants in the mammalian embryo. Nature 585, 404–409 (2020).
Ho, L. et al. An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency. Proc. Natl Acad. Sci. USA 106, 5181–5186 (2009).
Cairns, B. R. et al. RSC, an essential, abundant chromatin-remodeling complex. Cell 87, 1249–1260 (1996).
Laurent, B. C., Yang, X. & Carlson, M. An essential Saccharomyces cerevisiae gene homologous to SNF2 encodes a helicase-related protein in a new family. Mol. Cell Biol. 12, 1893–1902 (1992).
Tsuchiya, E. et al. The Saccharomyces cerevisiae NPS1 gene, a novel CDC gene which encodes a 160 kDa nuclear protein involved in G2 phase control. EMBO J. 11, 4017–4026 (1992).
Tsukiyama, T., Palmer, J., Landel, C. C., Shiloach, J. & Wu, C. Characterization of the imitation switch subfamily of ATP-dependent chromatin-remodeling factors in Saccharomyces cerevisiae. Genes. Dev. 13, 686–697 (1999).
Alén, C. et al. A role for chromatin remodeling in transcriptional termination by RNA polymerase II. Mol. Cell 10, 1441–1452 (2002).
Gkikopoulos, T. et al. A role for Snf2-related nucleosome-spacing enzymes in genome-wide nucleosome organization. Science 333, 1758–1760 (2011).
Kubik, S. et al. Opposing chromatin remodelers control transcription initiation frequency and start site selection. Nat. Struct. Mol. Biol. 26, 744–754 (2019).
Krietenstein, N. et al. Genomic nucleosome organization reconstituted with pure proteins. Cell 167, e712 (2016).
Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020).
Rice, A. M. & McLysaght, A. Dosage sensitivity is a major determinant of human copy number variant pathogenicity. Nat. Commun. 8, 14366 (2017).
Firth, H. V. et al. DECIPHER: database of chromosomal imbalance and phenotype in humans using Ensembl resources. Am. J. Hum. Genet. 84, 524–533 (2009).
Valencia, A. M. et al. Landscape of mSWI/SNF chromatin remodeling complex perturbations in neurodevelopmental disorders. Nat. Genet. 55, 1400–1412 (2023).
Morrill, S. A. & Amon, A. Why haploinsufficiency persists. Proc. Natl Acad. Sci. USA 116, 11866–11871 (2019). Morill and Amon provide an insightful perspective on how genetic dosage and haploinsufficiency contribute to cellular fitness.
Wenderski, W. et al. Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism. Proc. Natl Acad. Sci. USA 117, 10055–10066 (2020). The authors identified recessive missense variants in a neuron-specific subunit of the BAF complex in individuals with autism spectrum disorder, and mapped their biochemical contributions to autism-spectrum-disorder-related phenotypes in flies, human organoids and mouse models, finding that these mutations produce specific defects in social behaviour and neuronal-activity-dependent responses.
Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).
Minikel, E. V. et al. Evaluating drug targets through human loss-of-function genetic variation. Nature 581, 459–464 (2020).
The Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519, 223–228 (2015).
Kennison, J. A. & Tamkun, J. W. Dosage-dependent modifiers of Polycomb and Antennapedia mutations in Drosophila. Proc. Natl Acad. Sci. USA 85, 8136–8140 (1988). In this study, Kennison and Tamkun identified the ATPase Brahma (part of the BAF complex) and its role in opposing Polycomb complexes; the opposition between Polycomb and BAF complexes is a crucial underlying mechanism that has been observed in many human malignancies and developmental disorders.
Deal, R. B., Henikoff, J. G. & Henikoff, S. Genome-wide kinetics of nucleosome turnover determined by metabolic labeling of histones. Science 328, 1161–1164 (2010). Deal, Henikoff and Henikoff develop a chemical biological method to measure rates of nucleosome turnover and find that turnover occurs faster than a cell cycle across most of the genome, implying that nucleosome remodelling itself can regulate active or repressive gene expression states simply by modulating local DNA accessibility.
Lai, B. et al. Principles of nucleosome organization revealed by single-cell micrococcal nuclease sequencing. Nature 562, 281–285 (2018).
Yildirim, O. et al. Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell 147, 1498–1510 (2011).
Narlikar, G. J., Fan, H.-Y. & Kingston, R. E. Cooperation between complexes that regulate chromatin structure and transcription. Cell 108, 475–487 (2002).
Cirillo, L. A. et al. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol. Cell 9, 279–289 (2002).
Soufi, A. et al. Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming. Cell 161, 555–568 (2015).
Barozzi, I. et al. Coregulation of transcription factor binding and nucleosome occupancy through DNA features of mammalian enhancers. Mol. Cell 54, 844–857 (2014).
Miller, E. L. et al. TOP2 synergizes with BAF chromatin remodeling for both resolution and formation of facultative heterochromatin. Nat. Struct. Mol. Biol. 24, 344–352 (2017).
King, H. W. & Klose, R. J. The pioneer factor OCT4 requires the chromatin remodeller BRG1 to support gene regulatory element function in mouse embryonic stem cells. eLife 6, e22631 (2017).
Friman, E. T. et al. Dynamic regulation of chromatin accessibility by pluripotency transcription factors across the cell cycle. eLife 8, e50087 (2019).
Xiao, L. et al. Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer. Nature 601, 434–439 (2021).
Wang, W. et al. Architectural DNA binding by a high-mobility-group/kinesin-like subunit in mammalian SWI/SNF-related complexes. Proc. Natl Acad. Sci. USA 95, 492–498 (1998).
Smith, M. J. et al. Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nat. Genet. 45, 295–298 (2013).
Barisic, D., Stadler, M. B., Iurlaro, M. & Schubeler, D. Mammalian ISWI and SWI/SNF selectively mediate binding of distinct transcription factors. Nature 569, 136–140 (2019). Barisic and colleagues use functional genomic and epigenomic analyses to identify the unique contributions of different remodellers to the binding of different transcription factors in mouse embryonic stem cells.
Swinstead, E. E., Paakinaho, V., Presman, D. M. & Hager, G. L. Pioneer factors and ATP-dependent chromatin remodeling factors interact dynamically: a new perspective. BioEssays 38, 1150–1157 (2016).
Grossman, S. R. et al. Positional specificity of different transcription factor classes within enhancers. Proc. Natl Acad. Sci. USA 115, E7222–E7230 (2018).
Kim, J. M. et al. Single-molecule imaging of chromatin remodelers reveals role of ATPase in promoting fast kinetics of target search and dissociation from chromatin. eLife 10, e69387 (2021). Kim and colleagues measure rates of remodeller association with chromatin and find very fast residence times (less than ten seconds), proposing a ‘tug-of-war’ model between many remodellers and other regulators and loci on chromatin.
Erin et al. Steroid receptors reprogram FoxA1 occupancy through dynamic chromatin transitions. Cell 165, 593–605 (2016).
Iurlaro, M. et al. Mammalian SWI/SNF continuously restores local accessibility to chromatin. Nat. Genet. 53, 279–287 (2021).
Schick, S. et al. Acute BAF perturbation causes immediate changes in chromatin accessibility. Nat. Genet. 53, 269–278 (2021).
Johnson, T. A. et al. Conventional and pioneer modes of glucocorticoid receptor interaction with enhancer chromatin in vivo. Nucleic Acids Res. 46, 203–214 (2018).
Paun, O. et al. Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at distal regulatory elements to regulate human neural differentiation. Genes. Dev. 37, 218–242 (2023).
Esch, D. et al. A unique Oct4 interface is crucial for reprogramming to pluripotency. Nat. Cell Biol. 15, 295–301 (2013).
Takaku, M. et al. GATA3-dependent cellular reprogramming requires activation-domain dependent recruitment of a chromatin remodeler. Genome Biol. 17, 36 (2016).
Zentner, G. E., Tsukiyama, T. & Henikoff, S. ISWI and CHD chromatin remodelers bind promoters but act in gene bodies. PLoS Genet. 9, e1003317 (2013).
Weber, C. M. et al. mSWI/SNF promotes Polycomb repression both directly and through genome-wide redistribution. Nat. Struct. Mol. Biol. 28, 501–511 (2021).
Satterstrom, F. K. et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell 180, 568–584.e523 (2020).
Son, E. Y. & Crabtree, G. R. The role of BAF (mSWI/SNF) complexes in mammalian neural development. Am. J. Med. Genet. C 166, 333–349 (2014).
Snijders Blok, L. et al. CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. Nat. Commun. 9, 4619 (2018).
Ronan, J. L., Wu, W. & Crabtree, G. R. From neural development to cognition: unexpected roles for chromatin. Nat. Rev. Genet. 14, 347–359 (2013).
Sood, S. et al. CHD8 dosage regulates transcription in pluripotency and early murine neural differentiation. Proc. Natl Acad. Sci. USA 117, 22331–22340 (2020).
Breuss, M. W. & Gleeson, J. G. When size matters: CHD8 in autism. Nat. Neurosci. 19, 1430–1432 (2016).
Durak, O. et al. Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling. Nat. Neurosci. 19, 1477–1488 (2016).
Rhee, S. et al. Endothelial deletion of Ino80 disrupts coronary angiogenesis and causes congenital heart disease. Nat. Commun. 9, 368 (2018).
Tuoc, T. C. et al. Chromatin regulation by BAF170 controls cerebral cortical size and thickness. Dev. Cell 25, 256–269 (2013).
Goljanek-Whysall, K. et al. myomiR-dependent switching of BAF60 variant incorporation into Brg1 chromatin remodeling complexes during embryo myogenesis. Development 141, 3378–3387 (2014).
Saccone, V. et al. HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibro-adipogenic progenitors in dystrophic muscles. Genes. Dev. 28, 841–857 (2014).
Goodwin, L. R. & Picketts, D. J. The role of ISWI chromatin remodeling complexes in brain development and neurodevelopmental disorders. Mol. Cell Neurosci. 87, 55–64 (2018).
Alberini, C. M. & Kandel, E. R. The regulation of transcription in memory consolidation. Cold Spring Harb. Perspect. Biol. 7, a021741 (2014).
Kim, B. et al. Neuronal activity-induced BRG1 phosphorylation regulates enhancer activation. Cell Rep. 36, 109357 (2021).
Yang, Y. et al. Chromatin remodeling inactivates activity genes and regulates neural coding. Science 353, 300–305 (2016).
Wu, J. I. et al. Regulation of dendritic development by neuron-specific chromatin remodeling complexes. Neuron 56, 94–108 (2007).
Aizawa, H. et al. Dendrite development regulated by CREST, a calcium-regulated transcriptional activator. Science 303, 197–202 (2004). Aizawa and colleagues discovered that CREST (a subunit of the BAF complex) is required for activity-dependent dendritic outgrowth; these findings initiated further studies by this group and many others to understand the contributions of remodellers to activity-dependent neuronal processes.
Tea, J. S. & Luo, L. The chromatin remodeling factor Bap55 functions through the TIP60 complex to regulate olfactory projection neuron dendrite targeting. Neural Dev. 6, 5 (2011).
Walsh, J. J. et al. Systemic enhancement of serotonin signaling reverses social deficits in multiple mouse models for ASD. Neuropsychopharmacology 46, 2000–2010 (2021).
Valencia, A. M. et al. Recurrent SMARCB1 mutations reveal a nucleosome acidic patch interaction site that potentiates mSWI/SNF complex chromatin remodeling. Cell 179, 1342–1356.e1323 (2019). Valencia and colleagues used hotspot disease mutations in a BAF subunit to elucidate its biochemical interactions with the nucleosome; the study provides a roadmap for how human genetics data can be used for studies of remodeller mechanisms.
Mashtalir, N. et al. A structural model of the endogenous human BAF complex informs disease mechanisms. Cell 183, 802–817 e824 (2020).
Zhao, K. et al. Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell 95, 625–636 (1998).
Riviere, J. B. et al. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat. Genet. 44, 440–444 (2012).
Cuvertino, S. et al. ACTB loss-of-function mutations result in a pleiotropic developmental disorder. Am. J. Hum. Genet. 101, 1021–1033 (2017).
He, S. et al. Structure of nucleosome-bound human BAF complex. Science 367, 875–881 (2020).
Clapier, C. R. et al. Regulation of DNA translocation efficiency within the chromatin remodeler RSC/Sth1 potentiates nucleosome sliding and ejection. Mol. Cell 62, 453–461 (2016).
Xie, X., Jankauskas, R., Mazari, A. M. A., Drou, N. & Percipalle, P. β-actin regulates a heterochromatin landscape essential for optimal induction of neuronal programs during direct reprograming. PLoS Genet. 14, e1007846 (2018).
Mahmood, S. R. et al. β-actin dependent chromatin remodeling mediates compartment level changes in 3D genome architecture. Nat. Commun. 12, 5240 (2021).
Gibbons, R. J., Picketts, D. J., Villard, L. & Higgs, D. R. Mutations in a putative global transcriptional regulator cause X-linked mental retardation with α-thalassemia (ATR-X syndrome). Cell 80, 837–845 (1995).
Goldberg, A. D. et al. Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140, 678–691 (2010).
Noh, K. M. et al. ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons. Proc. Natl Acad. Sci. USA 112, 6820–6827 (2015).
Sachs, P. et al. SMARCAD1 ATPase activity is required to silence endogenous retroviruses in embryonic stem cells. Nat. Commun. 10, 1335 (2019).
Kadoch, C. & Crabtree, G. R. Mammalian SWI/SNF chromatin remodeling complexes and cancer: mechanistic insights gained from human genomics. Sci. Adv. 1, e1500447 (2015).
Dunaief, J. L. et al. The retinoblastoma protein and BRGI form a complex and cooperateto induce cell cycle arrest. Cell 79, 119–130 (1994). This paper describes the first evidence that remodellers can act as tumour suppressors.
Wong, A. K. C. et al. BRG1, a component of the SWI–SNF complex, is mutated in multiple human tumor cell lines. Cancer Res. 60, 6171–6177 (2000).
Knudson, A. G. Jr. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. USA 68, 820–823 (1971).
Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998).
Biegel, J. A. et al. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 59, 74–79 (1999).
Sevenet, N. et al. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am. J. Hum. Genet. 65, 1342–1348 (1999).
Biegel, J. A. et al. Germline INI1 mutation in a patient with a central nervous system atypical teratoid tumor and renal rhabdoid tumor. Genes Chromosomes Cancer 28, 31–37 (2000).
Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).
Sanchez-Vega, F. et al. Oncogenic signaling pathways in the Cancer Genome Atlas. Cell 173, 321–337.e310 (2018).
Davoli, T. et al. Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell 155, 948–962 (2013).
Kolla, V., Zhuang, T., Higashi, M., Naraparaju, K. & Brodeur, G. M. Role of CHD5 in human cancers: 10 years later. Cancer Res. 74, 652–658 (2014).
Burkhardt, L. et al. CHD1 is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer. Cancer Res. 73, 2795–2805 (2013).
Graf, M. et al. Single-cell transcriptomics identifies potential cells of origin of MYC rhabdoid tumors. Nat. Commun. 13, 1544 (2022).
Wu, J. N. & Roberts, C. W. ARID1A mutations in cancer: another epigenetic tumor suppressor? Cancer Discov. 3, 35–43 (2013).
Bultman, S. J. et al. Characterization of mammary tumors from Brg1 heterozygous mice. Oncogene 27, 460–468 (2008).
Wanior, M., Kramer, A., Knapp, S. & Joerger, A. C. Exploiting vulnerabilities of SWI/SNF chromatin remodelling complexes for cancer therapy. Oncogene 40, 3637–3654 (2021).
Garbarino, J., Eckroate, J., Sundaram, R. K., Jensen, R. B. & Bindra, R. S. Loss of ATRX confers DNA repair defects and PARP inhibitor sensitivity. Transl. Oncol. 14, 101147 (2021).
Hoffman, G. R. et al. Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Proc. Natl Acad. Sci. USA 111, 3128–3133 (2014).
Helming, K. C. et al. ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat. Med. 20, 251–254 (2014).
Meyers, R. M. et al. Computational correction of copy number effect improves specificity of CRISPR–Cas9 essentiality screens in cancer cells. Nat. Genet. 49, 1779–1784 (2017).
Shen, J. et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat. Med. 24, 556–562 (2018).
Okamura, R. et al. ARID1A alterations function as a biomarker for longer progression-free survival after anti-PD-1/PD-L1 immunotherapy. J. Immunother. Cancer 8, e000438 (2020).
Pan, D. et al. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 359, 770–775 (2018).
Miao, D. et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359, 801–806 (2018).
Krishnamurthy, N., Kato, S., Lippman, S. & Kurzrock, R. Chromatin remodeling (SWI/SNF) complexes, cancer, and response to immunotherapy. J. Immunother. Cancer 10, e004669 (2022).
Guo, A. et al. cBAF complex components and MYC cooperate early in CD8+ T cell fate. Nature 607, 135–141 (2022).
Nakayama, R. T. et al. SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters. Nat. Genet. 49, 1613–1623 (2017).
Wang, X. et al. SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. Nat. Genet. 49, 289–295 (2017).
Liu, W. et al. Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer. Oncogene 31, 3939–3948 (2012).
Augello, M. A. et al. CHD1 loss alters AR binding at lineage-specific enhancers and modulates distinct transcriptional programs to drive prostate tumorigenesis. Cancer Cell 35, 603–617.e608 (2019).
Egan, C. M. et al. CHD5 is required for neurogenesis and has a dual role in facilitating gene expression and Polycomb gene repression. Dev. Cell 26, 223–236 (2013).
Dykhuizen, E. C. et al. BAF complexes facilitate decatenation of DNA by topoisomerase II α. Nature 497, 624–627 (2013).
Fillmore, C. M. et al. EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors. Nature 563, E27 (2015).
Seoane, J. A., Kirkland, J. G., Caswell-Jin, J. L., Crabtree, G. R. & Curtis, C. Chromatin regulators mediate anthracycline sensitivity in breast cancer. Nat. Med. 25, 1721–1727 (2019).
Kakarougkas, A. et al. Requirement for PBAF in transcriptional repression and repair at DNA breaks in actively transcribed regions of chromatin. Mol. Cell 55, 723–732 (2014).
Chan, C. S. et al. ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct α-cell signature subgroup. Nat. Commun. 9, 4158 (2018).
Heaphy, C. M. et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science 333, 425 (2011).
Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).
Xia, L. et al. CHD4 has oncogenic functions in initiating and maintaining epigenetic suppression of multiple tumor suppressor genes. Cancer Cell 31, 653–668.e657 (2017).
Clark, J. et al. Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Nat. Genet. 7, 502–508 (1994).
de Leeuw, B., Balemans, M., Olde Weghuis, D. & Geurts van Kessel, A. Identification of two alternative fusion genes, SYT-SSX1 and SYT-SSX2, in t(X;18)(p11.2;q11.2)-positive synovial sarcomas. Hum. Mol. Genet. 4, 1097–1099 (1995).
Skytting, B. et al. A novel fusion gene, SYT-SSX4, in synovial sarcoma. J. Natl Cancer Inst. 91, 974–975 (1999).
McBride, M. J. et al. The nucleosome acidic patch and H2A ubiquitination underlie mSWI/SNF recruitment in synovial sarcoma. Nat. Struct. Mol. Biol. 27, 836–845 (2020).
McBride, M. J. et al. The SS18–SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma. Cancer Cell 33, 1128–1141.e1127 (2018).
Kadoch, C. & Crabtree, G. R. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18–SSX oncogenic fusion in synovial sarcoma. Cell 153, 71–85 (2013). These two studies provide an example of how a remodeller may function directly as an oncogene; in this case, by virtue of a genetic translocation in a subunit creating a fusion protein that then drives aberrant remodelling activity.
Brien, G. L. et al. Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma. eLife 7, e41305 (2018).
Barretina, J. et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat. Genet. 42, 715–721 (2010).
Sima, X. et al. The genetic alteration spectrum of the SWI/SNF complex: the oncogenic roles of BRD9 and ACTL6A. PLoS One 14, e0222305 (2019).
Zhao, D. et al. Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer. Nature 542, 484–488 (2017).
Zhao, D. et al. Chromatin regulator CHD1 remodels the immunosuppressive tumor microenvironment in PTEN-deficient prostate cancer. Cancer Discov. 10, 1374–1387 (2020).
Boulay, G. et al. Cancer-specific retargeting of BAF complexes by a prion-like domain. Cell 171, 163–178.e119 (2017).
The Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature 542, 433–438 (2017).
Lelieveld, S. H. et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat. Neurosci. 19, 1194–1196 (2016).
Rauch, A. et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380, 1674–1682 (2012).
de Ligt, J. et al. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367, 1921–1929 (2012).
Jin, S. C. et al. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat. Genet. 49, 1593–1601 (2017).
Kadoch, C. et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat. Genet. 45, 592–601 (2013). This study extensively surveyed Cancer Genome Atlas data and found that BAF complexes were mutated in almost 20% of all human cancers.
Chun, H. E. et al. Genome-wide profiles of extra-cranial malignant rhabdoid tumors reveal heterogeneity and dysregulated developmental pathways. Cancer Cell 29, 394–406 (2016).
George, J. et al. Comprehensive genomic profiles of small cell lung cancer. Nature 524, 47–53 (2015).
Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).
Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).
Neigeborn, L. & Carlson, M. Genes affecting the regulation of SUC2 gene expression by glucose repression in Saccharomyces cerevisiae. Genetics 108, 845–858 (1984).
Stern, M., Jensen, R. & Herskowitz, I. Five SWI genes are required for expression of the HO gene in yeast. J. Mol. Biol. 178, 853–868 (1984). These papers discovered SWI/SNF from screens in yeast for defects in sucrose fermentation and pheromone-dependent mating-type switching.
Kruger, W. et al. Amino acid substitutions in the structured domains of histones H3 and H4 partially relieve the requirement of the yeast SWI/SNF complex for transcription. Genes. Dev. 9, 2770–2779 (1995).
Laurent, B. C., Treich, I. & Carlson, M. Role of yeast SNF and SWI proteins in transcriptional activation. Cold Spring Harb. Symp. Quant. Biol. 58, 257–263 (1993).
Laurent, B., Treitel, M. A. & Carlson, M. Functional interdependence of the yeast SNF2, SNF5, and SNF6 proteins in transcriptional activation. Proc. Natl Acad. Sci. USA 88, 2687–2691 (1991).
Peterson, C. L. & Herskowitz, I. Characterization of the yeast SWl, SW2, and SW13 genes, which encode a global activator of transcription. Cell 68, 573–583 (1992).
Tamkun, J. W. et al. Brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWl2. Cell 66, 561–572 (1992).
Kingston, R. E. & Tamkun, J. W. Transcriptional regulation by trithorax-group proteins. Cold Spring Harb. Perspect. Biol. 6, a019349 (2014).
Siebenlist, U. et al. Promoter region of interleukin-2 gene undergoes chromatin structure changes and confers inducibility on chloramphenicol acetyltransferase gene during activation of T cells. Mol. Cell Biol. 6, 3042–3049 (1986).
Goldsmith, M. A., Desai, D. M., Schultz, T. & Weiss, A. Function of a heterologous muscarinic receptor in T cell antigen receptor signal transduction mutants. J. Biol. Chem. 264, 17190–17197 (1989).
Socolovsky, M., Dusanter-Fourt, I. & Lodish, H. F. The prolactin receptor and severely truncated erythropoietin receptors support differentiation of erythroid progenitors. J. Biol. Chem. 272, 14009–14012 (1997).
Brisken, C., Socolovsky, M., Lodish, H. F. & Weinberg, R. The signaling domain of the erythropoietin receptor rescues prolactin receptor-mutant mammary epithelium. Proc. Natl Acad. Sci. USA 99, 14241–14245 (2002).
Northrop, J. P. et al. NF-AT components define a family of transcription factors targeted in T-cell activation. Nature 369, 497–502 (1994).
Khavari, P. A., Peterson, C. L., Tamkun, J. W., Mendel, D. B. & Crabtree, G. R. BRG1 contains a conserved domain of the SWI2/SNF2 family necessary for normal mitotic growth and transcription. Nature 366, 170–174 (1993).
Muchardt, C. & Yaniv, M. A human homologue of Saccharomyces cerevisiae SNF2/SWI2 and Drosophila brm genes potentiates transcriptional activation by the glucocorticoid receptor. EMBO J. 12, 4279–4290 (1993).
Stanton, B. Z., Chory, E. J. & Crabtree, G. R. Chemically induced proximity in biology and medicine. Science 359, aa05902 (2018).
Hathaway, N. A. et al. Dynamics and memory of heterochromatin in living cells. Cell 149, 1447–1460 (2012).
Gourisankar, S. et al. Rewiring cancer drivers to activate apoptosis. Nature 620, 417–425 (2023).
Braun, S. M. G. et al. Rapid and reversible epigenome editing by endogenous chromatin regulators. Nat. Commun. 8, 560 (2017).
Ren, J., Hathaway, N. A., Crabtree, G. R. & Muegge, K. Tethering of Lsh at the Oct4 locus promotes gene repression associated with epigenetic changes. Epigenetics 13, 173–181 (2017).
Marian, C. A. et al. Small molecule targeting of specific BAF (mSWI/SNF) complexes for HIV latency reversal. Cell Chem. Biol. 25, 1443–1455.e1414 (2018).
Papillon, J. P. N. et al. Discovery of orally active inhibitors of Brahma homolog (BRM)/SMARCA2 ATPase activity for the treatment of Brahma related gene 1 (BRG1)/SMARCA4-mutant cancers. J. Med. Chem. 61, 10155–10172 (2018).
Chory, E. J. et al. Chemical inhibitors of a selective SWI/SNF function synergize with ATR inhibition in cancer cell killing. ACS Chem. Biol. 15, 1685–1696 (2020).
Kishtagari, A. et al. A first-in-class inhibitor of ISWI-mediated (ATP-dependent) transcription repression releases terminal-differentiation in AML cells while sparing normal hematopoiesis. Blood 132, 216 (2018).
Remillard, D. et al. Degradation of the BAF complex factor BRD9 by heterobifunctional ligands. Angew. Chem. Int. Edn Engl. 56, 5738–5743 (2017).
Farnaby, W. et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat. Chem. Biol. 15, 672–680 (2019).
Schick, S. et al. Systematic characterization of BAF mutations provides insights into intracomplex synthetic lethalities in human cancers. Nat. Genet. 51, 1399–1410 (2019).
Rago, F. et al. Exquisite sensitivity to dual BRG1/BRM ATPase inhibitors reveals broad SWI/SNF dependencies in acute myeloid leukemia. Mol. Cancer Res. 20, 361–372 (2022).
Dann, G. P. et al. ISWI chromatin remodellers sense nucleosome modifications to determine substrate preference. Nature 548, 607–611 (2017).
Mashtalir, N. et al. Chromatin landscape signals differentially dictate the activities of mSWI/SNF family complexes. Science 373, 306–315 (2021).
Chory, E. J. et al. Nucleosome turnover regulates histone methylation patterns over the genome. Mol. Cell 73, 61–72 e63 (2019).
Butler, K. V., Chiarella, A. M., Jin, J. & Hathaway, N. A. Targeted gene repression using novel bifunctional molecules to harness endogenous histone deacetylation activity. ACS Synth. Biol. 7, 38–45 (2018).
Chiarella, A. M. et al. Dose-dependent activation of gene expression is achieved using CRISPR and small molecules that recruit endogenous chromatin machinery. Nat. Biotechnol. 38, 50–55 (2020).
Abbott, J. M. et al. First-in-class inhibitors of oncogenic CHD1L with preclinical activity against colorectal cancer. Mol. Cancer Ther. 19, 1598–1612 (2020).
Prigaro, B. J. et al. Design, synthesis, and biological evaluation of the first inhibitors of oncogenic CHD1L. J. Med. Chem. 65, 3943–3961 (2022).
Vangamudi, B. et al. The SMARCA2/4 ATPase domain surpasses the bromodomain as a drug target in SWI/SNF-mutant cancers: insights from cDNA rescue and PFI-3 inhibitor studies. Cancer Res. 75, 3865–3878 (2015).
Martin, L. J. et al. Structure-based design of an in vivo active selective BRD9 inhibitor. J. Med. Chem. 59, 4462–4475 (2016).
Remillard, D. et al. Chemoproteomics enabled discovery of selective probes for NuA4 factor BRD8. ACS Chem. Biol. 16, 2185–2192 (2021).
Chen, P. et al. Discovery and characterization of GSK2801, a selective chemical probe for the bromodomains BAZ2A and BAZ2B. J. Med. Chem. 59, 1410–1424 (2016).
Lu, T. et al. Discovery of high-affinity inhibitors of the BPTF bromodomain. J. Med. Chem. 64, 12075–12088 (2021).
Zahid, H. et al. New design rules for developing potent cell-active inhibitors of the nucleosome remodeling factor (NURF) via BPTF bromodomain inhibition. J. Med. Chem. 64, 13902–13917 (2021).
Park, S. G., Lee, D., Seo, H. R., Lee, S. A. & Kwon, J. Cytotoxic activity of bromodomain inhibitor NVS-CECR2-1 on human cancer cells. Sci. Rep. 10, 16330 (2020).
Shishodia, S. et al. Selective and cell-active PBRM1 bromodomain inhibitors discovered through NMR fragment screening. J. Med. Chem. 65, 13714–13735 (2022).
Londregan, A. T. et al. Discovery of high-affinity small-molecule binders of the epigenetic reader YEATS4. J. Med. Chem. 66, 460–472 (2023).
Coffey, K. et al. Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer. PLoS One 7, e45539 (2012).
Li, Y. & Seto, E. HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb. Perspect. Med. 6, a026831 (2016).
Kofink, C. et al. A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo. Nat. Commun. 13, 5969 (2022).
Zoppi, V. et al. Iterative design and optimization of initially inactive proteolysis targeting chimeras (PROTACs) identify VZ185 as a potent, fast, and selective von Hippel–Lindau (VHL) based dual degrader probe of BRD9 and BRD7. J. Med. Chem. 62, 699–726 (2019).
Nabet, B. et al. The dTAG system for immediate and target-specific protein degradation. Nat. Chem. Biol. 14, 431–441 (2018).
Nishimura, K., Fukagawa, T., Takisawa, H., Kakimoto, T. & Kanemaki, M. An auxin-based degron system for the rapid depletion of proteins in nonplant cells. Nat. Methods 6, 917–922 (2009). These two papers describe two chemical biological tools that use chemically induced proximity to recruit endogenous proteins to the proteosome in order to rapidly delete them in living cells and organisms and have been increasingly deployed to define the direct functions of remodellers.
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The authors apologize to all co-workers who have contributed to this large field whose work we have been unable to cite for want of space.
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G.R.C., S.G., A.K. and W.W. researched data for the article. G.R.C., S.G. and A.K. wrote the article. All authors contributed substantially to discussion of the content. All authors reviewed and/or edited the manuscript before submission.
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G.R.C. is a founder and scientific adviser for Foghorn Therapeutics and a founder of Shenandoah Therapeutics. The other authors declare no competing interests.
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Supplementary information
41576_2023_666_MOESM1_ESM.xlsx
Supplementary Table 1 Nomenclature of chromatin remodellers. Alternate protein and gene nomenclature for the human chromatin remodelling complexes and their subunits, details on their canonical transcripts, data about their tolerance to loss-of-function, constraint on missense mutation, and copy-number variation conservation, and references to their associated structures if available.
41576_2023_666_MOESM2_ESM.xlsx
Supplementary Table 2 Developmental disorder mutations in chromatin remodellers. A tabulated list of mutations in genes encoding chromatin remodellers and their subunits that are implicated in human developmental disorders, detailing the published reference to the source human genetic study characterizing the disorder, the cohort size analysed, mutation types catalogued, mutation class (such as de novo if this information was available), and detail about the number and type of mutation in remodeller subunit genes in that disorder.
Glossary
- Assay for transposase-accessible chromatin with sequencing (ATAC-seq)
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An assay to measure accessible (open) chromatin that uses the transposase Tn5, which preferentially targets open chromatin sites to insert sequencing primers.
- Chromatin immunoprecipitation (with sequencing)
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An assay to measure chromatin–protein interactions by immunoprecipitating the DNA bound to a protein (ChIP) and sequencing it (ChIP-seq).
- Constraint on missense variants
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A transcript is more intolerant of variation (more constrained) if there are fewer rare missense variants per transcript observed than expected (as predicted by a sequence-context-based mutational model)61.
- Dosage sensitivity
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Genetic dosage sensitivity defines steps in a biological pathway in which a reduction in functional protein or a gain in protein copy leads to a phenotypic effect.
- Haploinsufficiency
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Haploinsufficient genes are a subset of dosage-sensitive genes where loss of function of a single allele produces a phenotype, defining a rate-limiting role for a gene in a biological process.
- Micrococcal nuclease digestion with sequencing (MNase-seq)
-
An assay to determine nucleosome structure where genomic DNA is treated with micrococcal nuclease, which digests open DNA, leaving sequences bound by nucleosomes and other chromatin-bound proteins.
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Gourisankar, S., Krokhotin, A., Wenderski, W. et al. Context-specific functions of chromatin remodellers in development and disease. Nat Rev Genet 25, 340–361 (2024). https://doi.org/10.1038/s41576-023-00666-x
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DOI: https://doi.org/10.1038/s41576-023-00666-x
