The nucleosome acidic patch and H2A ubiquitination underlie mSWI/SNF recruitment in synovial sarcoma

McBride, Matthew J.; Mashtalir, Nazar; Winter, Ethan S.; Dao, Hai T.; Filipovski, Martin; D’Avino, Andrew R.; Seo, Hyuk-Soo; Umbreit, Neil T.; Pierre, Roodolph St.; Valencia, Alfredo M.; Qian, Kristin; Zullow, Hayley; Jaffe, Jacob D.; Dhe‐Paganon, Sirano; Muir, Tom W.; Kadoch, Cigall

doi:10.1038/s41594-020-0466-9

Cited by 44 publications

(43 citation statements)

References 46 publications

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“…Indeed, we observed a slightly increased portion of CBAF remaining on insoluble chromatin after nuclear extraction in the presence of the fusion (Fig. 7F), fitting the increased affinity for chromatin conferred by the fusion's SSX tail 38 .…”

Section: Eps the Reportedly Recovered Distribution Of Baf-family Complexes To Particular Tsssmentioning

confidence: 61%

A Role for SMARCB1 in Synovial Sarcomagenesis Reveals That SS18–SSX Induces Canonical BAF Destruction

Mulvihill

et al. 2021

Cancer Discovery

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Reduced protein levels of SMARCB1 (a.k.a. BAF47, INI1, SNF5) have long been observed in synovial sarcoma (SS). Here, we show that combined Smarcb1 genetic loss with SS18-SSX expression in mice synergized to produce aggressive tumors with histomorphology, transcriptomes, and genome-wide BAF-family complex distributions distinct from SS18-SSX alone, indicating a defining role for SMARCB1 in SS. Smarcb1 silencing alone in mesenchyme modeled epithelioid sarcomagenesis. In mouse and human SS cells, SMARCB1 was identified within PBAF and canonical BAF (CBAF) complexes, co-incorporated with SS18-SSX in the latter. Recombinant expression of CBAF components in human cells reconstituted CBAF sub-complexes that contained equal levels of SMARCB1, regardless of SS18 or SS18-SSX inclusion. In vivo, SS18-SSX expression led to whole-complex CBAF degradation, rendering increases in the relative prevalence of other BAF-family subtypes, PBAF and GBAF complexes, over time. Thus, SS18-SSX alters BAF subtypes levels/balance and genome distribution, driving synovial sarcomagenesis.Research.

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Section: Eps the Reportedly Recovered Distribution Of Baf-family Complexes To Particular Tsssmentioning

confidence: 61%

A Role for SMARCB1 in Synovial Sarcomagenesis Reveals That SS18–SSX Induces Canonical BAF Destruction

Mulvihill

et al. 2021

Cancer Discovery

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“…Our understanding of how sequence-non-specific chromatin remodeling complexes achieve specificity at genomic loci is still developing. Prior work has uncovered myriad remodeler-targeting ‘cues,’ including post-translational histone modifications (Clapier et al, 2001; Dann et al, 2017; Mashtalir et al, 2021), TFs (Barisic et al, 2019; Brahma and Henikoff, 2019; de Dieuleveult et al, 2016), three-dimensional (3D) chromosomal architecture (Barisic et al, 2019; Barutcu et al, 2016; Weber et al, 2021), composition of the nucleosome core particle (Dann et al, 2017; Gamarra et al, 2018; McBride et al, 2020), and, as discussed here, availability of extranucleosomal flanking DNA (Stockdale et al, 2006; Yang et al, 2006; Zofall et al, 2004). Here, we elaborate on the length-sensing model by connecting DNA length-sensing on mononucleosomes to nucleosome density of individual chromatin fibers.…”

Section: Discussionmentioning

confidence: 93%

Single-fiber nucleosome density shapes the regulatory output of a mammalian chromatin remodeling enzyme

Abdulhay

Hsieh

McNally

et al. 2021

Preprint

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ATP-dependent chromatin remodelers regulate the DNA accessibility required of virtually all nuclear processes. Biochemical studies have provided insight into remodeler action at the nucleosome level, but how these findings translate to activity on chromatin fibers in vitro and in vivo remains poorly understood. Here, we present a massively multiplex single-molecule platform allowing high-resolution mapping of nucleosomes on fibers assembled on mammalian genomic sequences. We apply this method to distinguish between competing models for chromatin remodeling by the essential ISWI ATPase SNF2h: linker-length-dependent dynamic positioning versus fixed-linker-length static clamping. Our single-fiber data demonstrate that SNF2h operates as a density-dependent, length-sensing chromatin remodeler whose ability to decrease or increase DNA accessibility depends on single-fiber nucleosome density. In vivo, this activity manifests as different regulatory modes across epigenomic domains: at canonically-defined heterochromatin, SNF2h generates evenly-spaced nucleosome arrays of multiple nucleosome repeat lengths; at SNF2h-dependent accessible sites, SNF2h slides nucleosomes to increase accessibility of motifs for the essential transcription factor CTCF. Overall, our generalizable approach provides molecularly-precise views of the processes that shape nuclear physiology. Concurrently, our data illustrate how a mammalian chromatin remodeling enzyme can effectively sense nucleosome density to induce diametrically-opposed regulatory effects within the nucleus.

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“…Together, these observations primarily favor a titration model that is further supported by reduced PRC2 occupancy at target sites. Alternatively, a number of new H2AK119ub1 sensors have been reported recently ( McBride et al., 2020 ; Weinberg et al., 2021 ), but their effective role in PR-DUB- and PRC1-related processes remains to be fully established.…”

Section: Discussionmentioning

confidence: 99%

BAP1 enhances Polycomb repression by counteracting widespread H2AK119ub1 deposition and chromatin condensation

et al. 2021

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Summary BAP1 is mutated or deleted in many cancer types, including mesothelioma, uveal melanoma, and cholangiocarcinoma. It is the catalytic subunit of the PR-DUB complex, which removes PRC1-mediated H2AK119ub1, essential for maintaining transcriptional repression. However, the precise relationship between BAP1 and Polycombs remains elusive. Using embryonic stem cells, we show that BAP1 restricts H2AK119ub1 deposition to Polycomb target sites. This increases the stability of Polycomb with their targets and prevents diffuse accumulation of H2AK119ub1 and H3K27me3. Loss of BAP1 results in a broad increase in H2AK119ub1 levels that is primarily dependent on PCGF3/5-PRC1 complexes. This titrates PRC2 away from its targets and stimulates H3K27me3 accumulation across the genome, leading to a general chromatin compaction. This provides evidence for a unifying model that resolves the apparent contradiction between BAP1 catalytic activity and its role in vivo , uncovering molecular vulnerabilities that could be useful for BAP1-related pathologies.

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The nucleosome acidic patch and H2A ubiquitination underlie mSWI/SNF recruitment in synovial sarcoma

Cited by 44 publications

References 46 publications

A Role for SMARCB1 in Synovial Sarcomagenesis Reveals That SS18–SSX Induces Canonical BAF Destruction

A Role for SMARCB1 in Synovial Sarcomagenesis Reveals That SS18–SSX Induces Canonical BAF Destruction

Single-fiber nucleosome density shapes the regulatory output of a mammalian chromatin remodeling enzyme

BAP1 enhances Polycomb repression by counteracting widespread H2AK119ub1 deposition and chromatin condensation

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