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Human BAF complex (HA-DPF2 pulldown and SS18-Flag pulldown)

ABSTRACT: Mammalian SWI/SNF (mSWI/SNF) ATP-dependent chromatin remodeling complexes are large, multisubunit molecular machines that play vital roles in regulating genomic architecture and are frequently disrupted in human cancer and developmental disorders.Using affinity purification of endogenous complexes from mammalian and Drosophila cells coupled with cross linking-mass spectrometry, we uncover three distinct and evolutionarily conserved modules, their organization, and the temporal incorporation of these modules into each complete mSWI/SNF complex class.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Jie Luo

LAB HEAD: Jeff Ranish

PROVIDER: PXD010124 | Pride | 2018-10-18

REPOSITORIES: Pride

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

Mashtalir Nazar N D'Avino Andrew R AR Michel Brittany C BC Luo Jie J Pan Joshua J Otto Jordan E JE Zullow Hayley J HJ McKenzie Zachary M ZM Kubiak Rachel L RL St Pierre Roodolph R Valencia Alfredo M AM Poynter Steven J SJ Cassel Seth H SH Ranish Jeffrey A JA Kadoch Cigall C

Cell 20181018 5

Mammalian SWI/SNF (mSWI/SNF) ATP-dependent chromatin remodeling complexes are multi-subunit molecular machines that play vital roles in regulating genomic architecture and are frequently disrupted in human cancer and developmental disorders. To date, the modular organization and pathways of assembly of these chromatin regulators remain unknown, presenting a major barrier to structural and functional determination. Here, we elucidate the architecture and assembly pathway across three classes of m ...[more]

PMID: 30343899

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Human pBAF complex (HA-BRD7, PHF10-HA pulldown)

Project description:Mammalian SWI/SNF (mSWI/SNF) ATP-dependent chromatin remodeling complexes are large, multisubunit molecular machines that play vital roles in regulating genomic architecture and are frequently disrupted in human cancer and developmental disorders. To date, the organization and pathway of assembly of these chromatin regulators remain unknown, presenting a major barrier to structural and functional determination. Here we elucidate the architecture and assembly pathway of three different classes of mammalian SWI/SNF complexes: canonical BAF, PBAF, and a newly defined complex, ncBAF, and define the requirement of each subunit for complex formation and stability. Using affinity purification of endogenous complexes from mammalian and Drosophila cells coupled with cross linking-mass spectrometry, we uncover three distinct and evolutionarily conserved modules, their organization, and the temporal incorporation of these modules into each complete mSWI/SNF complex class.

2018-10-18 | PXD010122 | Pride

Drosophila BAF complex crosslinking (

2018-10-18 | PXD010123 | Pride

Crosslinking Mapping of yeast Komagataella phaffii TFIID complex

Project description:Transcription preinitiation complex assembly on the promoters of protein encoding genes is nucleated in vivo by TFIID composed of the TATA-box Binding Protein (TBP) and 13 TBP-associate factors (Tafs) providing regulatory and chromatin binding functions. We used CXMS to study the organization and structure of the purified TFIID complex from Komagataella phaffii. Together with Cryo-EM, We confirm the unique subunit stoichiometry prevailing in TFIID and uncover a hexameric arrangement of Tafs containing a HF domain. Interaction with promoter DNA highlights two non-selective binding sites consistent with a DNA scanning mode.

2018-10-08 | PXD011092 | Pride

A structural model of the human mSWI/SNF (BAF) complex bound to the nucleosome informs disease mechanisms

Project description:Mammalian SWI/SNF complexes are multi-component ATP-dependent chromatin-remodeling complexes that regulate genomic architecture. Here we present the first structural model of the human canonical BAF chromatin-remodeling complex bound to a nucleosome generated using cryo-EM, cross-linking mass spectrometry, and homology modeling. Endogenously-purified BAF tethers to the nucleosome H2A/H2B acidic patch regions bilaterally through the SMARCB1 C-terminal helix and a SMARCA4 C-terminal post-SnAc region, each of which are mutated in disease and disrupt nucleosome remodeling. We describe the structural organization of the BAF core module, a connecting ARP module and the ATPase module, scaffolded by the SMARCA4/2 ATPase subunits. Importantly, we assign and model disease-associated mutations throughout the entire BAF complex, identifying mutations that break identified subunit–nucleosome contacts and subunit–subunit interfaces of BAF in the nucleosome-bound conformation. Taken together, this comprehensive structural model of the human BAF complex provides the first insights into the functional impact of mutations that cause cancer and other diseases.

2021-02-10 | PXD020992 | Pride

TAF8 regions important for TFIID lobe B assembly are required for embryonic stem cell survival

Project description:The human general transcription factor TFIID is composed of the TATA-binding protein (TBP) and 13 TBP-associated factors (TAFs). In eukaryotic cells, TFIID is thought to nucleate RNA polymerase II (Pol II) preinitiation complex formation on all protein coding gene promoters and thus, be crucial for Pol II transcription. TFIID is composed of three lobes, named A, B and C. Structural studies showed that TAF8 is forming a histone fold pair in lobe B and connecting lobe B to lobe C. In the present study, we have investigated the requirement of the different regions of TAF8 for in vitro TFIID assembly, and the importance of certain TAF8 regions for mouse embryonic stem cell (ESC) viability. We have identified a TAF8 region, different from the histone fold domain of TAF8, important for assembling with the 5TAF core complex in lobe B, and four regions of TAF8 each individually required for interacting with TAF2 in lobe C. Moreover, we show that the 5TAF core-interacting TAF8 domain, and the proline rich domain of TAF8 interacting with TAF2, are both required for mouse embryonic stem cell survival. Thus, our study demonstrates that TAF8 regions involving in the connection of lobe B to lobe C are crucial for TFIID function and consequent ESC survival.

2021-10-02 | PXD026575 | Pride

Histone octamer structure is altered early in ISW2 ATP-dependent remodeling of nucleosomes

Project description:Histone octamers are thought to be a rigid part of nucleosomes that shape chromatin and block cellular machinery from accessing DNA. ATP-dependent chromatin remodelers like ISW2 mobilize nucleosomes to provide DNA access. We find evidence for histone octamer distortion preceding DNA being moved into nucleosomes and processive movement of the ATPase motor of ISW2 on nucleosomal DNA. DNA entering nucleosome is uncoupled from the ATPase activity of ISW2 and alterations of the histone octamer structure mediated by ISW2 by deletion of the SANT domain from the C-terminus of the Isw2 catalytic subunit. We also find that restricting histone movement by chemical crosslinking traps remodeling intermediates resembling those seen by loss of the SANT domain, further supporting the importance of changes in histone octamer structure early in ISW2 remodeling. Transient octamer distortions are stabilized by H3-H4 tetramer disulfide crosslinking, thereby linking intrinsic histone octamer flexibility to chromatin remodeling.

2020-05-27 | PXD013967 | Pride

Yeast SWI/SNF complex - Loss of Snf5 Induces Formation of an Aberrant SWI/SNF Complex

Project description:This project uses crosslinked based mass spectrometry (CXMS) to study the architecture of yeast SWI/SNF complex.

2018-06-14 | PXD005948 | Pride

SWI/SNF is positively auto-regulated by an AT-hook in the catalytic subunit

Project description:The SWI/SNF ATP-dependent chromatin remodeler is a master regulator of the epigenome; controlling pluripotency, cell fate determination and differentiation. There is a sparsity of information on the autoregulation of SWI/SNF, the domains involved and their mode of action. We find a DNA or RNA binding module conserved from yeast to humans located in the C-terminus of the catalytic subunit of SWI/SNF called the AT-hook that positively regulates the chromatin remodeling activity of yeast and mouse SWI/SNF. The AT-hook in yeast SWI/SNF interacts with the SnAC and ATPase domains, which after binding to nucleosome switches to contacting the N-terminus of histone H3. Deletion of the AT-hooks in yeast SWI/SNF and mouse esBAF complexes reduces the remodeling activity of SWI/SNF without affecting complex integrity or its recruitment to nucleosomes. In addition, deletion of the AT-hook impairs the ATPase and nucleosome mobilizing activities of yeast SWI/SNF without disrupting the interactions of the ATPase domain with nucleosomal DNA. The AT-hook is also important in vivo for SWI/SNF-dependent response to amino acid starvation in yeast and for cell lineage priming in mouse embryonic stem cells. In summary, the AT-hook is shown to be an evolutionarily conserved autoregulatory domain of SWI/SNF that positively regulates SWI/SNF both in vitro and in vivo.

2023-06-15 | PXD040664 | Pride

A chemically-targetable transcription factor-chromatin remodeler interaction underlies SARS-CoV-2 susceptibility

Project description:Identification of host determinants of coronavirus infection informs mechanisms of viral pathogenesis and provides novel therapeutic targets. Here, we demonstrate that the mSWI/SNF chromatin remodeling complex promotes coronavirus infection and represents a host-directed therapeutic target. SMARCA4 catalytic activity is required for mSWI/SNF-driven chromatin accessibility at the ACE2 locus, which is essential for ACE2 expression and virus susceptibility. Recruitment of mSWI/SNF complexes to ACE2 is mediated by mSWI/SNF binding to the transcription factor, HNF1A, enabling complex occupancy and chromatin accessibility at sites containing high HNF1A motif density. Notably, small molecule inhibition of mSWI/SNF catalytic activity abrogates ACE2 expression confers resistance to SARS-CoV-2 variants and infection of primary human airway cells by 5-logs. These data highlight the role for mSWI/SNF-mediated chromatin remodeling activities in conferring SARS-CoV-2 susceptibility and identify a potential new class of inhibitors to combat COVID-19.

2022-10-11 | GSE186201 | GEO

Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer

Project description:Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility and gene regulatory signatures of osimertinib sensitive and resistant EGFR-mutant cell and patient-derived models and uncover a role for mammalian SWI/SNF chromatin remodeling complexes in TKI resistance. By profiling mSWI/SNF genome-wide localization, we identify both shared and cancer cell line-specific gene targets underlying the resistant state. Importantly, genetic and pharmacologic disruption of the SMARCA4/SMARCA2 mSWI/SNF ATPases re-sensitizes a subset of resistant models to osimertinib via inhibition of mSWI/SNF-mediated regulation of cellular programs governing cell proliferation, epithelial-to-mesenchymal transition, epithelial cell differentiation, and NRF2 signaling. These data highlight the role of mSWI/SNF complexes in supporting TKI resistance and suggest potential utility of mSWI/SNF inhibitors in TKI-resistant lung cancers.

2023-08-03 | GSE202864 | GEO

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