SWI/SNF chromatin remodeling controls Notch-responsive enhancer accessibility

Pillidge, Zoe; Bray, Sarah

doi:10.1101/399501

Cited by 4 publications

(5 citation statements)

References 51 publications

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“…A similar time course of enrichment was also observed for the proteins FUS and EWSR1, two FET proteins that enter nuclear condensates and can influence transcription, and for several HNRNP proteins implicated in the regulation of splicing (Mittal & Roberts, 2020) (Figure 5B). Together, these data indicate that NICD2 has initiated the induction of a transcriptional response as early as 30 min after GSI washout and that the response is robust within 2 h, consistent with other reports showing that dynamic Notch binding sites in the genome become loaded with NICD and other co-factors within 2 h (Fryer et al, 2004; Fryer et al, 2002; Mittal & Roberts, 2020; Pillidge & Bray, 2019).…”

Section: Resultssupporting

confidence: 91%

“…In addition to MAML1, the nuclear proteins most rapidly recruited to NICD2 are CREBBP/p300, a well-established partner of MAML1 in NICD-dependent transcriptional induction (Fryer et al, 2004; Fryer et al, 2002; Oswald et al, 2001; Wallberg et al, 2002), and components of the BAF chromatin remodeling complex. Strikingly, the SWI/SNF chromatin remodeling complex is crucial to render enhancers responsive to Notch in Drosophila (Pillidge & Bray, 2019); the basis for recruitment of the BAF complex to Notch-responsive elements should be fertile ground for future study.…”

Section: Discussionmentioning

confidence: 99%

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A Spatiotemporal Notch Interaction Map from Membrane to Nucleus

Martin

Bradshaw

Eisert

et al. 2022

Preprint

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Notch signaling relies on ligand-induced proteolysis to liberate a nuclear effector that drives cell fate decisions. The location and timing of individual steps required for proteolysis and movement of Notch from membrane to nucleus, however, remain unclear. Here, we use proximity labeling with quantitative multiplexed mass spectrometry to monitor the microenvironment of endogenous Notch2 after ligand stimulation in the presence of a gamma secretase inhibitor and then as a function of time after inhibitor removal. Our studies show that gamma secretase cleavage of Notch2 occurs in an intracellular compartment and that formation of nuclear complexes and recruitment of chromatin-modifying enzymes occurs within 45 minutes of inhibitor washout. This work provides a spatiotemporal map of unprecedented detail tracking the itinerary of Notch from membrane to nucleus after activation and identifies molecular events in signal transmission that are potential targets for modulating Notch signaling activity.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

A Spatiotemporal Notch Interaction Map from Membrane to Nucleus

Martin

Bradshaw

Eisert

et al. 2022

Preprint

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“…While our data implicate H3.3 in the ARID1A mutant endometrium, few reports have linked SWI/SNF activity to H3.3 containing nucleosomes [38,39]. To gain insight into factors associated with H3.3 regulation by ARID1A, Fig.…”

Section: Arid1a Co-regulates H33 With Chd4 and Zmynd8mentioning

confidence: 67%

ARID1A-dependent maintenance of H3.3 is required for repressive CHD4-ZMYND8 chromatin interactions at super-enhancers

et al. 2022

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Background SWI/SNF (BAF) chromatin remodeling complexes regulate lineage-specific enhancer activity by promoting accessibility for diverse DNA-binding factors and chromatin regulators. Additionally, they are known to modulate the function of the epigenome through regulation of histone post-translational modifications and nucleosome composition, although the way SWI/SNF complexes govern the epigenome remains poorly understood. Here, we investigate the function of ARID1A, a subunit of certain mammalian SWI/SNF chromatin remodeling complexes associated with malignancies and benign diseases originating from the uterine endometrium. Results Through genome-wide analysis of human endometriotic epithelial cells, we show that more than half of ARID1A binding sites are marked by the variant histone H3.3, including active regulatory elements such as super-enhancers. ARID1A knockdown leads to H3.3 depletion and gain of canonical H3.1/3.2 at ARID1A-bound active regulatory elements, and a concomitant redistribution of H3.3 toward genic elements. ARID1A interactions with the repressive chromatin remodeler CHD4 (NuRD) are associated with H3.3, and ARID1A is required for CHD4 recruitment to H3.3. ZMYND8 interacts with CHD4 to suppress a subset of ARID1A, CHD4, and ZMYND8 co-bound, H3.3+ H4K16ac+ super-enhancers near genes governing extracellular matrix, motility, adhesion, and epithelial-to-mesenchymal transition. Moreover, these gene expression alterations are observed in human endometriomas. Conclusions These studies demonstrate that ARID1A-containing BAF complexes are required for maintenance of the histone variant H3.3 at active regulatory elements, such as super-enhancers, and this function is required for the physiologically relevant activities of alternative chromatin remodelers.

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“…Nevertheless, a more specific molecule targeting FBXO42 needs to be identified for use in clinical settings. SWI/SNF complex components have been reported to be involved in Notch-responsive gene activation, which correlates with increased chromatin accessibility (55,56); however, the detailed mechanism remains largely unknown. K63 polyubiquitination of several transcription factors/cofactors involved in DNA damage repair has been reported to facilitate chromatin opening and remodeling (57,58).…”

Section: Discussionmentioning

confidence: 99%

FBXO42 facilitates Notch signaling activation and global chromatin relaxation by promoting K63-linked polyubiquitination of RBPJ

et al. 2022

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Dysregulation of the Notch–RBPJ (recombination signal-binding protein of immunoglobulin kappa J region) signaling pathway has been found associated with various human diseases including cancers; however, precisely how this key signaling pathway is fine-tuned via its interactors and modifications is still largely unknown. In this study, using a proteomic approach, we identified F-box only protein 42 (FBXO42) as a previously unidentified RBPJ interactor. FBXO42 promotes RBPJ polyubiquitination on lysine-175 via lysine-63 linkage, which enhances the association of RBPJ with chromatin remodeling complexes and induces a global chromatin relaxation. Genetically depleting FBXO42 or pharmacologically targeting its E3 ligase activity attenuates the Notch signaling–related leukemia development in vivo. Together, our findings not only revealed FBXO42 as a critical regulator of the Notch pathway by modulating RBPJ-dependent global chromatin landscape changes but also provided insights into the therapeutic intervention of the Notch pathway for leukemia treatment.

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SWI/SNF chromatin remodeling controls Notch-responsive enhancer accessibility

Cited by 4 publications

References 51 publications

A Spatiotemporal Notch Interaction Map from Membrane to Nucleus

A Spatiotemporal Notch Interaction Map from Membrane to Nucleus

ARID1A-dependent maintenance of H3.3 is required for repressive CHD4-ZMYND8 chromatin interactions at super-enhancers

FBXO42 facilitates Notch signaling activation and global chromatin relaxation by promoting K63-linked polyubiquitination of RBPJ

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