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

Abstract

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.

ARID1A governs the silencing of sex-linked transcription during male meiosis in the mouse

“…Although previous work described the association of H3.3 with the sex body (van der Heijden et al, 2007; Yuen et al, 2014) and its requirement for meiotic repression of sex-linked genes (Fontaine et al, 2022), our study revealed the need for BAF-A in the preferential localization of H3.3 to the sex body relative to autosomes. Interestingly, a similar role for BAF-A in promoting H3.3 incorporation occurs in human endometriotic cells (Reske et al, 2022). In this case, the genomic localization of H3.3 to super-enhancers required ARID1A.…”

“…The latter outcome is interesting in the context of MSCI, given that the sex body typically displays a striking enrichment of the variant histone H3.3 while concomitantly appearing depleted of the canonical histones H3.1/3.2 (van der Heijden et al, 2007;Yuen et al, 2014). Given that human ARID1A is known to regulate H3.3 genomic associations (Reske et al, 2022), we tested whether a similar mechanism governed H3.3 localization to the sex chromosomes. To address this, we monitored H3.3 localization in pachytene spermatocytes by IF, simultaneously staining for ARID1A and HORMAD1.…”

Involvement of the H3.3 Histone Variant in the Epigenetic Regulation of Gene Expression in the Nervous System, in Both Physiological and Pathological Conditions

“…It was also reported that some chromatin remodeling complexes, such as the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex and, in particular, its subunit “T-rich interactive domain-containing protein 1A” (ARAD1A) are required for maintaining the H3.3 histone at the level of regulatory sequences, among which are the so-called super-enhancers [ 47 ]. On the other hand, by interacting with the ATRX/DAXX chaperones, H3.3 might also be loaded on pericentric heterochromatin and telomeres [ 38 , 48 , 49 ].…”

ARID1A governs the silencing of sex-linked transcription during male meiosis in the mouse

“…1/3.2 (van der Heijden et al, 2007 ;Yuen et al, 2014 ). Given that human ARID1A regulates H3.3 genomic associations (Reske et al, 2022 ), we tested whether a similar mechanism governed H3.3 localization to the sex chromosomes. To address this, we monitored H3.3 localization in pachytene spermatocytes by IF, simultaneously staining for ARID1A and HORMAD1.…”