Transcription-associated histone pruning demarcates macroH2A chromatin domains

Sun, Zhen; Filipescu, Dan; Andrade, Joshua; Gaspar-Maia, Alexandre; Ueberheide, Beatrix; Bernstein, Emily

doi:10.1038/s41594-018-0134-5

Cited by 42 publications

(50 citation statements)

References 77 publications

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“…A recent study showed that the de novo incorporation of MacroH2A is genome-wide. It is then removed from transcribed chromatin in a transcription-associated mechanism, leading to the specific localization at repressed chromatin (44). Our data may be able to explain why this two-step mechanism is needed for MacroH2A localization in closed chromatin.…”

Section: Discussionmentioning

confidence: 78%

Chromatin structure-dependent histone incorporation revealed by a genome-wide deposition assay

Tachiwana

Dacher

Maehara

et al. 2019

Preprint

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In eukaryotes, histone variant distribution within the genome is the key epigenetic feature. To understand how each histone variant is targeted to the genome, we developed a new method, in which epitope-tagged histone complexes are introduced into permeabilized cells and incorporated into their chromatin. We found that the incorporation of histones H2A and H2A.Z mainly occurred at less condensed chromatin (open), suggesting that the condensed chromatin (closed) is a barrier for histone incorporation. To overcome this barrier, H2A, but not H2A.Z, uses a replication-coupled deposition mechanism. This led to the recapitulation of the preexisting chromatin structure: the genome-wide even distribution of H2A and the exclusion of H2A.Z from the closed chromatin. Intriguingly, an H2A.Z mutant with mutations in the developmentally essential region was incorporated into closed chromatin. Our study revealed that the combination of chromatin structure and DNA replication dictates the differential histone deposition for maintaining the epigenetic chromatin states.

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Section: Discussionmentioning

confidence: 78%

Chromatin structure-dependent histone incorporation revealed by a genome-wide deposition assay

Tachiwana

Dacher

Maehara

et al. 2019

Preprint

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“…At time of writing the mechanisms underlying the connection between PRC2 and MacroH2A during XCI are unknown. MacroH2A is enriched at H3K27me3 enriched chromatin throughout the genome (reviewed in 45), but appears to be established independently (46). It remains to be determined whether MacroH2A directly interacts with XIST; however, the lack of its presence in the interactome screens may implicate intermediate factors, which perhaps bind upstream of the D repeat (26,29,39,47).…”

Section: Discussionmentioning

confidence: 99%

Independent recruitment of PRC1 and PRC2 by human XIST

Dixon-McDougall

Brown

2020

Preprint

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XIST establishes inactivation across its chromosome of origin, even when expressed from autosomal transgenes. To identify the regions of human XIST essential for recruiting heterochromatic marks we generated a series of overlapping deletions in an autosomal inducible XIST transgene. We examined the ability of each construct to enrich its unified XIST territory with the histone marks established by PRC1 and PRC2 as well as the heterochromatin factors MacroH2A and SMCHD1. PRC1 recruitment required four distinct regions of XIST, and these were completely distinct from the two domains crucial for PRC2 recruitment. Both the domains required and the impact of inhibitors suggest that PRC1 is required for SMCHD1 while PRC2 function is necessary for MacroH2A recruitment, although incomplete overlap of regions implicates a role for additional factors. The independence of the PRC1/PRC2 pathways, yet important of all regions tested, demonstrate both modularity and cooperativity across the XIST lncRNA.Author SummaryXIST functions as a long, non-protein coding, RNA to initiate various pathways for the silencing of one of the two X chromosomes in female placental mammals. CRISPR-directed mutations of an inducible human XIST construct in somatic cells allowed us to discover which regions of the RNA are required for chromatin modification and protein recruitment. This was the first large-scale dissection of human XIST domains, and every function assessed was dependent on multiple regions of XIST, suggesting considerable interactions between domains of XIST. We observed similarities, but also differences, with the domains previously identified in mouse Xist and demonstrated the presence of independent pathways for chromosome reorganization in humans as well as ascribing new functionality to regions of XIST. The ability of XIST to inactivate large sections of chromosomes from which it is expressed makes it both an exciting potential therapeutic for chromosome number abnormalities as well as a paradigm for how non-coding RNA genes are able to regulate cellular biology.

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“…We used Lsh−/− and Lsh+/+ MEFs (Fig. 3a) 12,49 , since they expressed higher levels of macroH2A1.2 compared to ES cells and since differentiated cells are known to express more macroH2A2 compared to ES cells ( Supplementary Fig. 4a) 13,[45][46][47] .…”

Section: Lsh Tethering Induces Transcriptional Repressionmentioning

confidence: 99%

LSH mediates gene repression through macroH2A deposition

Ren

et al. 2020

Nat Commun

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The human Immunodeficiency Centromeric Instability Facial Anomalies (ICF) 4 syndrome is a severe disease with increased mortality caused by mutation in the LSH gene. Although LSH belongs to a family of chromatin remodeling proteins, it remains unknown how LSH mediates its function on chromatin in vivo. Here, we use chemical-induced proximity to rapidly recruit LSH to an engineered locus and find that LSH specifically induces macroH2A1.2 and macroH2A2 deposition in an ATP-dependent manner. Tethering of LSH induces transcriptional repression and silencing is dependent on macroH2A deposition. Loss of LSH decreases macroH2A enrichment at repeat sequences and results in transcriptional reactivation. Likewise, reduction of macroH2A by siRNA interference mimicks transcriptional reactivation. ChIP-seq analysis confirmed that LSH is a major regulator of genome-wide macroH2A distribution. Tethering of ICF4 mutations fails to induce macroH2A deposition and ICF4 patient cells display reduced macroH2A deposition and transcriptional reactivation supporting a pathogenic role for altered marcoH2A deposition. We propose that LSH is a major chromatin modulator of the histone variant macroH2A and that its ability to insert marcoH2A into chromatin and transcriptionally silence is disturbed in the ICF4 syndrome.

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Transcription-associated histone pruning demarcates macroH2A chromatin domains

Cited by 42 publications

References 77 publications

Chromatin structure-dependent histone incorporation revealed by a genome-wide deposition assay

Chromatin structure-dependent histone incorporation revealed by a genome-wide deposition assay

Independent recruitment of PRC1 and PRC2 by human XIST

LSH mediates gene repression through macroH2A deposition

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