RNA inhibits dMi-2/CHD4 chromatin binding and nucleosome remodeling

Ullah, Ikram; Thölken, Clemens; Zhong, Yichen; John, Mara; Roßbach, Oliver; Lenz, Jonathan; Gößringer, Markus; Nist, Andrea; Albert, Lea; Stiewe, Thorsten; Hartmann, Roland K.; Vázquez, Olalla; Chung, Ho-Ryung; Mackay, J.P.; Brehm, Alexander

doi:10.1016/j.celrep.2022.110895

Cited by 8 publications

(5 citation statements)

References 54 publications

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“…The precise mechanism of NuRD complex recruitment and modulation of activity, respectively, is not known to date and represents a matter of ongoing research. However, recent studies have revealed CHD4 as actual RNAbinding subunit of NuRD, thus tethering ncRNAs to target chromatin sites mediating DNA-RNA triplexes (Zhao et al, 2018;Ullah et al, 2022). In summary, our findings revealed the mode of action of LINC00941 involved in epidermal homeostasis.…”

Section: Discussionmentioning

confidence: 55%

The long non-coding RNA LINC00941 modulates MTA2/NuRD occupancy to suppress premature human epidermal differentiation

Morgenstern¹,

Schwartz²,

Graf³

et al. 2023

Preprint

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Numerous long non-coding RNAs (lncRNAs) were shown to have functional impact on cellular processes such as human epidermal homeostasis. However, the mechanism of action for many lncRNAs remains unclear to date. Here, we report that lncRNA LINC00941 regulates keratinocyte differentiation on an epigenetic level through association with the NuRD complex, one of the major chromatin remodelers in cells. We find that LINC00941 interacts with NuRD-associated MTA2 in human primary keratinocytes. LINC00941 perturbation changes MTA2/NuRD occupancy at bivalent chromatin domains in close proximity to transcriptional regulator genes, including theEGR3gene coding for a transcription factor regulating epidermal differentiation. Notably, LINC00941 depletion resulted in reduced NuRD occupancy at theEGR3gene locus, increased EGR3 expression in human primary keratinocytes, as well as increased abundance of EGR3-regulated epidermal differentiation genes in cells and human organotypic epidermal tissue. Our results therefore indicate a role for LINC00941/NuRD in repressing EGR3 expression in non-differentiated keratinocytes, consequentially preventing premature differentiation of human epidermal tissue.

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Section: Discussionmentioning

confidence: 55%

The long non-coding RNA LINC00941 modulates MTA2/NuRD occupancy to suppress premature human epidermal differentiation

Morgenstern¹,

Schwartz²,

Graf³

et al. 2023

Preprint

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“…Again, CHD4-GFP was efficiently coenriched in the presence of conjugated NEAT1_1, which also impaired the enrichment of endogenously biotinylated proteins. Interestingly, the protein domains that mediate binding of CHD4 to RNA have recently been mapped to the N-terminal part of CHD4 in D. melanogaster and human cells(74). Thus, we created the N-terminal deletion mutant ΔN-CHD4-GFP (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Likewise, the recruitment of CHD4 to broken chromatin is well-documented and, for instance, requires interaction with sequencespecific DNA binding proteins (77,78). Intriguingly, CHD4 has also been described as binder of pre-mRNA transcripts (74). In this scenario, nascent pre-mRNA synthesis shields CHD4 from actively-transcribed promoters and thus maintains RNAPII activity.…”

Section: Discussionmentioning

confidence: 99%

NEAT1 promotes genome stability via m6A methylation-dependent regulation of CHD4

Mamontova,

Trifault,

Gribling-Burrer

et al. 2024

Preprint

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Long non-coding (lnc)RNA emerge as regulators of genome stability. The nuclear enriched abundant transcript 1 (NEAT1) locus encodes two lncRNA isoforms that modulate gene expression, growth and proliferation in mammals. Interestingly, NEAT1 transcripts are overexpressed in many tumours and induced by DNA damage, suggesting a genome-protective function. However, the precise role of NEAT1 in the DNA damage response (DDR) is unclear. Here, we investigate the expression, modification levels, localization and structure of NEAT1 in response to DNA double-strand breaks (DSBs) induced by the topoisomerase-II inhibitor etoposide or the locus-specific endonuclease AsiSI. We find that induction of DSBs increases both the levels and N6-methyladenosine (m6A) marks on NEAT1, which promotes alterations in NEAT1 secondary structure and accumulation of hyper-methylated NEAT1 at a subset of promoter-associated DSBs to facilitate efficient DSB signalling. The depletion of NEAT1, in turn, delays the response to DSBs and triggers elevated DNA damage. The genome-protective role of NEAT1 is mediated by the RNA methyltransferase 3 (METTL3) and involves spreading of the chromodomain helicase DNA binding protein 4 (CHD4) upon release from NEAT1. Together, we describe a novel RNA-dependent DDR pathway that couples NEAT1 to the recognition and repair of DSBs.

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“…MSL2 has been shown to bind not only to roX RNA, but to 120 nascent transcripts from the X chromosome in close proximity of MSL2 binding sites ( 75 ). Moreover, nascent RNA has been shown to disrupt the interactions of many epigenetic regulators with chromatin ( 76 , 77 ), including polycomb complexes ( 78–83 ). Recently, it was shown that G-quadruplex RNA induces a PRC2 dimer, in which the nucleosome binding domain is occluded ( 84 ).…”

Section: Discussionmentioning

confidence: 99%

Processivity and specificity of histone acetylation by the male-specific lethal complex

Kiss,

Venkatasubramani,

Pathirana

et al. 2024

Nucleic Acids Research

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Acetylation of lysine 16 of histone H4 (H4K16ac) stands out among the histone modifications, because it decompacts the chromatin fiber. The metazoan acetyltransferase MOF (KAT8) regulates transcription through H4K16 acetylation. Antibody-based studies had yielded inconclusive results about the selectivity of MOF to acetylate the H4 N-terminus. We used targeted mass spectrometry to examine the activity of MOF in the male-specific lethal core (4-MSL) complex on nucleosome array substrates. This complex is part of the Dosage Compensation Complex (DCC) that activates X-chromosomal genes in male Drosophila. During short reaction times, MOF acetylated H4K16 efficiently and with excellent selectivity. Upon longer incubation, the enzyme progressively acetylated lysines 12, 8 and 5, leading to a mixture of oligo-acetylated H4. Mathematical modeling suggests that MOF recognizes and acetylates H4K16 with high selectivity, but remains substrate-bound and continues to acetylate more N-terminal H4 lysines in a processive manner. The 4-MSL complex lacks non-coding roX RNA, a critical component of the DCC. Remarkably, addition of RNA to the reaction non-specifically suppressed H4 oligo-acetylation in favor of specific H4K16 acetylation. Because RNA destabilizes the MSL-nucleosome interaction in vitro we speculate that RNA accelerates enzyme-substrate turn-over in vivo, thus limiting the processivity of MOF, thereby increasing specific H4K16 acetylation.

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RNA inhibits dMi-2/CHD4 chromatin binding and nucleosome remodeling

Cited by 8 publications

References 54 publications

The long non-coding RNA LINC00941 modulates MTA2/NuRD occupancy to suppress premature human epidermal differentiation

The long non-coding RNA LINC00941 modulates MTA2/NuRD occupancy to suppress premature human epidermal differentiation

NEAT1 promotes genome stability via m6A methylation-dependent regulation of CHD4

Processivity and specificity of histone acetylation by the male-specific lethal complex

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