METTL3 regulates heterochromatin in mouse embryonic stem cells

Xu, Wenqi; Li, Jiahui; He, Chenxi; Wen, Jing; Ma, Honghui; Rong, Bowen; Diao, Jiang; Wang, Liyong; Jia-hua, Wang; Wu, Feizhen; Tan, Li; Shi, Yujiang Geno; Shi, Yang; Shen, Hongjie

doi:10.1038/s41586-021-03210-1

Cited by 225 publications

(219 citation statements)

References 45 publications

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“…Therefore, YTHDC1 is naturally capable of working as a connecting mediator for the communication between RNA modifications and the chromatin. The YTHDC1-mediated co-transcriptional regulation was raised in two recent studies, in one of which YTHDC1 was reported to recruit KDM3B to promote H3K9me2 demethylation on m 6 A-associated chromatin regions (Li et al, 2020 ), and in another study YTHDC1 was considered to stabilize METTL3 on chromatin through the METTL3-catalysed m 6 A modifications of RNAs to facilitate the integrity of IAP heterochromatin in mouse ESCs (Xu et al, 2021 ). In these two models, the function of YTHDC1 is highly related with METTL3-catalysed m 6 A marks and works in a manner of cis-regulation.…”

Section: Discussionmentioning

confidence: 99%

Nuclear m6A reader YTHDC1 regulates the scaffold function of LINE1 RNA in mouse ESCs and early embryos

et al. 2021

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N6-methyladenosine (m6A) on chromosome-associated regulatory RNAs (carRNAs), including repeat RNAs, plays important roles in tuning the chromatin state and transcription, but the intrinsic mechanism remains unclear. Here, we report that YTHDC1 plays indispensable roles in the self-renewal and differentiation potency of mouse embryonic stem cells (ESCs), which highly depends on the m6A-binding ability. Ythdc1 is required for sufficient rRNA synthesis and repression of the 2-cell (2C) transcriptional program in ESCs, which recapitulates the transcriptome regulation by the LINE1 scaffold. Detailed analyses revealed that YTHDC1 recognizes m6A on LINE1 RNAs in the nucleus and regulates the formation of the LINE1-NCL partnership and the chromatin recruitment of KAP1. Moreover, the establishment of H3K9me3 on 2C-related retrotransposons is interrupted in Ythdc1-depleted ESCs and inner cell mass (ICM) cells, which consequently increases the transcriptional activities. Our study reveals a role of m6A in regulating the RNA scaffold, providing a new model for the RNA-chromatin cross-talk.

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Section: Discussionmentioning

confidence: 99%

Nuclear m6A reader YTHDC1 regulates the scaffold function of LINE1 RNA in mouse ESCs and early embryos

et al. 2021

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“…In the nucleus, the METTL3/14 complex and YTHDC1 are key interactors with m6A-modified RNA that have been shown to regulate chromatin. Work in mouse embryonic stem cells has shown that METTL3 interacts with the SETD1B histone modifying complex, and this plays a role in repression of specific families of endogenous retroviruses (Xu et al, 2021). However, due to the nature of HOTAIR's mechanism of repressing genes in trans, it is unlikely that the METTL3/14 complex remains bound to HOTAIR to induce repression of target loci.…”

Section: M6a In Gene Repression and Heterochromatin Formationmentioning

confidence: 99%

A single N6-methyladenosine site in lncRNA HOTAIR regulates its function in breast cancer cells

Porman

Roberts

Chrupcala

et al. 2020

Preprint

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N6-methyladenosine (m6A) is one of the most abundant RNA modifications with important roles in normal and cancer biology, but knowledge of its function on long noncoding RNAs (lncRNAs) remains limited. In this study, we investigate whether m6A plays a role in regulating the function of the HOTAIR lncRNA which contributes to multiple pro-tumor phenotypes in triple-negative breast cancer (TNBC) cells. We identify 14 individual m6A sites within HOTAIR, with a single site (A783) being consistently methylated.Mutation of A783 impairs cellular proliferation and colony formation in TNBC cells. We find that HOTAIR interacts with the nuclear m6A reader YTHDC1 at methylated A783 and additional sites. Interestingly, we determine that modifications at different sites in HOTAIR have differential effects on HOTAIR regulation. Specifically, m6A at A783 regulates HOTAIR localization to chromatin, whereas other m6A sites mediate high HOTAIR levels. We further find that YTHDC1-HOTAIR interactions are required for gene repression, independent of expression level and chromatin recruitment. Altogether, our work suggests a mechanism whereby m6A regulates the function of HOTAIR via mediating the interaction of YTHDC1 with specific m6A sites, promoting chromatin-mediated repression and breast cancer cell aggressiveness.

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“…By estimation, there are 98,000 copies of ERVs and their derivatives, with human endogenous retrovirus H (HERVH) being one of the most abundant groups, comprising a total of ~2000 copies among which ~100 are close to full-length 25,26 . ERVs are largely in heterochromatin and transcriptionally repressed by an expanding battery of epigenetic mechanisms 4,27,28 , including methylation of histone H3 on lysine 9 (H3K9) or lysine 27 (H3K27), DNA methylation, as well as the RNA N(6)-methyladenosine (m(6)A) modification 29,30 . Of note, these regulatory mechanisms are often redundant and function in a context-specific manner 31,32 , reflecting the sophisticated evolutionary arms race between viral sequences and the host genome [2][3][4] .…”

Section: Introductionmentioning

confidence: 99%

ARID1A loss derepresses human endogenous retrovirus-H to modulate BRD4-dependent transcription

Lei

Chen

et al. 2021

Preprint

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The transposable elements (TEs) through evolutionary exaptation have become an integral part of human genome, offering ample regulatory sequences and shaping chromatin 3D architecture. While the functional impacts of TE-derived sequences on early embryogenesis are recognized, their role in malignancy has only started to emerge. Here we show that many TEs, especially the pluripotency-related endogenous retrovirus H (HERVH), are abnormally activated in colorectal cancer (CRC) samples. The transcriptional upregulation of HERVH is associated with mutations of several tumor suppressors including ARID1A. Knockout of ARID1A in CRC cells leads to increased accessibility at HERVH loci and enhanced transcription, which is dependent on ARID1B. Suppression of HERVH in CRC cells and patient-derived organoids impairs tumor growth. Mechanistically, HERVH transcripts colocalize with nuclear BRD4 foci, modulate their dynamics, and co-regulate many target genes. Altogether, we uncover a critical role for ARID1A in restraining HERVH, which can promote tumorigenesis by stimulating BRD4-dependent transcription when ARID1A is mutated.

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METTL3 regulates heterochromatin in mouse embryonic stem cells

Cited by 225 publications

References 45 publications

Nuclear m6A reader YTHDC1 regulates the scaffold function of LINE1 RNA in mouse ESCs and early embryos

Nuclear m6A reader YTHDC1 regulates the scaffold function of LINE1 RNA in mouse ESCs and early embryos

A single N6-methyladenosine site in lncRNA HOTAIR regulates its function in breast cancer cells

ARID1A loss derepresses human endogenous retrovirus-H to modulate BRD4-dependent transcription

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