Abstract
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.
Highlights
We proved that YTHDC1 facilitates KAP1 recruitment to targets of the long interspersed nuclear element-1 (LINE1) scaffold, including 2C-related retrotransposons, and promotes the installation of histone 3 lysine 9 trimethylation (H3K9me3) as well as the transcription silencing on these sites in both embryonic stem cell (ESC) and inner cell mass (ICM) cells, which further contributes to ESC identity and embryonic development
As a nuclear m6A reader, YTHDC1 is localized in the YT bodies, which contain focal sites of transcription and are found adjacent to nuclear speckles (Nayler et al, 2000), and pervious data revealed that YTHDC1 directly binds m6Amarked nascent RNAs, chromatin-associated RNAs and transcripts of retrotransposons (Xiao et al, 2016; Liu et al, 2020)
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 m6A-associated chromatin regions (Li et al, 2020), and in another study YTHDC1 was considered to stabilize METTL3 on chromatin through the METTL3-catalysed m6A modifications of RNAs to facilitate the integrity of IAP heterochromatin in mouse ESCs (Xu et al, 2021)
Summary
N6-methyladenosine (m6A) is the most prevalent internal modification of messenger RNAs (mRNAs), repeat RNAs and long non-coding RNAs (lncRNAs) (Dominissini et al, 2012; Meyer et al, 2012; Chelmicki et al, 2021), and this mark is involved in the regulation of various RNA-related processes, including premRNA splicing, nuclear RNA transport, mRNA translation and RNA decay (Wang et al, 2014; Wang et al, 2015; Xiao et al, 2016; Roundtree et al, 2017b; Shi et al, 2017). YTHDC1 is implicated in regulating the redistribution of m6A-marked transcripts from the nucleus to the cytoplasm (Roundtree et al, 2017b), pre-mRNA splicing (Xiao et al, 2016), co-transcriptional interplay (Li et al, 2020), the function of lncRNA Xist (Patil et al, 2016) and the decay of chromatin-associated RNAs (caRNAs) (Patil et al, 2016; Xiao et al, 2016; Li et al, 2020; Liu et al, 2020). The nuclear binding of m6A by YTHDC1 was proved to be indispensable for gamete maturation and embryonic development (Kasowitz et al, 2018), suggesting that the YTHDC1-dependent regulation on nuclear RNAs is important for development processes
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