Coordination of m 6 A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming

Abstract

SUMMARY Epigenetic and epitranscriptomic networks have important functions in maintaining pluripotency of embryonic stem cells (ESCs) and somatic cell reprogramming. However the mechanisms integrating the actions of these distinct networks are only partially understood. Here, we show that the chromatin-associated zinc finger protein 217 (ZFP217) coordinates epigenetic and epitranscriptomic regulation. ZFP217 interacts with several epigenetic regulators, activates transcription of key pluripotency genes, and modulates N6-methyladenosine (m6A) deposition on their transcripts by sequestering the enzyme m6A methyltransferase-like 3 (METTL3). Consistently, Zfp217 depletion compromises ESC self-renewal and somatic cell reprogramming, globally increases m6A RNA levels, and enhances m6A modification of Nanog, Sox2, Klf4, and c-Myc mRNAs, promoting their degradation. ZFP217 binds its own target gene mRNAs, which are also METTL3-associated, and is enriched at promoters of m6A-modified transcripts. Collectively, these findings shed light on how a transcription factor can tightly couple gene transcription to m6A RNA modification to insure ESC identity.

YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA

“…mRNA delivery and localization are also important in processes such as cell differentiation and animal development [32]. YTHDF3 has been reported to be upregulated by p63 in skin development and differentiation [33], and its transcript is m 6 A-methylated in ZFP217-mediated pluripotency and reprogramming regulation [34]. These biological contexts could be informative in investigating m 6 A-mediated spatial regulation of mRNAs.…”

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

“…In addition, ALKBH5 depletion impaired hypoxia‐induced BCSCs enrichment and tumour formation 72. Further study showed that ALKBH5 expression was required for breast cancer initiation and lung metastasis 73. Zinc finger protein 217 (also known as ZNF217) plays a complementary role with ALKBH5 in negatively regulating m 6 A methylation.…”

“…Zinc finger protein 217 (also known as ZNF217) plays a complementary role with ALKBH5 in negatively regulating m 6 A methylation. ZNF217 was identified to function as the m 6 A methyltransferase inhibitor by sequestering METTL3, consequently promoting the expression and stability of NANOG mRNA and KLF4 mRNA 73. In addition, ZNF217 expression is also induced in an HIF‐dependent manner under hypoxic conditions.…”

Mettl3-mediated m6A regulates spermatogonial differentiation and meiosis initiation

“…Recent studies revealed m 6 A modulation of mRNA expression to be involved in obesity [19], the circadian clock [20], and the DNA damage response [21]. Additionally, it also plays important roles in a variety of biological processes including pluripotency maintenance of stem cells [22][23][24], the maternal-to-zygotic transition [25], sex determination [26,27] and plant shoot stem cell fate determination [28]. As the key 'writer' of m 6 A modification, Mettl3 has been demonstrated to modulate neuronal functions and sex determination in Drosophila and regulate early embryonic development and stem cell pluripotency in mice [22-24, 26, 27].…”