ZFP207 sustains pluripotency by coordinating OCT4 stability, alternative splicing and RNA export

Abstract

The pluripotent state is not solely governed by the action of the core transcription factors OCT4, SOX2, and NANOG, but also by a series of co-transcriptional and post-transcriptional events, including alternative splicing (AS) and the interaction of RNA-binding proteins (RBPs) with defined subpopulations of RNAs. Zinc Finger Protein 207 (ZFP207) is an essential transcription factor for mammalian embryonic development. Here, we employ multiple functional analyses to characterize its role in mouse embryonic stem cells (ESCs). We find that ZFP207 plays a pivotal role in ESC maintenance, and silencing of Zfp207 leads to severe neuroectodermal differentiation defects. In striking contrast to human ESCs, mouse ZFP207 does not transcriptionally regulate neuronal and stem cell-related genes but exerts its effects by controlling AS networks and by acting as an RBP. Our study expands the role of ZFP207 in maintaining ESC identity, and underscores the functional versatility of ZFP207 in regulating neural fate commitment.

METTL3 regulates breast cancer-associated alternative splicing switches

“…AS functions in diverse biological processes including cell growth [5], stem cell-renewal and differentiation [6], and cell death [7], to name a few examples. Despite the advantage to expand cellular function, aberrant AS leads to human disease [8].…”

“…N 6 -methyladenosine (m 6 A), the most abundant internal modification in eukaryotic mRNA, has been shown to influence AS [14][15][16][17]. m 6 A is co-transcriptionally deposited by the methyltransferase-like 3 (METTL3) and METTL14 methyltransferase complex, which partially localizes to nuclear speckles, where splicing occurs [18][19][20]. It has been shown that depletion of the Drosophila METTL3 methyltransferase homolog, results in altered AS patterns that influence sex determination [21][22][23].…”

“…It has been shown that depletion of the Drosophila METTL3 methyltransferase homolog, results in altered AS patterns that influence sex determination [21][22][23]. In addition, depletion of METTL3 led to an m 6 A-dependent RNA structural remodeling that alters the accessibility to m 6 A-binding proteins, affecting the recruitment of the splicing factor hnRNPC, and thereby influencing AS [24].…”

“…Indeed, hnRNPC has been recently reported to regulate AS in pancreatic ductal adenocarcinoma and non-small cell lung cancer [25,26]. Another mechanism by which m 6 A regulates splicing is through the m 6 A reader YTHDC1 [14]. YTHDC1 binds to m 6 A-modified mRNA and recruits the splicing factor SRSF3, which promotes exon inclusion, but impedes the binding of SRSF10, which facilitates exon skipping.…”

METTL3 regulates breast cancer-associated alternative splicing switches

“…AS functions in diverse biological processes including cell growth (6), stem cell-renewal and differentiation (7), and cell death (8), to name a few examples. Despite the advantage to expand cellular function, aberrant AS is typically deleterious to cells and leads to human disease (9).…”