Methylation of transcription factor YY2 regulates its transcriptional activity and cell proliferation

Abstract

Yin Yang 1 (YY1) is a multifunctional DNA-binding transcription factor shown to be critical in a variety of biological processes, and its activity and function have been shown to be regulated by multitude of mechanisms, which include but are not limited to post-translational modifications (PTMs), its associated proteins and cellular localization. YY2, the paralog of YY1 in mouse and human, has been proposed to function redundantly or oppositely in a context-specific manner compared with YY1. Despite its functional importance, how YY2’s DNA-binding activity and function are regulated, particularly by PTMs, remains completely unknown. Here we report the first PTM with functional characterization on YY2, namely lysine 247 monomethylation (K247me1), which was found to be dynamically regulated by SET7/9 and LSD1 both in vitro and in cultured cells. Functional study revealed that SET7/9-mediated YY2 methylation regulated its DNA-binding activity in vitro and in association with chromatin examined by chromatin immunoprecipitation coupled with sequencing (ChIP-seq) in cultured cells. Knockout of YY2, SET7/9 or LSD1 by CRISPR (clustered, regularly interspaced, short palindromic repeats)/Cas9-mediated gene editing followed by RNA sequencing (RNA-seq) revealed that a subset of genes was positively regulated by YY2 and SET7/9, but negatively regulated by LSD1, which were enriched with genes involved in cell proliferation regulation. Importantly, YY2-regulated gene transcription, cell proliferation and tumor growth were dependent, at least partially, on YY2 K247 methylation. Finally, somatic mutations on YY2 found in cancer, which are in close proximity to K247, altered its methylation, DNA-binding activity and gene transcription it controls. Our findings revealed the first PTM with functional implications imposed on YY2 protein, and linked YY2 methylation with its biological functions.

Hydrogen Sulfide Promotes Bone Homeostasis by Balancing Inflammatory Cytokine Signaling in CBS-Deficient Mice through an Epigenetic Mechanism

“…CBS KO BMMSCs were generated by using CRISPR/Cas9 system as previously described 53 . Briefly, BMMSCs were transfected with CRISPR/Cas9 KO Plasmid (Santacruz Biotechnology, sc-400877, CA, USA), by using UltraCruz® Transfection Reagent (Santacruz Biotechnology, sc-395739, CA, USA).…”

PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors

“…1E). These transcription factors, particularly E2F4 and YY2, are essential to control progenitor self-renewal and cell cycle progression (26)(27)(28), suggesting a potential role of PHF2 in cell proliferation. To reinforce these data, we analyzed the colocalization of PHF2 and E2F4 using previously published ChIP-seq data in HeLa S3 cells.…”

Simultaneous smoothing and detection of topological units of genome organization from sparse chromatin contact count matrices with matrix factorization

“…We also found other factors in the same zinc finger protein family as CTCF [44], such as ZBTB14, Plagl2/1, ZIC1/3/4/5, CTCFL, YY1/2 that were enriched across the cell types. YY1 and YY2 (which are 65 and 56% identical in their DNA and protein sequence respectively in humans [45]), are of interest, as YY1 has been identified as an enforcer of long-range enhancer-promoter loops [46]. Interestingly, we found several hematopoietic lineage factors, such as STAT3 and FOXP3, ranked highly in the pre-B cell TADs compared to other time points.…”