As opposed to YY1, the gene is not ubiquitously expressed [8, 10]. SET7/9-mediated YY2 methylation regulated its DNA-binding activity 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. is a duplication product from that has been generated through retroposition and inserted into another gene locus named (membrane-bound transcription factor PLX8394 protease site 2), which occurred after the divergence of placental mammals from other vertebrates based on the presence of in only the placental mammals . As opposed to YY1, the gene is not ubiquitously expressed [8, 10]. Because of the high degree of conservation in the zinc-finger regions between YY1 and YY2, YY2 was shown to bind to the YY1-binding sequence 5-(A/c/g)(A/ t)NATG(G/a/t)(C/a)(G/c/t)-3as well as some YY1-bound gene promoters in cultured cells [8,11,12,13]. Similar to YY1, YY2 displays both transcriptional activation and repression functions . Mouse embryonic fibroblast cells from mice carrying alleles expressing various amounts of yy1 display a dosage-dependent requirement of yy1 for cell proliferation. Accordingly, inhibition of YY1 in cultured cells led to cytokinesis defects and cell cycle arrest . In contrast, inhibition of YY2 resulted in accelerated cell proliferation and reversed the antiproliferative effects of YY1 deficiency . Similarly, knockdown of YY1 or YY2 caused inverse changes in ultraviolet sensitivity, suggesting that YY2 is not PLX8394 redundant to YY1, and YY2 might have distinguished roles in cellular physiology . The opposing functions of YY1 and YY2 could be due to that they compete for a common set of binding sites in the genome [8, 16], therefore regulating the transcription of a common set of genes in an opposite way . Alternatively, YY1 and YY2 could possess distinct binding programs and, therefore, regulate unique gene sets. Chromatin immunoprecipitation coupled with sequencing (ChIP-seq) analysis revealed that YY1 binds in close proximity to the transcription start sites of many coding genes as well as intragenic and intergenic regions [17, 18]. However, the distribution of YY2 and its correlation with YY1 has never been assessed in a genome-wide scale. A multitude of mechanisms have been shown to regulate the DNA-binding activity and function of YY1, such as its associated proteins, post-translational modifications (PTMs) and subcellular localization. YY1 has been shown to interact with several transcriptional factors, such as SP1, c-MYC, p53, GATA1 and PLX8394 GATA4, which can regulate YY1 function in transcription either in a PLX8394 cooperative or in a competitive manner [19C23]. In addition, YY1 was found to associate with an array of enzymes, which result in a variety of PTMs on YY1, such as poly(ADP-ribosyl)ation, ubiquitination, acetylation, O-linked glycosylation, S-nitrosation, sumoylation, phosphorylation and methylation. These PTMs can either regulate YY1-binding activity with DNA/proteins or YY1 protein stability, therefore regulating YY1 function in gene transcription, cell cycle and apoptosis control [24C37]. Recently, we reported that YY1 is targeted by SET7/9, and SET7/9-mediated lysine methylation of YY1 is critical for its DNA-binding activity . YY1 was also known to be regulated by its subcellular distribution patterns, with its localization mainly being cytoplasmic at G1, nuclear at early and middle S and then cytosolic again in later S phase. Consequently, YY1 DNA-binding activity and the transcription of YY1-regulated replication-dependent histone genes increased markedly early in S phase . YY1 transcriptional function was also shown to be repressed by cytoplasmic localization during development . However, how YY2 DNA-binding activity and function is regulated, particularly by PTMs, remains completely unknown. Histone methylation is a widespread type of chromatin modification that is known to influence chromatin structure and gene expression, therefore having important roles in biological processes in the context of development and cellular responses [40, 41]. Aberrant histone LTBR antibody methylation has been linked with a variety of human diseases including cancers [42, 43]. It can occur on all basic residues: arginines, lysines and histidines [44,.