The Non-Specific Lethal (NSL) Histone Acetyltransferase Complex Transcriptionally Regulates Yin Yang 1-Mediated Cell Proliferation in Human Cells

Abstract

The human males absent on the first (MOF)-containing non-specific lethal (NSL) histone acetyltransferase (HAT) complex acetylates histone H4 at lysine K5, K8, and K16. This complex shares several subunits with other epigenetic regulatory enzymes, which highlights the complexity of its intracellular function. However, the effect of the NSL HAT complex on the genome and target genes in human cells is still unclear. By using a CRISPR/Cas9-mediated NSL3-knockout 293T cell line and chromatin immunoprecipitation-sequencing (ChIP-Seq) approaches, we identified more than 100 genes as NSL HAT transcriptional targets, including several transcription factors, such as Yin Yang 1 (YY1) which are mainly involved in cell proliferation, biological adhesion, and metabolic processes. We found here that the ChIP-Seq peaks of MOF and NSL3 co-localized with H4K16ac, H3K4me2, and H3K4me3 at the transcriptional start site of YY1. In addition, both the mRNA and protein expression levels of YY1 were regulated by silencing or overexpressing NSL HAT. Interestingly, the expression levels of cell division cycle 6, a downstream target gene of YY1, were regulated by MOF or NSL3. In addition, the suppressed clonogenic ability of HepG2 cells caused by siNSL3 was reversed by overexpressing YY1, suggesting the involvement of YY1 in NSL HAT functioning. Additionally, de novo motif analysis of MOF and NSL3 targets indicated that the NSL HAT complex may recognize the specific DNA-binding sites in the promoter region of target genes in order to regulate their transcription.

YY1 mediated DCUN1D5 transcriptional activation promotes triple-negative breast cancer progression by targeting FN1/PI3K/AKT pathway

“…Yin Yang 1 (YY1) is a zinc finger DNA-binding protein and a member of the GLI-Krüppel family. Accumulating evidence have suggested that YY1 could participate in numerous biological functions, such as cell proliferation [35][36][37], apoptosis [38][39][40], epithelialmesenchymal transition (EMT) [41,42] and drug resistance [43][44][45]. For triple-negative breast cancer, YY1 has also been identified as a critical promoter for tumor proliferation and invasion [25,26].…”

The Males Absent on the First (MOF) Mediated Acetylation Alters the Protein Stability and Transcriptional Activity of YY1 in HCT116 Cells

“…In our previous study, we noticed that YY1 protein expression levels were regulated by NSL HAT [20]. In addition, MOF-containing complexes have been reported to be broad transcription regulators of constitutively expressed genes in both flies and mammals [31,32].…”

“…Chromatin immunoprecipitation sequence (ChIP-Seq) analysis showed that the peaks of MOF co-localized with H4K16ac, H3K4me2, and H3K4me3 at the transcriptional start site of YY1. Furthermore, silencing the NSL complex suppressed the clonogenic ability of HepG2 hepatocellular carcinoma cells [20]. However, the precise mechanism by which MOF-containing complexes regulate YY1 is still unclear.…”

Can O-GIcNAc Transferase (OGT) Complex Be Used as a Target for the Treatment of Hematological Malignancies?

“…The complex subunit population of the NSL complex gives itself a relatively broad substrate specificity, including the lysine (K) 16, K5, and K8 sites of acetylated histone H4 [ 94 ]. Further mediated indicated target gene transcription, such as yin-yang 1 (YY1), X-box binding protein 1 (XBP1), and kruppel-like factor 6 (KLF6), affect the fundamental processes in tumor cells, such as cell proliferation, cell cycle, cell autophagy, and apoptosis [ 95 , 96 ]. MLL-AF9 gene defects are formed by reciprocal translocation of t (9;11).…”