UC Riverside

Deregulation of the MYC oncoprotein is one of the most prevalent alterations leading to cancer in humans. MYC is known to bind and interact with various transcription cofactors, including histone acetyl-transferases (HATs), and components of the basal transcription machinery influencing transcription initiation and elongation. MYC was previously reported by our laboratory and others to be post-translationally modified via acetylation. However, the functions of MYC acetylation had remained largely unclear. Here, I analyzed the possible gene regulatory and oncogenic cell transforming functions of MYC acetylation at three main lysine (K) residues K149, K158 and K323. By overexpressing MYC in Rat1a fibroblasts, I demonstrated that acetylation-defective MYC lysine(K)-to-arginine(R) mutants are defective in cell transformation and prevent MYC induction of anchorage-independent cell proliferation, a hallmark of cancer cells. Upon genome-wide identification of genes deregulated by the three MYC R-mutants, I confirmed by RT-qPCR that substitution of the acetylated K residues alters the expression of only a small number of specific MYC target genes. These results underly the functional importance of MYC acetylation and its potential as targets for treatment of cancer. Histone acetyltransferase (HAT) complexes are involved in the activation and transcription of the human genome and can be used as a prognostic indicator of cancers. Increased presence of the proteins that compose these complexes are a sign of cancerous cells, one of which is the YEATS2 protein. The YEATS2 protein is a previously characterized scaffolding and histone reader subunit of the ADA2a-containing (ATAC) complex. However, the functions of YEATS2 are still poorly understood and most studies so far have concentrated in cancer cells. Here, I analyzed the functions of the Yaf9, ENL, AF9, Taf14, Sas5 (YEATS) domain and the C-terminal histone fold domain of YEATS2 on gene regulation and cell growth and differentiation of non-malignant (non-cancer) cells. I found that loss of function of either domain inhibits cell growth/proliferation. Knockdown of YEATS2 in HEK293 cells and genome-wide RNA-sequencing analyses identified the ribosomal protein genes as a gene set activated by YEATS2. I further found that activation of the ribosomal protein genes requires both the YEATS and C-terminal histone fold domains of YEATS2. Finally, I showed that YEATS2 protein expression is lost during retinoic acid induced differentiation of proliferating pluripotent embryonic stem cells to neuronal precursor cells in vitro. Together, these results suggest a key role of YEATS2 as a component of the ATAC complex in normal cell growth and proliferation in part via the regulation of the translation machinery. These results expand our knowledge of ATAC complex function in non-tumor cells and give new insights into the functional domains of YEATS2.