Tissue-specific metabolism and TRIM24

regulation of metabolism is critical to maintain cellular homeostasis in response to cellular demands and resources. Changes in the microenvironment impact functions of epigenetic regulatory enzymes and metabolic balance must maintained to avoid metabolic reprogramming and tumor progression [1]. Epigenetic regulatory proteins with catalytic functions include histone " writers " or " erasers " , which effect post-translational modifications (PTMs) of histones or non-histone proteins; chromatin remodelers, fueled by ATP to alter chromatin structure; and, enzymes that methylate DNA or reverse DNA methylation. Genes encoding key factors in metabolic signaling pathways are regulated by the activities of these enzymes, which remodel or modify chromatin. Additionally, epigenetic regulatory enzymes themselves serve as environmental sensors by relying on available metabolites as cofactors. For example, mutations in IDH1/IDH2, which encode isocitrate dehydrogenases of the tricarboxylic acid (TCA) cycle, are associated with low-grade gliomas, adult de novo acute myeloid leukemias and lymphomas. Mutant IDH1/2 exhibit gain-of-function by catalyzing conversion of α-ketoglutarate (α-KG) to 2-hydroxy glutarate (2-HG) at 100-fold higher levels than found in normal cells. 2-HG is a competitive inhibitor of α-KG-dependent dioxygenases, including TET2, which acts in reversal of DNA methylation, and Jumonji-C-domain-containing histone demethylases, which alter histone PTMS; either of which may disrupt regulated gene expression [2]. In addition to epigenetic regulatory enzymes that act as sensors of cellular metabolites and/or directly alter chromatin structure of genes that encode metabolic enzymes, proteins known as " histone readers " serve as relay switches in regulatory networks, including metabolism. Histone readers have specific domains that bind defined " signatures " of histone PTMs and act as platforms for recruitment of transcription factors, mediators or additional epigenetic response factors to chromatin. Our laboratory showed that histone reader Tripartite motif-containing protein 24 (TRIM24) not only negatively regulates p53 as an E3-ubiquitin ligase [3] but also interacts with and recruits transcription factors, such as estrogen receptor, to chromatin via a tandem plant homeodomain (PHD) and Bromodomain that binds unmethylated lysine 4 and acetylated lysine Editorial 23 of histone H3 (H3K4me0/H3K23ac) [4]. More recently, we found that ectopic expression of TRIM24 promoted oncogenic transformation of immortalized human mammary epithelial cells (TRIM24-iHMECs) and efficient growth of intermediate to high-grade xenograft tumors [5]. Molecular analysis of TRIM24-iHMECs revealed a TRIM24-dependent glycolytic and TCA cycle gene expression signature, which led to increased glucose uptake. Gene Set Enrichment Analysis revealed the glucose transport pathway as one of the top 10 pathways positively …