Dr. Xiaodong Cheng
The University of Texas MD Anderson Cancer Center
Department of Molecular & Cellular Oncology
Molecular coupling of DNA modification and histone methylation
My current primary research interests are:
- How are the patterns of mammalian epigenetic DNA modifications generated, recognized and erased, and
- What are the associated histone modifications, and how are they generated, recognized and erased?
In mammalian DNA, cytosine exists in at least five chemical forms: unmodified (C), 5-methylated (5mC), 5-hydroxymethylated (5hmC), 5-formylated (5fC), and 5-carboxylated (5caC). These five forms exhibit base-pairing and protein-coding, but differ in their interactions with transcription factors and strongly influence gene expression. DNA methyltransferases convert specific cytosines to 5mC, and a subset of the 5mC residues is then converted to 5hmC, 5fC, and 5caC consecutively by ten-eleven translocation (Tet) dioxygenases. Mammalian DNA methylation is intricately connected to histone modifications, such as the methylation status of lysine 4 in histone H3 (H3K4).
Cancer is associated with an altered ‘epigenome’, with widespread changes in DNA and histone modifications reprogramming gene expression and affecting genome stability. Many epigenetic regulators, including the DNA modifiers (DNMT3A, TET2), histone modifiers (EZH2, MLL1/2/3) or demodifiers (UTX, JARID1), undergo mutation or are misexpressed in human cancers. This raises the possibility that epigenetic dysregulation is causally associated with the development and progression of the disease. As a result, there is great interest in targeting epigenetic regulators by small molecule inhibitors with the goal of returning the cancer epigenome to a normal state.