A primer for epigenetics of hematological malignancies

Epigenetic marks, such as histone modifications or DNA methylation, regulate tissue specific gene expression by affecting the structures and accessibility of chromatin or DNA. Epigenetics, the molecular mechanisms regulating the epigenome, would therefore be critically involved in development and cell differentiation versus proliferation. Histone modifications include methylation, acetylation, phosphorylation and ubiquitination of specific lysine, arginine or serine residues on histone tails, and each modification has its own specific effect on gene expressions. Modification of histones is accomplished by multimeric protein complexes including polycomb and trithorax group proteins. Regulation of DNA methylation is another mechanism of epigenetic regulation, which is achieved by DNA methyltransferase (DNMT) and TET family proteins. Methylation of cysteine residues on DNA generally leads to transcriptional repression, and oxidation of methylated cysteines provides another type of molecular mark on DNA that regulates gene expression. Next generation sequencing of tumor genomes has uncovered recurrent somatic mutations of epigenetic genes such as DNMT3A, TET2, and ASXL1 in hematologic malignancies, showing that epigenetic dysregulation is a critical step leading to the transformation of hematopoietic cells. Rigorous integrated functional analyses of mutated epigenetic genes are currently underway, and are anticipated to lead to the development of novel molecularly targeted therapies for hematologic malignancies.