Chromatin and oncogenesis

DNA is packed inside the nucleus of our cells, folded around proteins in a "yarn" called chromatin. In an older post I discussed how chromatin changes affect gene expression. A recent PNAS paper [1] explores the relationship between chromatin conformational changes and cancer. They studied one family of genes in particular, ERG, which is part of the larger family of genes called ETS. In order to understand the paper I had to learn about this ETS family of genes and, let me tell you, it's quite fascinating.

The ETS genes are a family of transcription factors, proteins that bind to particular loci in the DNA and thus control DNA transcription. From the Wikipedia page: "The ETS family is present throughout the body and is involved in a wide variety of functions including the regulation of cellular differentiation, cell cycle control, cell migration, cell proliferation, apoptosis (programmed cell death) and angiogenesis."

ETS stands for "E Twenty-Six," which is actually a leukemia virus. This is because the founder of the family, ETS-1, is the precursor of a retroviral oncogene: yes, another endogenous viral sequence! This particular gene is transduced (transferred) by the E26 virus. Several studies have associated the deregulation of the expression of this gene with tumorigenic processes.

Back to the paper: Rickman et al. investigated oncogene-mediated chromatin structure changes in ERG, a subfamily of ETS that is often rearranged and overexpressed in prostate cancer.

"ERG interacts with several cofactors and other transcription factors including AR to regulate the expression of thousands of genes that favor de-differentiation, cell invasion, and neoplastic transformation of prostate epithelium when overexpressed. We therefore hypothesized that changes in global gene expression induced by ERG overexpression could be associated with global changes in the 3D structure of chromosomes."

"Our data show that overexpression of ERG is associated with broad chromatin topology changes and, interestingly, that ERG binding is significantly associated with hotspots of differential chromatin interactions."

This association still does not prove causality, as the pathway from overexpression to chromatin conformational changes could be more convoluted, but it certainly points to a correlation between these changes in chromatin topology and the expression of genes responsible for prostate cancer. This association is likely to be found in other sets of genes relevant to other types of cancers.

[1] Rickman DS, Soong TD, Moss B, Mosquera JM, Dlabal J, Terry S, Macdonald TY, Tripodi J, Bunting K, Najfeld V, Demichelis F, Melnick AM, Elemento O, & Rubin MA (2012). Oncogene-mediated alterations in chromatin conformation. Proceedings of the National Academy of Sciences of the United States of America, 109 (23), 9083-8 PMID: 22615383