Superfund Research Program
Epigenetic Mechanisms of Ni, As, Chromate and BaP Carcinogenesis (ARRA Funded)
Project Leader: Max Costa
Grant Number: P42ES010344
Funding Period: 2009-2011
Project Summary (2009-2011)
The environment is known to have a significant impact upon the epigenetic program of gene expression. Exposure to various toxic and carcinogenic chemicals, derived from superfund sites, is likely to alter our epigenetic program. The modifications of histone tails, including histone acetylation, methylation, phosphorylation and ubiquitination, are critical components of epigenetically regulated gene expression.
Among these modifications, methylation of histone H3 lysine 9 (H3K9) is particularly interesting due to the well-known connection between its occupancy in the promoter region and epigenetic gene silencing. The persistent methylation of H3K9 leads to cytosine methylation in the same nucleosome and loss of gene expression when that nucleosome is in the promoter region of an epigenetically regulated gene. Recent findings have identified a new class of enzymes that specifically demethylate H3K9 when it becomes mono-, di-, or trimethylated. These enzymes belong to the 2-oxoglutarate (2OG)-Fe(ll)-dependent dioxygenase family, which use iron Fe(ll), oxoglutarate, ascorbic acid, and oxygen to oxidatively demethylate the N-methyl bond on H3K9. This yields a demethylated product, formaldehyde, and CO2 released from the decarboxylation of oxoglutarate. Environmental agents that target Fe (II), ascorbic acid, and oxygen are able to affect the activity of these demethylases. For example, Fe (II) is not tightly bound to a two-histidine carboxylic acid facial triad in the jumonji C (JmjC) domain of these demethylases. Nickel (Ni) or cobalt (Co) ions as well as other metal ions can readily bind in place of Fe and inactivate these enzymes. Additionally, other toxic metals such as chromate (Cr) are known to react avidly with ascorbic acid leading to depletion of reduced ascorbate which is required for the oxidative demethylation. Arsenic (As) and benzo[a]pyrene (Bap) may also affect H3K9 methylation by inducing oxidative stress which may indirectly deplete reduced ascorbate.
Dr. Costa’s goals in this project are to investigate the individual and combined effects of toxic metals and compounds on H3K9 methylation and study the role of these effects in the changes of gene expression pattern and the role of these alterations in cell transformation and tumor progression induced by these metals and compounds. The research group is studying the global changes of H3K9 methylation by single or combined toxic chemicals. They will study the gene-specific promoter H3K9 methylation induced by nickel and other toxic chemicals using ChlP-onchip and analyze gene expression alterations as a consequence of these acquired epigenetic marks. The group is also studying the interplay between alterations of H3K9 methylation and DNA methylation at a gene-specific and global level in BEAS-2B cells following exposure to nickel and other toxic chemicals. Finally, the researchers will determine the importance of H3K9 promoter methylation in chemical induced cell transformation.