Influence of Arsenic on Global Levels of Histone Posttranslational Modifications: a Review of the Literature and Challenges in the Field

Abstract

Arsenic is a human carcinogen and also increases the risk for non-cancer outcomes. Arsenic-induced epigenetic dysregulation may contribute to arsenic toxicity. Although there are several reviews on arsenic and epigenetics, these have largely focused on DNA methylation. Here, we review investigations of the effects of arsenic on global levels of histone posttranslational modifications (PTMs). Multiple studies have observed that arsenic induces higher levels of H3 lysine 9 dimethylation (H3K9me2) and also higher levels of H3 serine 10 phosphorylation (H3S10ph), which regulate chromosome segregation. In contrast, arsenic causes a global loss of H4K16ac, a histone PTM that is a hallmark of human cancers. Although the findings for other histone PTMs have not been entirely consistent across studies, we discuss biological factors which may contribute to these inconsistencies, including differences in the dose, duration, and type of arsenic species examined; the tissue or cell line evaluated; differences by sex; and exposure timing. We also discuss two important considerations for the measurement of histone PTMs: proteolytic cleavage of histones and arsenic-induced alterations in histone expression.

Keywords: Arsenic; Histone posttranslational modifications.

Figure 1

Nucleosome structure. The basic unit of chromatin is the nucleosome, which is composed of 147 base pairs of DNA wrapped around a histone octamer. The histone octamer is comprised of two copies of each of the four core histone proteins: H2A, H2B, H3, and H4. Histones H2A and H2B form two dimers, while two copies of histones H3 and H4 form a tetramer. (Adapted from [107] by permission from Macmillan Publishers Ltd.)