Understanding the mechanistic insight of arsenic exposure and decoding the histone cipher

Abstract

Background

The study of heritable epigenetic changes in arsenic exposure has intensified over the last decade. Groundwater arsenic contamination causes a great threat to humans and, to date, no accurate measure has been formulated for remediation. The fascinating possibilities of epi-therapeutics identify the need for an in-depth mechanistic understanding of the epigenetic landscape.

Objective

In this comprehensive review, we have set to analyze major studies pertaining to histone post-translational modifications in arsenic-mediated disease development and carcinogenesis during last ten years (2008–2018).

Results

The role of the specific histone marks in arsenic toxicity has been detailed. A comprehensive list that includes major arsenic-induced histone modifications identified for the last 10 years has been documented and details of different states of arsenic, organisms, exposure type, study platform, and findings were provided. An arsenic signature panel was suggested to help in early prognosis. An attempt has been made to identify the grey areas of research.

Prospects

Future prospective multi-target analyses of the inter-molecular crosstalk among different histone marks are needed to be explored further in order to understand the mechanism of arsenic toxicity and carcinogenicity and to confirm the suitability of these epi-marks as prognostic markers.

Introduction

Chromatin contains information that encodes the basic components to build-up an organism as a whole. With nearly 3.2 × 10⁹ nucleotides making up the DNA content in the nucleus of each human cell alone (Brown, 2002), it is a massive factory of molecules that regulate required functions within the cell: metabolism, transport, cell division, repair, etc. Approximately 147 base pairs of DNA wrap around the histone octamer core composed of canonical histone proteins and their variants (Cosgrove and Wolberger, 2005). Approximately 20,000 genes are actively transcribed from the human genome, which accounts for 3300 mega base-pairs according to the recently updated database (GRCh38.p12, NCBI). Of the largest chromosomes, hChr-1 (human chromosome-1) has approximately 2000 protein-coding genes while the smallest hChr-Y has approximately 71 identified protein-coding genes; the hChr-19 is almost 1/4th time smaller than hChr-1, yet it has 1500 protein-coding genes. Thus, the size of a chromosome might not be positively correlated with the total number of genes that it can house and hence, it is possible that a highly orchestrated and stratified mechanism exists within this chromatin micro-environment for regulation of gene expression within the cell. In a very recent study, using single cell Hi-C, the authors showed how the chromatin compartmentalizes into an active and in-active segment, the former being closer to the nuclear membrane (Stevens et al., 2017). Accessibility to the chromatin to the interacting molecules (transcription factors, polymerases, ATP dependent chromatin remodeling complexes, etc.) ultimately determines the fate of the cell (Armstrong et al., 2018; Lamparter et al., 2017; Zhou et al., 2016). Further, epigenetic alteration of the histone and the DNA fine-tunes this accessibility. For example, N terminal histone tail plays a critical role in determining the epigenetic profile of a section of chromosome. Specific enzymatic activities chemically modify these tails like acetylation, sumoylation, ribosylation, ubiquitination, and methylation which may increase or decrease the activity of the genomic niche (Xu et al., 2017). To add on to these mechanisms, ATP dependent chromatin remodelers act like motors and identify the characteristic DNA and histone elements within the nucleosomes as well as extra-nucleosomal regions and translocate the nucleosomal core leading to alteration in accessibility of the chromatin (Paul and Bartholomew, 2018; Tyagi et al., 2016).

In this review, we refer to the array of histone post-translational modifications (PTMs) as the histone “code”, encrypting various functions of the cell-like transcriptional regulation, DNA damage repair and replication, progression of the cell cycle and its regulation and developmental processes processes (Cosgrove and Wolberger, 2005; Escargueil et al., 2008; Jenuwein and Allis, 2001; Paquin and Howlett, 2018; Williamson et al., 2012). Different cells have different ways to respond to certain cues within the micro-environment, leading to changes in histone signatures. An ensemble of these histone codes literally forms a “cypher” that are being regularly read by the chromatin-binding proteins that regulate normal as well as abnormal processes within the cells. For example, the change of a stem cell towards a more committed or differentiated form changes the global histone signatures significantly (Corley and Kroll, 2015). Owing to its covalent nature, these modifications are reversible and have been researched for targeted therapeutic strategies. For example, hypo-acetylation of H4 is associated with the breast cancer malignancy while acetylation of H3K9 has been associated with the hepatocellular carcinoma (Suzuki et al., 2009a). This dynamic property of the histone modifying enzymes has attracted much attention from the pharmaceutical companies in recent years (Liu et al., 2006; Oh et al., 2015; Rahman and Grundy, 2011). Unfortunately, not much is known about arsenic-induced alterations in theese post-translational modifications, although chronic exposure to arsenic affects nearly 150 million people in about 70 countries with ever increasing evidence of cancerous outcomes (Ahsan et al., 2006; Garcia-Esquinas et al., 2013; Mendez et al., 2017).

Arsenic, a classified group 1 carcinogenic metalloid, enters our system through environmental exposure (drinking water, dietary and/or occupational sources) leading to a plethora of human health disorders in the exposed population across the globe (WHO, 2010). A number of comprehensive reviews have described the mode of genotoxicity of arsenicosis: The major pathways identified are those involved in DNA damage repair pathway, cell cycle checkpoint regulators, oxidative stress mediators including nuclear and mitochondrial counterparts, etc. (Argos, 2015; Bhattacharjee et al., 2016, 2013a). In order to delineate the of role histone PTMs as a susceptibility factor and/or causal factor in arsenic toxicity, we have restricted our search on these major pathways: transcriptional regulation, oxidative stress, DNA damage repair pathway, and cell cycle check point regulators. Relevant search was conducted using keywords like “arsenic-induced histone post-translational modifications”, “transcriptional regulation”, “DNA damage”, “cell cycle check point regulators”, and “oxidative stress”. In this review, we will describe what is known about arsenic-induced toxicity but will focus mainly on the potential of identifying histone modifications as epigenetic biomarkers and on how epigenetic code alters with arsenic exposure.