Beyond the Usual Suspects: Examining the Role of Understudied Histone Variants in Breast Cancer.

The incorporation of histone variants has structural ramifications on nucleosome dynamics and stability. Due to their unique sequences, histone variants can alter histone-histone or histone-DNA interactions, impacting the folding of DNA around the histone octamer and the overall higher-order structure of chromatin fibers. These structural modifications alter chromatin compaction and accessibility of DNA by transcription factors and other regulatory proteins to influence gene regulatory processes such as DNA damage and repair, as well as transcriptional activation or repression. Histone variants can also generate a unique interactome composed of histone chaperones and chromatin remodeling complexes. Any of these perturbations can contribute to cellular plasticity and the progression of human diseases. Here, we focus on a frequently overlooked group of histone variants lying within the four human histone gene clusters and their contribution to breast cancer.

Epigenomic reprogramming in iAs-mediated carcinogenesis.

Arsenic is a naturally occurring metal carcinogen found in the Earth's crust. Millions of people worldwide are chronically exposed to arsenic through drinking water and food. Exposure to inorganic arsenic has been implicated in many diseases ranging from acute toxicities to malignant transformations. Despite the well-known deleterious health effects of arsenic exposure, the molecular mechanisms in arsenic-mediated carcinogenesis are not fully understood. Since arsenic is non-mutagenic, the mechanism by which arsenic causes carcinogenesis is via alterations in epigenetic-regulated gene expression. There are two possible ways by which arsenic may modify the epigenome-indirectly through an arsenic-induced generation of reactive oxygen species which then impacts chromatin remodelers, or directly through interaction and modulation of chromatin remodelers. Whether directly or indirectly, arsenic modulates epigenetic gene regulation and our understanding of the direct effect of this modulation on chromatin structure is limited. In this chapter we will discuss the various ways by which inorganic arsenic affects the epigenome with consequences in health and disease.

Arsenic-induced epigenetic changes in cancer development.

Arsenic is a ubiquitous metalloid whose high levels of toxicity pose major health concerns to millions of people worldwide by increasing susceptibility to various cancers and non-cancer illnesses. Since arsenic is not a mutagen, the mechanism by which it causes changes in gene expression and disease pathogenesis is not clear. One possible mechanism is through generation of reactive oxygen species. Another equally important mechanism still very much in its infancy is epigenetic dysregulation. In this review, we discuss recent discoveries underlying arsenic-induced epigenetic changes in cancer development. Importantly, we highlight the proposed mechanisms targeted by arsenic to drive oncogenic gene expression.

Chronic Exposure to Cadmium Induces Differential Methylation in Mice Spermatozoa.

Cadmium exposure is ubiquitous and has been linked to diseases including cancers and reproductive defects. Since cadmium is nonmutagenic, it is thought to exert its gene dysregulatory effects through epigenetic reprogramming. Several studies have implicated germline exposure to cadmium in developmental reprogramming. However, most of these studies have focused on maternal exposure, while the impact on sperm fertility and disease susceptibility has received less attention. In this study, we used reduced representation bisulfite sequencing to comprehensively investigate the impact of chronic cadmium exposure on mouse spermatozoa DNA methylation. Adult male C57BL/J6 mice were provided water with or without cadmium chloride for 9 weeks. Sperm, testes, liver, and kidney tissues were collected at the end of the treatment period. Cadmium exposure was confirmed through gene expression analysis of metallothionein-1 and 2, 2 well-known cadmium-induced genes. Analysis of sperm DNA methylation changes revealed 1788 differentially methylated sites present at regulatory regions in sperm of mice exposed to cadmium compared with vehicle (control) mice. Furthermore, most of these differential methylation changes positively correlated with changes in gene expression at both the transcription initiation stage as well as the splicing levels. Interestingly, the genes targeted by cadmium exposure are involved in several critical developmental processes. Our results present a comprehensive analysis of the sperm methylome in response to chronic cadmium exposure. These data, therefore, highlight a foundational framework to study gene expression patterns that may affect fertility in the exposed individual as well as their offspring, through paternal inheritance.

Monosomy X in Female Mice Influences the Regional Formation and Augments the Severity of Angiotensin II-Induced Aortopathies.

OBJECTIVE: Turner syndrome women (monosomy X) have high risk of aortopathies consistent with a role for sex chromosomes in disease development. We demonstrated that sex chromosomes influence regional development of Ang II (angiotensin II)-induced aortopathies in mice. In this study, we determined if the number of X chromosomes regulates regional development of Ang II-induced aortopathies. Approach and Results: We used females with varying numbers of X chromosomes (XX female mice [XXF] or XO female mice [XOF]) on an C57BL/6J (ascending aortopathies) or low-density lipoprotein receptor deficient (Ldlr-/-) background (descending and abdominal aortopathies) compared with XY males (XYM). To induce aortopathies, mice were infused with Ang II. XOF (C57BL/6J) exhibited larger percent increases in ascending aortic lumen diameters than Ang II-infused XXF or XYM. Ang II-infused XOF (Ldlr-/-) exhibited similar incidences of thoracic (XOF, 50%; XYM, 71%) and abdominal aortopathies (XOF, 83%; XYM, 71%) as XYM, which were greater than XXF (XXF, 0%). Abdominal aortic lumen diameters and maximal external diameters were similar between XOF and XYM but greater than XXF, and these effects persisted with extended Ang II infusions. Larger aortic lumen diameters, abdominal aortopathy incidence (XXF, 20%; XOF, 75%), and maximal aneurysm diameters (XXF, 1.02±0.17; XOF, 1.96±0.32 mm; P=0.027) persisted in ovariectomized Ang II-infused XOF mice. Data from RNA-seq demonstrated that X chromosome genes that escape X-inactivation (histone lysine demethylases Kdm5c and Kdm6a) exhibited lower mRNA abundance in aortas of XOF than XXF (P=0.033 and 0.024, respectively). Conversely, DNA methylation was higher in aortas of XOF than XXF (P=0.038). CONCLUSIONS: The absence of a second X chromosome promotes diffuse Ang II-induced aortopathies in females.