Epigenetics and Human Disease

Abstract

SUMMARYGenetic causes for human disorders are being discovered at an unprecedented pace. A growing subclass of disease-causing mutations involves changes in the epigenome or in the abundance and activity of proteins that regulate chromatin structure. This article focuses on research that has uncovered human diseases that stem from such epigenetic deregulation. Disease may be caused by direct changes in epigenetic marks, such as DNA methylation, commonly found to affect imprinted gene regulation. Also described are disease-causing genetic mutations in epigenetic modifiers that either affect chromatin in trans or have a cis effect in altering chromatin configuration.

A Structural Perspective on Readout of Epigenetic Histone and DNA Methylation Marks

“…A growing number of human diseases ranging from imprinting disorders (e.g., Beckwith -Wiedemann, Prader-Willi, and Angelman syndromes) to repeat-instability diseases (e.g., fragile X syndrome and facioscapulohumeral muscular dystrophy) and cancer are associated with aberrant DNA methylation (as discussed in Robertson 2005;Jones 2011, 2014;Zoghbi and Beaudet 2014). This may involve the improper establishment or maintenance of methylation, resulting in the alteration of chromatin states and/or nucleosome positioning (reviewed in Baylin and Jones 2011).…”

“…A second 5mC-binding protein, MeCP2, is of interest because of its role in the maintenance of neuronal function; mutations in the MECP2 gene are responsible for the majority of cases of Rett syndrome, a late-onset autism spectrum disorder (discussed more extensively in Zhang 2014 andBeaudet 2014; see also Amir et al 1999). The crystal structure of MeCP2 bound to a 5mCpG/ 5mCpG-containing DNA duplex (Fig.…”

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

“…Alterations in this mechanism can lead to pathological dysfunctions. 8,9 In the present work, we focus on the 3 major categories of epigenetic mechanisms: DNA methylation, posttranslational histone modifications (PTHMs), and RNA-based mechanisms. These mechanisms are involved in the altered pattern of gene expression that underlies the progressive insulin resistance and insulin insufficiency of T2DM (Fig.…”

Targeting the epigenome in malignant pleural mesothelioma

“…Whereas genome wide DNA demethylation may be attributable to deficient DNA repair (18,19), decreased DNA methyltransferase 1 expression (20,21), glycosylase-mediated excision of 5-MC (16), and aberrant expression/targeting of TET proteins (22), the mechanisms mediating this phenomenon have not been fully elucidated. Genome-wide DNA demethylation facilitates de-repression of imprinted alleles, endogenous retroviruses, and transposable elements, thereby inducing genomic instability (11,23). Global DNA demethylation also results in de-repression of a variety of cancer-germline (CG) genes that are silent in normal somatic cells, yet exhibit stage-specific expression during germ cell development in testes or ovary (24).…”