Abstract
The regulation of chromatin by epigenetic mechanisms plays a central role in gene expression and is essential for development and maintenance of cell identity and function. Aberrant chromatin regulation is observed in many diseases where it leads to defects in epigenetic gene regulation resulting in pathological gene expression programmes. These defects are caused by inherited or acquired mutations in genes encoding enzymes that deposit or remove DNA and histone modifications and that shape chromatin architecture. Chromatin deregulation often results in neurodevelopmental disorders and intellectual disabilities, frequently linked to physical and developmental abnormalities, but can also cause neurodegenerative diseases, immunodeficiency, or muscle wasting syndromes. Epigenetic diseases can either be of monogenic origin or manifest themselves as complex multifactorial diseases such as in congenital heart disease, autism spectrum disorders, or cancer in which mutations in chromatin regulators are contributing factors. The environment directly influences the epigenome and can induce changes that cause or predispose to diseases through risk factors such as stress, malnutrition or exposure to harmful chemicals. The plasticity of chromatin regulation makes targeting the enzymatic machinery an attractive strategy for therapeutic intervention and an increasing number of small molecule inhibitors against a variety of epigenetic regulators are in clinical use or under development. In this review, we will give an overview of the molecular lesions that underlie epigenetic diseases, and we will discuss the impact of the environment and prospects for epigenetic therapies.
Highlights
Epigenetics describes biological phenomena resulting in heritable changes to gene expression that occur without alterations to the DNA sequence
Selective gene expression from the genome is shaped by epigenetic mechanisms and as a consequence cells vary from tissue to tissue in their epigenomes whilst the genome remains largely unchanged
The primary and repeating units of chromatin are the nucleosomes, which consist of 147 bp of DNA wrapped around an octamer of histone proteins formed by two copies of each of the core histones H2A, H2B, H3 and H4, with the linker histone H1 bound to the DNA between nucleosomes
Summary
Epigenetics describes biological phenomena resulting in heritable changes to gene expression that occur without alterations to the DNA sequence. A similar situation is found in Kabuki syndrome, which can result from loss-of function mutations in either the H3K4 MTase MLL2 or the H3K27 de-methylase KDM6A (Lederer et al 2012; Miyake et al 2013; Ng et al 2010) In both cases, mutations presumably lead to reduced active marks and increased repressive marks in the diseased state, possibly causing reduced gene expression at common target loci since MLL2 and KDM6a have been show to reside in the same protein complex. Nutrition The link between nutrition and epigenetics is exceptionally important as nutrients and bioactive food components directly influence epigenetic events and impact on gene expression at the transcription level (discussed in JimenezChillaron et al 2012) Nutrients such as vitamin B-12, choline, folate and methionine affect histone and DNA methylation through their involvement in 1-carbon metabolism and were shown to be capable of increasing DNA methylation levels at specific loci in animal models (Waterland 2006) and humans (Waterland et al 2010). The ongoing development of drugs with improved characteristics and genomic and epigenomic profiling promise to catalyse personalised treatment strategies that will allow effective use of epigenetic drugs alongside other drugs in combination therapies tailored to a patient’s condition
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
