DNA methylation is of paramount importance for mammalian embryonic development. DNA methylation has numerous functions: it is implicated in the repression of transposons and genes, but is also associated with actively transcribed gene bodies and, in some cases, with gene activation per se. In recent years, sensitive technologies have been developed that allow the interrogation of DNA methylation patterns from a small number of cells. The use of these technologies has greatly improved our knowledge of DNA methylation dynamics and heterogeneity in embryos and in specific tissues. Combined with genetic analyses, it is increasingly apparent that regulation of DNA methylation erasure and (re-)establishment varies considerably between different developmental stages. In this Review, we discuss the mechanisms and functions of DNA methylation and demethylation in both mice and humans at CpG-rich promoters, gene bodies and transposable elements. We highlight the dynamic erasure and re-establishment of DNA methylation in embryonic, germline and somatic cell development. Finally, we provide insights into DNA methylation gained from studying genetic diseases. DNA methylation is essential for mammalian embryogenesis owing to its repression of transposons and genes, but it is also associated with gene activation. The recent use of sensitive technologies has revealed that DNA methylation dynamics vary considerably between embryonic, germline and somatic cell development, with implications for genetic diseases and cancer.

The diverse roles of DNA methylation in mammalian development and disease

Epigenetic research has accelerated rapidly in the twenty-first century, generating justified excitement and hope, but also a degree of hype. Here we review how the field has evolved over the last few decades and reflect on some of the recent advances that are changing our understanding of biology. We discuss the interplay between epigenetics and DNA sequence variation as well as the implications of epigenetics for cellular memory and plasticity. We consider the effects of the environment and both intergenerational and transgenerational epigenetic inheritance on biology, disease and evolution. Finally, we present some new frontiers in epigenetics with implications for human health.

/pdf/advances-in-epigenetics-link-genetics-to-the-environment-and-3a9hz9pcpi.pdf

Advances in epigenetics link genetics to the environment and disease

Mammalian sperm RNA is increasingly recognized as an additional source of paternal hereditary information beyond DNA. Environmental inputs, including an unhealthy diet, mental stresses and toxin exposure, can reshape the sperm RNA signature and induce offspring phenotypes that relate to paternal environmental stressors. Our understanding of the categories of sperm RNAs (such as tRNA-derived small RNAs, microRNAs, ribosomal RNA-derived small RNAs and long non-coding RNAs) and associated RNA modifications is expanding and has begun to reveal the functional diversity and information capacity of these molecules. However, the coding mechanism endowed by sperm RNA structures and by RNA interactions with DNA and other epigenetic factors remains unknown. How sperm RNA-encoded information is decoded in early embryos to control offspring phenotypes also remains unclear. Complete deciphering of the 'sperm RNA code' with regard to metabolic control could move the field towards translational applications and precision medicine, and this may lead to prevention of intergenerational transmission of obesity and type 2 diabetes mellitus susceptibility.

/pdf/sperm-rna-code-programmes-the-metabolic-health-of-offspring-ypuzqso9eo.pdf

Sperm RNA code programmes the metabolic health of offspring

Increasing evidence indicates that non-DNA sequence-based epigenetic information can be inherited across several generations in organisms ranging from yeast to plants to humans. This raises the possibility of heritable 'epimutations' contributing to heritable phenotypic variation and thus to evolution. Recent work has shed light on both the signals that underpin these epimutations, including DNA methylation, histone modifications and non-coding RNAs, and the mechanisms by which they are transmitted across generations at the molecular level. These mechanisms can vary greatly among species and have a more limited effect in mammals than in plants and other animal species. Nevertheless, common principles are emerging, with transmission occurring either via direct replicative mechanisms or indirect reconstruction of the signal in subsequent generations. As these processes become clearer we continue to improve our understanding of the distinctive features and relative contribution of DNA sequence and epigenetic variation to heritable differences in phenotype. 

/pdf/molecular-mechanisms-of-transgenerational-epigenetic-1738bd4q.pdf

Molecular mechanisms of transgenerational epigenetic inheritance

Adverse childhood experiences (ACEs) may be referred to by other terms (e.g., early life adversity or stress and childhood trauma) and have a lifelong impact on mental and physical health. For example, childhood trauma has been associated with posttraumatic stress disorder (PTSD), anxiety, depression, bipolar disorder, diabetes, and cardiovascular disease. The heritability of ACE-related phenotypes such as PTSD, depression, and resilience is low to moderate, and, moreover, is very variable for a given phenotype, which implies that gene by environment interactions (such as through epigenetic modifications) may be involved in the onset of these phenotypes. Currently, there is increasing interest in the investigation of epigenetic contributions to ACE-induced differential health outcomes. Although there are a number of studies in this field, there are still research gaps. In this review, the basic concepts of epigenetic modifications (such as methylation) and the function of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response are outlined. Examples of specific genes undergoing methylation in association with ACE-induced differential health outcomes are provided. Limitations in this field, e.g., uncertain clinical diagnosis, conceptual inconsistencies, and technical drawbacks, are reviewed, with suggestions for advances using new technologies and novel research directions. We thereby provide a platform on which the field of ACE-induced phenotypes in mental health may build.

/pdf/epigenetic-modifications-in-stress-response-genes-associated-2nxlugwc1o.pdf

Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma.

Identification, Characterization, and Heritability of Murine Metastable Epialleles: Implications for Non-genetic Inheritance.

RNA alternative splicing (AS) expands the regulatory potential of eukaryotic genomes. The mechanisms regulating liver-specific AS profiles and their contribution to liver function are poorly understood. Here, we identify a key role for the splicing factor RNA-binding Fox protein 2 (RBFOX2) in maintaining cholesterol homeostasis in a lipogenic environment in the liver. Using enhanced individual-nucleotide-resolution ultra-violet cross-linking and immunoprecipitation, we identify physiologically relevant targets of RBFOX2 in mouse liver, including the scavenger receptor class B type I (Scarb1). RBFOX2 function is decreased in the liver in diet-induced obesity, causing a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. Our findings demonstrate that specific AS programmes actively maintain liver physiology, and underlie the lipotoxic effects of obesogenic diets when dysregulated. Splice-switching oligonucleotides targeting this network alleviate obesity-induced inflammation in the liver and promote an anti-atherogenic lipoprotein profile in the blood, underscoring the potential of isoform-specific RNA therapeutics for treating metabolism-associated diseases. 

/pdf/liver-rbfox2-regulates-cholesterol-homeostasis-via-scarb1-1mw3e4a3.pdf

Elena Pahita

Papers

Identification, Characterization, and Heritability of Murine Metastable Epialleles: Implications for Non-genetic Inheritance.

Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice