Epigenetic inheritance and the missing heritability

Abstract

Genome-wide association studies of complex physiological traits and diseases consistently found that associated genetic factors, such as allelic polymorphisms or DNA mutations, only explained a minority of the expected heritable fraction. This discrepancy is known as "missing heritability", and its underlying factors and molecular mechanisms are not established. Epigenetic programs may account for a significant fraction of the "missing heritability." Epigenetic modifications, such as DNA methylation and chromatin assembly states, reflect the high plasticity of the genome and contribute to stably alter gene expression without modifying genomic DNA sequences. Consistent components of complex traits, such as those linked to human stature/height, fertility, and food metabolism or to hereditary defects, have been shown to respond to environmental or nutritional condition and to be epigenetically inherited. The knowledge acquired from epigenetic genome reprogramming during development, stem cell differentiation/de-differentiation, and model organisms is today shedding light on the mechanisms of (a) mitotic inheritance of epigenetic traits from cell to cell, (b) meiotic epigenetic inheritance from generation to generation, and (c) true transgenerational inheritance. Such mechanisms have been shown to include incomplete erasure of DNA methylation, parental effects, transmission of distinct RNA types (mRNA, non-coding RNA, miRNA, siRNA, piRNA), and persistence of subsets of histone marks.

Fig. 1

DNA methylation/demethylation mechanics. a Methyl groups (green circles) are transferred to C in order to generate 5-mC. DNA methyltransferases (DNMT) catalyze this process. In the “active DNA demethylation” the TET DNA demethylase converts 5-mC to 5-hmC, which is further processed to 5-fC and 5-caC. These residues are targets for the DNA repair pathway, whose most critical component is the hTDG, which is responsible also for the repair of U:G and T:G mismatches. DNA demethylation can also occur through spontaneous cytosine deamination, which is catalyzed by AID/APOBEC enzymes. This gives rise to 5-hmU and T bases. Transient U:G and T:G mismatches can be repaired by the TDG/BER pathway. b De novo and maintenance methylation occur using unmethylated DNA and hemimethylated/post-replication DNA as templates for DNMT enzymes. In the absence of maintenance methylation, progressive dilution of 5-mC or its oxidized derivatives at DNA replication can determine the appearance of unmethylated DNA. This process is known as “passive DNA demethylation”

Fig. 2

Histone modifications and DNA cooperate in re-shaping chromatin organization and regulating gene expression. a (left) De novo DNA methylation occurs on unmethylated DNA. It is catalyzed by the DNMT3, whose subunits can be positioned in proximity of their target sites through physical interaction with unmethylated H3K4. a (right) Maintenance DNA methylation occurs during the DNA replication and is catalyzed by the DNMT1. Uhrf1 and proliferating cell nuclear antigen (PCNA) associates to DNMT1 and recruit it to the replication fork, concentrating its activity on hemimethylated DNA. The Uhrf1 TTD domain interacts with H3K9me. This binding allows a faithful propagation of DNA methylation patterns throughout mitosis. b (top) HDAC and the transcription factor complex (TFC) can be recruited on sensitive promoters, leading to histone deacetylation. HMT-driven methylation of the histone tails causes tight wrapping of DNA around nucleosome cores and inhibition of gene expression. b (bottom) The accumulation of HAT-driven histone acetylation determines DNA relaxation around the nucleosomes surrounding HAT-sensitive promoters; this leads to increased transcription and gene expression. c Methylation of H3K9 plays a central role in non-DNA-dependent mechanisms of regulation of gene activity (top). Hsp90 has a strong effect on the histone code via stabilization of KDM4B, which demethylases H3K9 (middle). Non-coding RNAs alter the histone code through siRNA-dependent mechanisms that lead to direct competition between BORDERLINE ncRNAs and H3K9me for binding to the HP1 proteins, such as Swi6. This occurs at heterochromatin/euchromatin boundary sites and counteracts the spreading of heterochromatin into neighboring euchromatin (bottom). A acetyl groups, M methyl groups, HAT histone acetyltranferase, HDAC histone deacetylase, HMT histone methyltransferase

Fig. 3

Epigenetic factors influencing human development and growth. The human life cycle is represented in the scheme. Major factors influencing the epigenetic programs and the maintenance of epigenetic patterns at both DNA and chromatin (histone code) levels are the maternal lifestyle during pregnancy and the personal exposure to harmful environments during post-natal growth and adult life