Stability and Lability of Parental Methylation Imprints in Development and Disease.

Sabina Farhadova,Melisa Gomez-Velazquez,Robert Feil

doi:10.3390/genes10120999

Abstract

DNA methylation plays essential roles in mammals. Of particular interest are parental methylation marks that originate from the oocyte or the sperm, and bring about mono-allelic gene expression at defined chromosomal regions. The remarkable somatic stability of these parental imprints in the pre-implantation embryo—where they resist global waves of DNA demethylation—is not fully understood despite the importance of this phenomenon. After implantation, some methylation imprints persist in the placenta only, a tissue in which many genes are imprinted. Again here, the underlying epigenetic mechanisms are not clear. Mouse studies have pinpointed the involvement of transcription factors, covalent histone modifications, and histone variants. These and other features linked to the stability of methylation imprints are instructive as concerns their conservation in humans, in which different congenital disorders are caused by perturbed parental imprints. Here, we discuss DNA and histone methylation imprints, and why unravelling maintenance mechanisms is important for understanding imprinting disorders in humans.

Highlights

Epigenetic modification of the genome by cytosine methylation—which in mammals is found atCpG dinucleotides—plays diverse roles in the control of gene expression [1,2]
Methylation imprints at maternal imprinting control regions’ (ICRs) are acquired in the adult animal, during the final stages of oogenesis when oocytes expand in size [21]
Biochemical studies show that similar mechanisms maintain repressed chromatin and DNA methylation at ICRs and endogenous retroviruses (ERVs)— at intracisternal A particles (IAPs)—with involvement of the same nuclear complexes including specific Krüppel associated box (KRAB) domain zinc finger proteins (ZFPs), KAP1, SETDB1, HP1γ, ATRX/DAXX, and variant histone H3.3 [33]

Summary

Introduction

Epigenetic modification of the genome by cytosine methylation—which in mammals is found at. Methylation imprints at maternal ICRs are acquired in the adult animal, during the final stages of oogenesis when oocytes expand in size [21] Despite this divergence in timing [22], both in male and female germ cells the acquisition process involves de novo DNA methyltransferase (DNMT)3A [23,24]. More than a thousand CpG islands become methylated during oogenesis, but after fertilization, only some twenty of these maintain their maternal methylation imprint during preimplantation development [20,21] These are the maternal ICRs. In order to understand this specificity, it is important to understand the embryonic maintenance of differential methylation at ICRs [17], a process that strictly requires the maintenance methyltransferase DNMT1 [32]. Methylation Phenotype due to Loss of Expression, or Knock-Down, in Somatic Cells or Embryos

Embryonic Stability of Germline-Acquired DNA-Methylation Imprints

Protection of ICRs Against de Novo DNA Methylation

New Insights into Maintenance Mechanisms from Imprinting Disorders

Conclusions