Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders.

Guillaume Velasco,Sophie Rondeau,Valérie Cormier-Daire,Pauline Marzin,Claire Francastel,Damien Ulveling,Motoko Unoki

doi:10.3390/ijms22073735

Abstract

DNA methylation (DNAme) profiling is used to establish specific biomarkers to improve the diagnosis of patients with inherited neurodevelopmental disorders and to guide mutation screening. In the specific case of mendelian disorders of the epigenetic machinery, it also provides the basis to infer mechanistic aspects with regard to DNAme determinants and interplay between histone and DNAme that apply to humans. Here, we present comparative methylomes from patients with mutations in the de novo DNA methyltransferases DNMT3A and DNMT3B, in their catalytic domain or their N-terminal parts involved in reading histone methylation, or in histone H3 lysine (K) methylases NSD1 or SETD2 (H3 K36) or KMT2D/MLL2 (H3 K4). We provide disease-specific DNAme signatures and document the distinct consequences of mutations in enzymes with very similar or intertwined functions, including at repeated sequences and imprinted loci. We found that KMT2D and SETD2 germline mutations have little impact on DNAme profiles. In contrast, the overlapping DNAme alterations downstream of NSD1 or DNMT3 mutations underlines functional links, more specifically between NSD1 and DNMT3B at heterochromatin regions or DNMT3A at regulatory elements. Together, these data indicate certain discrepancy with the mechanisms described in animal models or the existence of redundant or complementary functions unforeseen in humans.

Highlights

Université de Paris, Epigenetics and Cell Fate, CNRS UMR7216, 75013 Paris, France; Imagine Institute, Université de Paris, Clinical Genetics, INSERM UMR 1163, Necker Enfants Malades
In the context where DNA methylation (DNAme) is established by de novo DNMT3 enzymes, which themselves act as readers of histone methylation in complex regulatory networks, we aimed at profiling DNAme alterations in a set of rare developmental diseases caused by
We included patients with genome-wide DNAme alterations caused by mutations in non-DNA methyltransferases (DNMTs) factors, i.e., in transcription factors ZBTB24 and CDCA7 (ICF2 and ICF3) or in the chromatin remodeler HELLS (ICF4), for which little overlap of DNAme alterations with that of ICF1 patients had already been documented [39]

Summary

Introduction

Université de Paris, Epigenetics and Cell Fate, CNRS UMR7216, 75013 Paris, France; Imagine Institute, Université de Paris, Clinical Genetics, INSERM UMR 1163, Necker Enfants Malades. We present comparative methylomes from patients with mutations in the de novo DNA methyltransferases DNMT3A and DNMT3B, in their catalytic domain or their N-terminal parts involved in reading histone methylation, or in histone H3 lysine (K) methylases NSD1 or SETD2 (H3 K36) or KMT2D/MLL2 (H3 K4). The overlapping DNAme alterations downstream of NSD1 or DNMT3 mutations underlines functional links, between NSD1 and DNMT3B at heterochromatin regions or DNMT3A at regulatory elements. Together, these data indicate certain discrepancy with the mechanisms described in animal models or the existence of redundant or complementary functions unforeseen in humans. DNA methylation (DNAme) has been assigned major roles in fundamental biological processes that include the regulation of gene expression programs and the silencing of inactiveX chromosome in females, imprinted genes, transposons, and repetitive elements [2,3,4]

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