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Article

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

1
Université de Paris, Epigenetics and Cell Fate, CNRS UMR7216, 75013 Paris, France
2
Imagine Institute, Université de Paris, Clinical Genetics, INSERM UMR 1163, Necker Enfants Malades Hospital, 75015 Paris, France
3
Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
*
Author to whom correspondence should be addressed.
Present address: Scipio Bioscience, ICM-iPEPS, Hôpital Pitié Salpêtrière, 75013 Paris, France.
Academic Editor: Bekim Sadikovic
Int. J. Mol. Sci. 2021, 22(7), 3735; https://doi.org/10.3390/ijms22073735
Received: 18 March 2021 / Revised: 30 March 2021 / Accepted: 1 April 2021 / Published: 3 April 2021
(This article belongs to the Special Issue Genome-Wide DNA Methylation Analysis in Hereditary Disorders)
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. View Full-Text
Keywords: rare diseases; DNA methylation profiling; histone methylation; biomarkers; epigenetic crosstalks rare diseases; DNA methylation profiling; histone methylation; biomarkers; epigenetic crosstalks
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MDPI and ACS Style

Velasco, G.; Ulveling, D.; Rondeau, S.; Marzin, P.; Unoki, M.; Cormier-Daire, V.; Francastel, C. Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders. Int. J. Mol. Sci. 2021, 22, 3735. https://doi.org/10.3390/ijms22073735

AMA Style

Velasco G, Ulveling D, Rondeau S, Marzin P, Unoki M, Cormier-Daire V, Francastel C. Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders. International Journal of Molecular Sciences. 2021; 22(7):3735. https://doi.org/10.3390/ijms22073735

Chicago/Turabian Style

Velasco, Guillaume, Damien Ulveling, Sophie Rondeau, Pauline Marzin, Motoko Unoki, Valérie Cormier-Daire, and Claire Francastel. 2021. "Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders" International Journal of Molecular Sciences 22, no. 7: 3735. https://doi.org/10.3390/ijms22073735

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