DNA methylation analysis of multiple imprinted DMRs in Sotos syndrome reveals IGF2-DMR0 as a DNA methylation-dependent, P0 promoter-specific enhancer.
CRISPR-Cas Systems
Child
Child, Preschool
DNA Methylation
Enhancer Elements, Genetic
Epigenome
Female
Gene Deletion
Genomic Imprinting
HEK293 Cells
Histone-Lysine N-Methyltransferase
/ genetics
Histones
/ chemistry
Humans
Infant
Infant, Newborn
Insulin-Like Growth Factor II
/ genetics
Lysine
/ chemistry
Male
Phenotype
Point Mutation
Promoter Regions, Genetic
Sotos Syndrome
/ genetics
NSD1
Beckwith‐Wiedemann syndrome
epigenome editing
genomic imprinting
histone modifications
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
13
07
2019
revised:
01
10
2019
accepted:
14
11
2019
entrez:
10
1
2020
pubmed:
10
1
2020
medline:
21
7
2020
Statut:
ppublish
Résumé
Haploinsufficiency of NSD1, which dimethylates histone H3 lysine 36 (H3K36), causes Sotos syndrome (SoS), an overgrowth syndrome. DNMT3A and DNMT3B recognizes H3K36 trimethylation (H3K36me3) through PWWP domain to exert de novo DNA methyltransferase activity and establish imprinted differentially methylated regions (DMRs). Since decrease of H3K36me3 and genome-wide DNA hypomethylation in SoS were observed, hypomethylation of imprinted DMRs in SoS was suggested. We explored DNA methylation status of 28 imprinted DMRs in 31 SoS patients with NSD1 defect and found that hypomethylation of IGF2-DMR0 and IG-DMR in a substantial proportion of SoS patients. Luciferase assay revealed that IGF2-DMR0 enhanced transcription from the IGF2 P0 promoter but not the P3 and P4 promoters. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) revealed active enhancer histone modifications at IGF2-DMR0, with high enrichment of H3K4me1 and H3 lysine 27 acetylation (H3K27ac). CRISPR-Cas9 epigenome editing revealed that specifically induced hypomethylation at IGF2-DMR0 increased transcription from the P0 promoter but not the P3 and P4 promoters. NSD1 knockdown suggested that NSD1 targeted IGF2-DMR0; however, IGF2-DMR0 DNA methylation and IGF2 expression were unaltered. This study could elucidate the function of IGF2-DMR0 as a DNA methylation dependent, P0 promoter-specific enhancer. NSD1 may play a role in the establishment or maintenance of IGF2-DMR0 methylation during the postimplantation period.
Identifiants
pubmed: 31914674
doi: 10.1096/fj.201901757R
pmc: PMC6973060
doi:
Substances chimiques
Histones
0
IGF2 protein, human
0
Insulin-Like Growth Factor II
67763-97-7
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
NSD1 protein, human
EC 2.1.1.43
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
960-973Informations de copyright
© 2019 The Authors. The FASEB Journal published by Wiley Periodicals, Inc. on behalf of Federation of American Societies for Experimental Biology.
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