Kabuki syndrome stem cell models reveal locus specificity of histone methyltransferase 2D (KMT2D/MLL4).
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
28 10 2022
28 10 2022
Historique:
received:
14
02
2022
revised:
07
05
2022
accepted:
18
05
2022
pubmed:
1
6
2022
medline:
2
11
2022
entrez:
31
5
2022
Statut:
ppublish
Résumé
Kabuki syndrome is frequently caused by loss-of-function mutations in one allele of histone 3 lysine 4 (H3K4) methyltransferase KMT2D and is associated with problems in neurological, immunological and skeletal system development. We generated heterozygous KMT2D knockout and Kabuki patient-derived cell models to investigate the role of reduced dosage of KMT2D in stem cells. We discovered chromosomal locus-specific alterations in gene expression, specifically a 110 Kb region containing Synaptotagmin 3 (SYT3), C-Type Lectin Domain Containing 11A (CLEC11A), Chromosome 19 Open Reading Frame 81 (C19ORF81) and SH3 And Multiple Ankyrin Repeat Domains 1 (SHANK1), suggesting locus-specific targeting of KMT2D. Using whole genome histone methylation mapping, we confirmed locus-specific changes in H3K4 methylation patterning coincident with regional decreases in gene expression in Kabuki cell models. Significantly reduced H3K4 peaks aligned with regions of stem cell maps of H3K27 and H3K4 methylation suggesting KMT2D haploinsufficiency impact bivalent enhancers in stem cells. Preparing the genome for subsequent differentiation cues may be of significant importance for Kabuki-related genes. This work provides a new insight into the mechanism of action of an important gene in bone and brain development and may increase our understanding of a specific function of a human disease-relevant H3K4 methyltransferase family member.
Identifiants
pubmed: 35640156
pii: 6594512
doi: 10.1093/hmg/ddac121
pmc: PMC9616574
doi:
Substances chimiques
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Histones
0
MLL4 protein, human
EC 2.1.1.43
KMT2D protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3715-3728Subventions
Organisme : NCI NIH HHS
ID : P01 CA196539
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS111997
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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