A super enhancer controls expression and chromatin architecture within the MHC class II locus.
B-Lymphocytes
Binding Sites
/ genetics
Blood Donors
Burkitt Lymphoma
/ pathology
CCCTC-Binding Factor
/ metabolism
CD4-Positive T-Lymphocytes
CRISPR-Cas Systems
Cell Line, Tumor
Chromatin
/ metabolism
Chromatin Assembly and Disassembly
/ genetics
Gene Deletion
Genes, MHC Class II
/ genetics
Genetic Loci
HLA-DQ alpha-Chains
/ genetics
HLA-DRB1 Chains
/ genetics
Haplotypes
Humans
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
/ genetics
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
03 02 2020
03 02 2020
Historique:
received:
12
04
2019
revised:
05
09
2019
accepted:
14
10
2019
pubmed:
23
11
2019
medline:
10
9
2020
entrez:
23
11
2019
Statut:
ppublish
Résumé
Super enhancers (SEs) play critical roles in cell type-specific gene regulation. The mechanisms by which such elements work are largely unknown. Two SEs termed DR/DQ-SE and XL9-SE are situated within the human MHC class II locus between the HLA-DRB1 and HLA-DQA1 genes and are highly enriched for disease-causing SNPs. To test the function of these elements, we used CRISPR/Cas9 to generate a series of mutants that deleted the SE. Deletion of DR/DQ-SE resulted in reduced expression of HLA-DRB1 and HLA-DQA1 genes. The SEs were found to interact with each other and the promoters of HLA-DRB1 and HLA-DQA1. DR/DQ-SE also interacted with neighboring CTCF binding sites. Importantly, deletion of DR/DQ-SE reduced the local chromatin interactions, implying that it functions as the organizer for the local three-dimensional architecture. These data provide direct mechanisms by which an MHC-II SE contributes to expression of the locus and suggest how variation in these SEs may contribute to human disease and altered immunity.
Identifiants
pubmed: 31753848
pii: jem.20190668
doi: 10.1084/jem.20190668
pmc: PMC7041702
pii:
doi:
Substances chimiques
CCCTC-Binding Factor
0
CTCF protein, human
0
Chromatin
0
HLA-DQ alpha-Chains
0
HLA-DQA1 antigen
0
HLA-DRB1 Chains
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM047310
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS092122
Pays : United States
Informations de copyright
© 2019 Majumder et al.
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