TCF21 and AP-1 interact through epigenetic modifications to regulate coronary artery disease gene expression.
AP-1
Deacetylase
Epigenomics
Histone acetyltransferase
TCF21
Transcription
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
02 05 2019
02 05 2019
Historique:
received:
19
12
2018
accepted:
03
04
2019
entrez:
25
4
2019
pubmed:
25
4
2019
medline:
28
12
2019
Statut:
epublish
Résumé
Genome-wide association studies have identified over 160 loci that are associated with coronary artery disease. As with other complex human diseases, risk in coronary disease loci is determined primarily by altered expression of the causal gene, due to variation in binding of transcription factors and chromatin-modifying proteins that directly regulate the transcriptional apparatus. We have previously identified a coronary disease network downstream of the disease-associated transcription factor TCF21, and in work reported here extends these studies to investigate the mechanisms by which it interacts with the AP-1 transcription complex to regulate local epigenetic effects in these downstream coronary disease loci. Genomic studies, including chromatin immunoprecipitation sequencing, RNA sequencing, and protein-protein interaction studies, were performed in human coronary artery smooth muscle cells. We show here that TCF21 and JUN regulate expression of two presumptive causal coronary disease genes, SMAD3 and CDKN2B-AS1, in part by interactions with histone deacetylases and acetyltransferases. Genome-wide TCF21 and JUN binding is jointly localized and particularly enriched in coronary disease loci where they broadly modulate H3K27Ac and chromatin state changes linked to disease-related processes in vascular cells. Heterozygosity at coronary disease causal variation, or genome editing of these variants, is associated with decreased binding of both JUN and TCF21 and loss of expression in cis, supporting a transcriptional mechanism for disease risk. These data show that the known chromatin remodeling and pioneer functions of AP-1 are a pervasive aspect of epigenetic control of transcription, and thus, the risk in coronary disease-associated loci, and that interaction of AP-1 with TCF21 to control epigenetic features, contributes to the genetic risk in loci where they co-localize.
Sections du résumé
BACKGROUND
Genome-wide association studies have identified over 160 loci that are associated with coronary artery disease. As with other complex human diseases, risk in coronary disease loci is determined primarily by altered expression of the causal gene, due to variation in binding of transcription factors and chromatin-modifying proteins that directly regulate the transcriptional apparatus. We have previously identified a coronary disease network downstream of the disease-associated transcription factor TCF21, and in work reported here extends these studies to investigate the mechanisms by which it interacts with the AP-1 transcription complex to regulate local epigenetic effects in these downstream coronary disease loci.
METHODS
Genomic studies, including chromatin immunoprecipitation sequencing, RNA sequencing, and protein-protein interaction studies, were performed in human coronary artery smooth muscle cells.
RESULTS
We show here that TCF21 and JUN regulate expression of two presumptive causal coronary disease genes, SMAD3 and CDKN2B-AS1, in part by interactions with histone deacetylases and acetyltransferases. Genome-wide TCF21 and JUN binding is jointly localized and particularly enriched in coronary disease loci where they broadly modulate H3K27Ac and chromatin state changes linked to disease-related processes in vascular cells. Heterozygosity at coronary disease causal variation, or genome editing of these variants, is associated with decreased binding of both JUN and TCF21 and loss of expression in cis, supporting a transcriptional mechanism for disease risk.
CONCLUSIONS
These data show that the known chromatin remodeling and pioneer functions of AP-1 are a pervasive aspect of epigenetic control of transcription, and thus, the risk in coronary disease-associated loci, and that interaction of AP-1 with TCF21 to control epigenetic features, contributes to the genetic risk in loci where they co-localize.
Identifiants
pubmed: 31014396
doi: 10.1186/s13073-019-0635-9
pii: 10.1186/s13073-019-0635-9
pmc: PMC6480881
doi:
Substances chimiques
Basic Helix-Loop-Helix Transcription Factors
0
CDKN2B protein, human
0
Cyclin-Dependent Kinase Inhibitor p15
0
SMAD3 protein, human
0
Smad3 Protein
0
TCF21 protein, human
0
Transcription Factor AP-1
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
23Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL109512
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01HL109512
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01HL134817
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107437
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL139478
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01HL145708
Pays : United States
Organisme : NHLBI NIH HHS
ID : K08 HL133375
Pays : United States
Organisme : NHLBI NIH HHS
ID : R33HL120757
Pays : United States
Organisme : NHLBI NIH HHS
ID : F32 HL143847
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01HL139478
Pays : United States
Organisme : NHLBI NIH HHS
ID : R33 HL120757
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01DK107437
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00HL125912
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL134817
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL125912
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL145708
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK116074
Pays : United States
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