Stress-induced RNA-chromatin interactions promote endothelial dysfunction.
Chromatin
/ physiology
DNA
/ metabolism
Diabetes Mellitus
/ genetics
Endothelial Cells
/ metabolism
Epigenomics
Gene Expression
/ drug effects
Gene Regulatory Networks
Glucose
/ metabolism
Human Umbilical Vein Endothelial Cells
Humans
Plasminogen Activator Inhibitor 1
/ genetics
RNA
/ metabolism
Stress, Physiological
/ physiology
Tumor Necrosis Factor-alpha
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 10 2020
15 10 2020
Historique:
received:
23
07
2019
accepted:
11
09
2020
entrez:
16
10
2020
pubmed:
17
10
2020
medline:
3
11
2020
Statut:
epublish
Résumé
Chromatin-associated RNA (caRNA) has been proposed as a type of epigenomic modifier. Here, we test whether environmental stress can induce cellular dysfunction through modulating RNA-chromatin interactions. We induce endothelial cell (EC) dysfunction with high glucose and TNFα (H + T), that mimic the common stress in diabetes mellitus. We characterize the H + T-induced changes in gene expression by single cell (sc)RNA-seq, DNA interactions by Hi-C, and RNA-chromatin interactions by iMARGI. H + T induce inter-chromosomal RNA-chromatin interactions, particularly among the super enhancers. To test the causal relationship between H + T-induced RNA-chromatin interactions and the expression of EC dysfunction-related genes, we suppress the LINC00607 RNA. This suppression attenuates the expression of SERPINE1, a critical pro-inflammatory and pro-fibrotic gene. Furthermore, the changes of the co-expression gene network between diabetic and healthy donor-derived ECs corroborate the H + T-induced RNA-chromatin interactions. Taken together, caRNA-mediated dysregulation of gene expression modulates EC dysfunction, a crucial mechanism underlying numerous diseases.
Identifiants
pubmed: 33060583
doi: 10.1038/s41467-020-18957-w
pii: 10.1038/s41467-020-18957-w
pmc: PMC7566596
doi:
Substances chimiques
Chromatin
0
Plasminogen Activator Inhibitor 1
0
SERPINE1 protein, human
0
TNF protein, human
0
Tumor Necrosis Factor-alpha
0
RNA
63231-63-0
DNA
9007-49-2
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5211Subventions
Organisme : NCI NIH HHS
ID : U01 CA200147
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL108735
Pays : United States
Organisme : NICHD NIH HHS
ID : DP1 HD087990
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL145170
Pays : United States
Organisme : NIDDK NIH HHS
ID : DP1 DK126138
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK081705
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA033572
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL121365
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK065073
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL122368
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL106089
Pays : United States
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