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PMID: 21336277 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural

Mapping of INS promoter interactions reveals its role in long-range regulation of SYT8 transcription.

Nature structural & molecular biology ·Vol. 18 ·No. 3 ·2011-03-00 ·Pages 372-8

Xu Z, Wei G, Chepelev I, Zhao K, Felsenfeld G

Abstract

Insulin (INS) synthesis and secretion from pancreatic β-cells are tightly regulated; their deregulation causes diabetes. Here we map INS-associated loci in human pancreatic islets by 4C and 3C techniques and show that the INS gene physically interacts with the SYT8 gene, located over 300 kb away. This interaction is elevated by glucose and accompanied by increases in SYT8 expression. Inactivation of the INS promoter by promoter-targeting siRNA reduces SYT8 gene expression. SYT8-INS interaction and SYT8 transcription are attenuated by CTCF depletion. Furthermore, SYT8 knockdown decreases insulin secretion in islets. These results reveal a nonredundant role for SYT8 in insulin secretion and indicate that the INS promoter acts from a distance to stimulate SYT8 transcription. This suggests a function for the INS promoter in coordinating insulin transcription and secretion through long-range regulation of SYT8 expression in human islets.

MeSH Terms
CCCTC-Binding Factor Cells, Cultured Gene Expression Regulation Genetic Loci Glucose/metabolism Humans Insulin/genetics Islets of Langerhans/cytology,metabolism Promoter Regions, Genetic Protein Binding Repressor Proteins/metabolism Synaptotagmins/genetics Transcription, Genetic Troponin I/genetics
Chemicals
CCCTC-Binding Factor CTCF protein, human Insulin Repressor Proteins SYT8 protein, human TNNI2 protein, human Troponin I Synaptotagmins Glucose
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Xu Zhixiong
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Wei Gang
Chepelev Iouri
Zhao Keji
Felsenfeld Gary
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Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9985
DOI
10.1038/nsmb.1993
Published
2011-03-00
Epub
2011-00-20
Pages
372-8
Language
English
Region
United States
NLM ID
101186374
PMCID
PMC6402586
Subset
IM
Grants
Intramural NIH HHS · Z01 DK033007-03 · United States
External Links
PubMed source DOI: 10.1038/nsmb.1993 PMC Full Text View journal details
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