Large parental differences in chromatin organization in pancreatic beta cell line explaining diabetes susceptibility effects.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34267199.
- Also identified by DOI 10.1038/s41467-021-24635-2 and PMC identifier 8282625.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Previous GWAS studies identified non-coding loci with parent-of-origin-specific effects on Type 2 diabetes susceptibility. Here we report the molecular basis for one such locus near the KRTAP5-6 gene on chromosome 11. We determine the pattern of long-range contacts between an enhancer in this locus and the human INS promoter 460 kb away, in the human pancreatic β-cell line, EndoC-βH1. 3C long range contact experiments distinguish contacts on the two sister chromosomes. Coupling with allele-specific SNPs allows construction of maps revealing marked differences in organization of the two sister chromosomes in the entire region between KRTAP5-6 and INS. Further mapping distinguishes maternal and paternal alleles. This reveals a domain of parent-of-origin-specific chromatin structure extending in the telomeric direction from the INS locus. This suggests more generally that imprinted loci may extend their influence over gene expression beyond those loci through long range chromatin structure, resulting in parent-of-origin-biased expression patterns over great distances.
Medical subject headings
- Chromatin
- Diabetes Mellitus, Type 2
- Insulin-Secreting Cells
- Mutant Chimeric Proteins