Title

A Transcription Start Site Map in Human Pancreatic Islets Reveals Functional Regulatory Signatures.

Document Type

Article

Publication Date

7-1-2021

Publication Title

Diabetes

Keywords

JGM, Enhancer Elements, Genetic, Genome-Wide Association Study, Humans, Islets of Langerhans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Transcription Initiation Site

JAX Source

Diabetes 2021 Jul; 70(7):1581-1591

Volume

70

Issue

7

First Page

1581

Last Page

1591

ISSN

1939-327X

PMID

33849996

DOI

https://doi.org/10.2337/db20-1087

Abstract

Identifying the tissue-specific molecular signatures of active regulatory elements is critical to understand gene regulatory mechanisms. Here, we identify transcription start sites (TSS) using cap analysis of gene expression (CAGE) across 57 human pancreatic islet samples. We identify 9,954 reproducible CAGE tag clusters (TCs), ∼20% of which are islet specific and occur mostly distal to known gene TSS. We integrated islet CAGE data with histone modification and chromatin accessibility profiles to identify epigenomic signatures of transcription initiation. Using a massively parallel reporter assay, we validated the transcriptional enhancer activity for 2,279 of 3,378 (∼68%) tested islet CAGE elements (5% false discovery rate). TCs within accessible enhancers show higher enrichment to overlap type 2 diabetes genome-wide association study (GWAS) signals than existing islet annotations, which emphasizes the utility of mapping CAGE profiles in disease-relevant tissue. This work provides a high-resolution map of transcriptional initiation in human pancreatic islets with utility for dissecting active enhancers at GWAS loci.

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