A map of open chromatin in human pancreatic islets.
Tissue-specific transcriptional regulation is central to human disease. To identify regulatory DNA active in human pancreatic islets, we profiled chromatin by formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq). We identified approximately 80,000 open chromatin sites. Comparison of FAIRE-seq data from islets to that from five non-islet cell lines revealed approximately 3,300 physically linked clusters of islet-selective open chromatin sites, which typically encompassed single genes that have islet-specific expression. We mapped sequence variants to open chromatin sites and found that rs7903146, a TCF7L2 intronic variant strongly associated with type 2 diabetes, is located in islet-selective open chromatin. We found that human islet samples heterozygous for rs7903146 showed allelic imbalance in islet FAIRE signals and that the variant alters enhancer activity, indicating that genetic variation at this locus acts in cis with local chromatin and regulatory changes. These findings illuminate the tissue-specific organization of cis-regulatory elements and show that FAIRE-seq can guide the identification of regulatory variants underlying disease susceptibility.
Gaulton
Kyle J
KJ
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Nammo
Takao
T
Pasquali
Lorenzo
L
Simon
Jeremy M
JM
Giresi
Paul G
PG
Fogarty
Marie P
MP
Panhuis
Tami M
TM
Mieczkowski
Piotr
P
Secchi
Antonio
A
Bosco
Domenico
D
Berney
Thierry
T
Montanya
Eduard
E
Mohlke
Karen L
KL
Lieb
Jason D
JD
Ferrer
Jorge
J
D001665:Binding Sites / Q000187:drug effects; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D002874:Chromosome Mapping; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005557:Formaldehyde / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism*; D020014:K562 Cells; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D012045:Regulatory Sequences, Nucleic Acid / Q000187:drug effects / Q000235:genetics*; D017422:Sequence Analysis, DNA; D051820:TCF Transcription Factors / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein
D002843:Chromatin; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D005557:Formaldehyde