Coding exons function as tissue-specific enhancers of nearby genes

Ramon Y. Birnbaum, E. Josephine Clowney, Orly Agamy, Mee J. Kim, Jingjing Zhao, Takayuki Yamanaka, Zachary Pappalardo, Shoa L. Clarke, Aaron M. Wenger, Loan Nguyen, Fiorella Gurrieri, David B. Everman, Charles E. Schwartz, Ohad S. Birk, Gill Bejerano, Stavros Lomvardas, Nadav Ahituv

Research output: Contribution to journalArticlepeer-review

165 Scopus citations


Enhancers are essential gene regulatory elements whose alteration can lead to morphological differences between species, developmental abnormalities, and human disease. Current strategies to identify enhancers focus primarily on noncoding sequences and tend to exclude protein coding sequences. Here, we analyzed 25 available ChIP-seq data sets that identify enhancers in an unbiased manner (H3K4me1, H3K27ac, and EP300) for peaks that overlap exons. We find that, on average, 7% of all ChIP-seq peaks overlap coding exons (after excluding for peaks that overlap with first exons). By using mouse and zebrafish enhancer assays, we demonstrate that several of these exonic enhancer (eExons) candidates can function as enhancers of their neighboring genes and that the exonic sequence is necessary for enhancer activity. Using ChIP, 3C, and DNA FISH, we further show that one of these exonic limb enhancers, Dync1i1 exon 15, has active enhancer marks and physically interacts with Dlx5/6 promoter regions 900 kb away. In addition, its removal by chromosomal abnormalities in humans could cause split hand and foot malformation 1 (SHFM1), a disorder associated with DLX5/6. These results demonstrate that DNA sequences can have a dual function, operating as coding exons in one tissue and enhancers of nearby gene(s) in another tissue, suggesting that phenotypes resulting from coding mutations could be caused not only by protein alteration but also by disrupting the regulation of another gene.

Original languageEnglish
Pages (from-to)1059-1068
Number of pages10
JournalGenome Research
Issue number6
StatePublished - 1 Jun 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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