RT Journal
A1 Birnbaum, Ramon Y.
A1 Clowney, E. Josephine
A1 Agamy, Orly
A1 Kim, Mee J.
A1 Zhao, Jingjing
A1 Yamanaka, Takayuki
A1 Pappalardo, Zachary
A1 Clarke, Shoa L.
A1 Wenger, Aaron M.
A1 Nguyen, Loan
A1 Gurrieri, Fiorella
A1 Everman, David B.
A1 Schwartz, Charles E.
A1 Birk, Ohad S.
A1 Bejerano, Gill
A1 Lomvardas, Stavros
A1 Ahituv, Nadav
T1 Coding exons function as tissue-specific enhancers of nearby genes
JF Genome Research 
JO Genome Research 
YR 2012 
FD June 01 
VO 22 
IS 6 
SP 1059 
OP 1068 
DO 10.1101/gr.133546.111 
UL http://genome.cshlp.org/content/22/6/1059.abstract 
AB 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.