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 ChIPseq 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.

The essential micronutrient selenium is found in proteins as selenocysteine (Sec), the only genetically encoded amino acid whose biosynthesis occurs on its cognate tRNA in humans. In the final step of selenocysteine formation, the essential enzyme SepSecS catalyzes the conversion of Sep-tRNA to Sec-tRNA. We demonstrate that SepSecS mutations cause autosomal-recessive progressive cerebellocerebral atrophy (PCCA) in Jews of Iraqi and Moroccan ancestry. Both founder mutations, common in these two populations, disrupt the sole route to the biosynthesis of the 21st amino acid, Sec, and thus to the generation of selenoproteins in humans.

Autosomal recessive PCCA type 2 is caused by VPS53 mutations.

Initial sweet taste transduction is expected to occur in the subsecond time range. We demonstrate a rapid and transient (75-250 ms) increase of cGMP (but not cAMP) level in rat intact circumvallate taste cells after stimulation by sucrose. This rapid increase does not occur in nonsensory epithelial cells. Pretreatment with a nonspecific phosphodiesterase (PDE) inhibitor (IBMX), a specific cAMP-PDE4 inhibitor (denbufylline), or an adenylyl cyclase activator (forskolin) all increased basal cAMP and abolished the sucrose-stimulated cGMP increase at 150 ms. Pretreatment with a soluble guanylyl cyclase inhibitor (1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one) reduced, whereas a specific cGMP-PDE inhibitor (zaprinast) abolished, the sucrose-stimulated cGMP increase. It is proposed that cGMP is involved in the initial stage of sugar taste transduction and that cGMP is more significant than cAMP at this stage. Activation of soluble guanylyl cyclase and inhibition of cGMP-PDE may be involved in the transient elevation of cGMP in response to sucrose stimulation. Moreover, it appears that cAMP level must remain low for sucrose to stimulate an increase in cGMP.