Abstract
We sought exonic transcriptional regulatory elements by shotgun cloning human cDNA fragments into luciferase reporter vectors and measuring the resulting expression levels in liver cells. We uncovered seven regulatory elements within coding regions and three within 3' untranslated regions (UTRs). Two of the putative regulatory elements were enhancers and eight were silencers. The regulatory elements were generally but not consistently evolutionarily conserved and also showed a trend toward decreased population diversity. Furthermore, the exonic regulatory elements were enriched in known transcription factor binding sites (TFBSs) and were associated with several histone modifications and transcriptionally relevant chromatin. Evidence was obtained for bidirectional cis-regulation of a coding region element within a tubulin gene, TUBA1B, by the transcription factors PPARA and RORA. We estimate that hundreds of exonic transcriptional regulatory elements exist, an unexpected finding that highlights a surprising multi-functionality of sequences in the human genome.
Highlights
An important key to deciphering the human genome is to identify the regulatory elements that control gene expression
From a pool of 1,932 random fragments we discovered 10 exonic regulatory elements active in liver within coding regions and 39 untranslated regions (UTRs)
A previous screen of 1,798 random fragments from a BAC containing both genic and intergenic DNA from the ApoE gene cluster on chromosome 19 yielded 10 regulatory elements active in liver [5], suggesting that regulatory elements are as common in exons as they are in the genome as a whole
Summary
An important key to deciphering the human genome is to identify the regulatory elements that control gene expression. Disruption of these elements has been linked to a number of human diseases including cancers [1], preaxial polydactyly [2], Van Buchem disease [3], and facioscapulohumeral muscular dystrophy [4]. Isolated examples of transcriptional regulatory elements have recently been found in exons, both coding [5,7,8] and non-coding [9,10]. These coding regulatory elements, though critically important given their dual function, are poorly understood and almost completely uncatalogued
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