Bioinformatic analysis of the human DHRS4 gene cluster and a proposed mechanism for its transcriptional regulation

The homologous comparison analysis suggests that DHRS4, DHRS4L2 and DHRS4L1 are three homologous genes in human. DHRS4L1 and DHRS4L2 are paralogues of DHRS4, and DHRS4L2 is the most recent member of the DHRS4 gene cluster. In the minus strand of the human DHRS4 gene cluster, a gene transcribed in an antisense direction was found containing a 5' sequence overlapping the region of exon 1 and promoter of DHRS4. By cloning the full length of RNA variants through 5'RACE and 3'RACE, we identified two transcription start sites, within exon a2 and exon 1, of this newly named gene DHRS4L1 using neuroblastoma cell line BE(2)-M17. Analysis of exon composition in the transcripts of DHRS4 gene cluster revealed that exon 1 was absent in all the transcripts initiated from exon a1 of DHRS4L2 and exon a2 of DHRS4L1.Alternatively spliced RNA variants are prevalent in the human DHRS4 gene cluster. Based on the analysis of gene transcripts and bioinformatic prediction, we propose here that antisense transcription may be involved in the transcriptional initiation regulation of DHRS4 and in the posttranscriptional splicing of DHRS4L2 and DRHS4L1 for the homologous identity of DHRS4 gene cluster. Beside the alternative transcriptional start sites, the antisense RNA is novel possible factor serving to remove exon 1 from the transcripts initiated from exon a1 and exon a2.DHRS4, the fourth member of the dehydrogenase/reductase (SDR) family, is a gene encoding NADP(H)-dependent retinol dehydrogenase/reductase (NRDR). Prior to December of 2008, an examination of the DHRS4 gene on chromosome 14q11.2 in GenBank revealed that the human DHRS4 gene cluster consisted of two genes, DHRS4 and DHRS4L2. In 1997, we identified the NRDR proteins from rabbit liver tissues, and found that this protein had strong retinol oxidation and retinal reduction activities and was a crucial enzyme in the metabolism and synthesis of retinoic acid [1], an important intracellular signaling molecule involved in the regula