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Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.

ABSTRACT: By analyzing 1,780,295 5'-end sequences of human full-length cDNAs derived from 164 kinds of oligo-cap cDNA libraries, we identified 269,774 independent positions of transcriptional start sites (TSSs) for 14,628 human RefSeq genes. These TSSs were clustered into 30,964 clusters that were separated from each other by more than 500 bp and thus are very likely to constitute mutually distinct alternative promoters. To our surprise, at least 7674 (52%) human RefSeq genes were subject to regulation by putative alternative promoters (PAPs). On average, there were 3.1 PAPs per gene, with the composition of one CpG-island-containing promoter per 2.6 CpG-less promoters. In 17% of the PAP-containing loci, tissue-specific use of the PAPs was observed. The richest tissue sources of the tissue-specific PAPs were testis and brain. It was also intriguing that the PAP-containing promoters were enriched in the genes encoding signal transduction-related proteins and were rarer in the genes encoding extracellular proteins, possibly reflecting the varied functional requirement for and the restricted expression of those categories of genes, respectively. The patterns of the first exons were highly diverse as well. On average, there were 7.7 different splicing types of first exons per locus partly produced by the PAPs, suggesting that a wide variety of transcripts can be achieved by this mechanism. Our findings suggest that use of alternate promoters and consequent alternative use of first exons should play a pivotal role in generating the complexity required for the highly elaborated molecular systems in humans.

SUBMITTER: Kimura K

PROVIDER: S-EPMC1356129 | biostudies-literature | 2006 Jan

REPOSITORIES: biostudies-literature

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Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.

Kimura Kouichi K Wakamatsu Ai A Suzuki Yutaka Y Ota Toshio T Nishikawa Tetsuo T Yamashita Riu R Yamamoto Jun-ichi J Sekine Mitsuo M Tsuritani Katsuki K Wakaguri Hiroyuki H Ishii Shizuko S Sugiyama Tomoyasu T Saito Kaoru K Isono Yuko Y Irie Ryotaro R Kushida Norihiro N Yoneyama Takahiro T Otsuka Rie R Kanda Katsuhiro K Yokoi Takahide T Kondo Hiroshi H Wagatsuma Masako M Murakawa Katsuji K Ishida Shinichi S Ishibashi Tadashi T Takahashi-Fujii Asako A Tanase Tomoo T Nagai Keiichi K Kikuchi Hisashi H Nakai Kenta K Isogai Takao T Sugano Sumio S

Genome research 20051212 1

By analyzing 1,780,295 5'-end sequences of human full-length cDNAs derived from 164 kinds of oligo-cap cDNA libraries, we identified 269,774 independent positions of transcriptional start sites (TSSs) for 14,628 human RefSeq genes. These TSSs were clustered into 30,964 clusters that were separated from each other by more than 500 bp and thus are very likely to constitute mutually distinct alternative promoters. To our surprise, at least 7674 (52%) human RefSeq genes were subject to regulation by ...[more]

PMID: 16344560

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Project description:BackgroundThe genomic organization of Hox clusters is fundamental for the precise spatio-temporal regulation and the function of each Hox gene, and hence for correct embryo patterning. Multiple overlapping transcriptional units exist at the Hoxa5 locus reflecting the complexity of Hox clustering: a major form of 1.8 kb corresponding to the two characterized exons of the gene and polyadenylated RNA species of 5.0, 9.5 and 11.0 kb. This transcriptional intricacy raises the question of the involvement of the larger transcripts in Hox function and regulation.Methodology/principal findingsWe have undertaken the molecular characterization of the Hoxa5 larger transcripts. They initiate from two highly conserved distal promoters, one corresponding to the putative Hoxa6 promoter, and a second located nearby Hoxa7. Alternative splicing is also involved in the generation of the different transcripts. No functional polyadenylation sequence was found at the Hoxa6 locus and all larger transcripts use the polyadenylation site of the Hoxa5 gene. Some larger transcripts are potential Hoxa6/Hoxa5 bicistronic units. However, even though all transcripts could produce the genuine 270 a.a. HOXA5 protein, only the 1.8 kb form is translated into the protein, indicative of its essential role in Hoxa5 gene function. The Hoxa6 mutation disrupts the larger transcripts without major phenotypic impact on axial specification in their expression domain. However, Hoxa5-like skeletal anomalies are observed in Hoxa6 mutants and these defects can be explained by the loss of expression of the 1.8 kb transcript. Our data raise the possibility that the larger transcripts may be involved in Hoxa5 gene regulation.SignificanceOur observation that the Hoxa5 larger transcripts possess a developmentally-regulated expression combined to the increasing sum of data on the role of long noncoding RNAs in transcriptional regulation suggest that the Hoxa5 larger transcripts may participate in the control of Hox gene expression.

Dataset Information

Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.

Publications

Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.

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