The alignment of full-length human cDNA sequences to the finished sequence of the human genome provides a unique opportunity to study the distribution of genes throughout the genome. By analyzing the distances between 23,752 genes, we identified a class of divergently transcribed gene pairs, representing more than 10% of the genes in the genome, whose transcription start sites are separated by less than 1000 base pairs. Although this bidirectional arrangement has been previously described in humans and other species, the prevalence of bidirectional gene pairs in the human genome is striking, and the mechanisms of regulation of all but a few bidirectional genes are unknown. Our work shows that the transcripts of many bidirectional pairs are coexpressed, but some are antiregulated. Further, we show that many of the promoter segments between two bidirectional genes initiate transcription in both directions and contain shared elements that regulate both genes. We also show that the bidirectional arrangement is often conserved among mouse orthologs. These findings demonstrate that a bidirectional arrangement provides a unique mechanism of regulation for a significant number of mammalian genes
Previous work has implicated heat shock transcription factor 1 (HSF1) as the primary transcription factor responsible for the transcriptional response to heat stress in mammalian cells. We characterized the heat shock response of mammalian cells by measuring changes in transcript levels and assaying binding of HSF1 to promoter regions for candidate heat shock genes chosen by a combination of genome-wide computational and experimental methods. We found that many heat-inducible genes have HSF1 binding sites (heat shock elements, HSEs) in their promoters that are bound by HSF1. Surprisingly, for 24 heat-inducible genes, we detected no HSEs and no HSF1 binding. Furthermore, of 182 promoters with likely HSE sequences, we detected HSF1 binding at only 94 of these promoters. Also unexpectedly, we found 48 genes with HSEs in their promoters that are bound by HSF1 but that nevertheless did not show induction after heat shock in the cell types we examined. We also studied the transcriptional response to heat shock in fibroblasts from mice lacking the HSF1 gene. We found 36 genes in these cells that are induced by heat as well as they are in wild-type cells. These results provide evidence that HSF1 does not regulate the induction of every transcript that accumulates after heat shock, and our results suggest that an independent posttranscriptional mechanism regulates the accumulation of a significant number of transcripts. INTRODUCTIONThe heat shock response was first described in 1962 as a puffing pattern on Drosophila polytene chromosomes after thermal stress (Ritossa, 1962). Since then, studies of individual genes have shown that the cellular heat shock response is conserved across kingdoms and is characterized by the strong induction of numerous heat shock proteins (HSPs), many of which are chaperone proteins that assist in protein folding.The heat shock transcription factor (HSF) transcriptionally regulates the induction of many HSPs in Drosophila (Clos et al., 1990) and Saccharomyces (Sorger and Pelham, 1987;Wiederrecht et al., 1988). HSF binds to a DNA sequence motif, the heat shock element (HSE), which is characterized by an array of inverted repeats of the motif nGAAn. Copies of the HSE are found in the promoters of genes encoding several known heat-inducible proteins, including the Drosophila and human hsp70 genes (Sarge et al., 1993;Pirkkala et al., 2001).Mammalian genomes encode three homologues of HSF: HSF1, HSF2, and HSF4 (reviewed in Pirkkala et al., 2001). Mammalian HSF1 is believed to be the paralog responsible for regulating the heat-induced transcriptional response in mammalian cells (Rabindran et al., 1991;Sarge et al., 1991Sarge et al., , 1993. In support of this hypothesis, mouse HSF1 knockout fibroblasts are unable to induce expression of hsp70 in response to heat stress (McMillan et al., 1998), whereas HSF2 knockout fibroblasts induce hsp70 normally (McMillan et al., 2002). The HSF1 knockout mouse has defects in extraembryonic development and postnatal growth, suggesting that the protein is important...
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