Long Human–Mouse Sequence Alignments Reveal Novel Regulatory Elements: A Reason to Sequence the Mouse Genome

Hardison, Ross C.; Oeltjen, John C.; Miller, Webb

doi:10.1101/gr.7.10.959

Cited by 296 publications

(198 citation statements)

References 41 publications

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“…Human BCL6 has two mRNA variants that differ in their first untranslated exon, but result in the same protein ( Figure 3a). Given that regulatory regions are often conserved among species (Hardison et al, 1997;Brudno et al, 2004), we searched for regions of homology in non-protein coding areas of the BCL6 gene for the STAT consensus site, TTC(N 3 )GAA. We focused on the first intron, as the majority of STAT5-binding sites occur within introns (Nelson et al, 2004).…”

Section: Identification Of Potential Stat-binding Sitesmentioning

confidence: 99%

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

2006

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Deregulated expression of BCL6 is a pathogenic event in many lymphomas. BCL6 blocks cellular differentiation by repressing transcription of its target genes, and this may promote tumorigenesis. Conversely, the transcription factor signal transducers and activators of transcription (STAT)5 promotes differentiation in many systems. STAT5 upregulates a number of genes repressed by BCL6, raising the possibility that STAT5 and BCL6 have opposing roles in transcriptional regulation. Therefore, we sought to determine the effects of STAT5 activation on BCL6 expression and function. We found that activation of STAT5 downregulates BCL6 expression in B-lymphoma cells and other hematopoietic cell lines. We identified two potential STAT-binding regions in the first exon and first intron of BCL6 that fell within regions of high interspecies homology, suggesting conservation of regulatory function. STAT5 can bind inducibly and regulate transcription at one of these regions, identifying BCL6 as a STAT5 target gene. Additionally, STAT5-mediated downregulation of BCL6 results in loss of BCL6 repression of its target genes, confirming that STAT5 is a negative regulator of BCL6 function. The STAT5 responsive region of the BCL6 gene is mutated frequently in B-cell lymphomas, suggesting that loss of the repressive effects of STAT5 on BCL6 might contribute to the pathogenesis of these cancers.

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Section: Identification Of Potential Stat-binding Sitesmentioning

confidence: 99%

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

2006

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“…In order to overcome this shortcoming, it will be necessary to devise new strategy for uncovering key transcription factors governing gene expression patterns that well reflect the clinicopathological features of human cancer. Although current computational in silico prediction methods of cisregulatory elements in genomic sequences are not sophisticated enough to overcome high rate of falsely predicted sites owing to short and degenerated nature of binding sites targeted by transcription factors, comparative genomics has long held the promise for the identification of cis-regulatory elements in mammalian genomes (Hardison et al, 1997). Previous study showed that cross-species comparison in binding sites prediction ('phylogenetic footprinting') enhances predictive sensitivity when analysing promoter sequences conserved between humans and mice (Lenhard et al, 2003).…”

Section: Integrative Functional Genomicsmentioning

confidence: 99%

Comparative and integrative functional genomics of HCC

2006

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Global gene expression profiling of hepatocellular carcinoma (HCC) is a promising new technology that has already refined the diagnosis and prognostic predictions of HCC patients. This has been accomplished by identifying genes whose expression pattern is associated with clinicopathological features of HCC tumors. Molecular characterization of HCC from gene expression profiling studies will undoubtedly improve the prediction of treatment responses, selection of treatments for specific molecular subtypes of HCC and ultimately the clinical outcome of HCC patients. The research focus is now shifting toward the identification of genetic determinants that are components of the specific regulatory pathways altered in cancers, and that may constitute novel therapeutic targets. Here we review the recent advances in gene expression profiling of HCC and discuss the future strategies for analysing large and complicated data sets from microarray studies and how to integrate these with diverse genomic data.

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“…Our assumption was that the genes regulated by SOX4 are likely to be present in the SOX4 synexpression group, namely, the T3>T1 gene group. The binding motifs of the evolutionarily conserved transcription factors tend to reside in humanmouse conserved noncoding blocks (CNBs) within the promoter regions of the putative target genes (Hardison et al, 1997;Wasserman et al, 2000). To unravel the SOX4 targets, we developed a bioinformatics screening strategy based on phylogenetic footprinting to identify SOX4-binding motifs in the T3>T1 gene group .…”

Section: Identification Of Genes Associated With Intrahepatic Metastamentioning

confidence: 99%

Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma

Yl¹,

et al. 2008

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A comprehensive microarray analysis of hepatocellular carcinoma (HCC) revealed distinct synexpression patterns during intrahepatic metastasis. Recent evidence has demonstrated that synexpression group member genes are likely to be regulated by master control gene(s). Here we investigate the functions and gene regulation of the transcription factor SOX4 in intrahepatic metastatic HCC. SOX4 is important in tumor metastasis as RNAi knockdown reduces tumor cell migration, invasion, in vivo tumorigenesis and metastasis. A multifaceted approach integrating gene profiling, binding site computation and empirical verification by chromatin immunoprecipitation and gene ablation refined the consensus SOX4 binding motif and identified 32 binding loci in 31 genes with high confidence. RNAi knockdown of two SOX4 target genes, neuropilin 1 and semaphorin 3C, drastically reduced cell migration activity in HCC cell lines suggesting that SOX4 exerts some of its action via regulation of these two downstream targets. The discovery of 31 previously unidentified targets expands our knowledge of how SOX4 modulates HCC progression and implies a range of novel SOX4 functions. This integrated approach sets a paradigm whereby a subset of member genes from a synexpression group can be regulated by one master control gene and this is exemplified by SOX4 and advanced HCC.

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Long Human–Mouse Sequence Alignments Reveal Novel Regulatory Elements: A Reason to Sequence the Mouse Genome

Cited by 296 publications

References 41 publications

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

Comparative and integrative functional genomics of HCC

Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma

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