http://www.sciencedaily.com/releases/2009/03/090318140518.htm
"Our studies show that enhancers play much more prominent role than previously appreciated in cell-type-specific gene expression, helping to explain what causes cells to differentiate into liver or brain or skin cells, or why these cells might become cancerous," said principal investigator Bing Ren, PhD, associate professor of Cellular and Molecular Medicine at the University of California, San Diego School of Medicine and head of the Laboratory of Gene Regulation at the Ludwig Institute for Cancer Research (LICR).
The research team has performed a type of genome-wide analysis called ChIP-chip analysis to locate promoters, enhancers, insulators and other regulatory DNA sequences for each gene, using this approach to identify these elements in multiple cell types and investigate their roles in gene expression. ChIP-chip is used to localize protein binding sites that may help identify functional elements of the genome.
"Using this process, we described signatures, or distinguishing patterns, on histone proteins that enabled us to distinguish promoters and enhancers in the genome," said Ren. "In our analyses, we were surprised to find that the chromatin signatures at promoter sites were similar across all cells. However, we found that enhancers are marked with highly cell-type specific modification patterns. These patterns suggested that enhancers are of primary importance in the differentiation of specific cell types."
The human body is composed of diverse cell types with distinct functions. Although it is known that lineage specification depends on cell-specific gene expression, which in turn is driven by promoters, enhancers, insulators and other cis-regulatory DNA sequences for each gene1, 2, 3, the relative roles of these regulatory elements in this process are not clear. We have previously developed a chromatin-immunoprecipitation-based microarray method (ChIP-chip) to locate promoters, enhancers and insulators in the human genome4, 5, 6. Here we use the same approach to identify these elements in multiple cell types and investigate their roles in cell-type-specific gene expression. We observed that the chromatin state at promoters and CTCF-binding at insulators is largely invariant across diverse cell types. In contrast, enhancers are marked with highly cell-type-specific histone modification patterns, strongly correlate to cell-type-specific gene expression programs on a global scale, and are functionally active in a cell-type-specific manner. Our results define over 55,000 potential transcriptional enhancers in the human genome, significantly expanding the current catalogue of human enhancers and highlighting the role of these elements in cell-type-specific gene expression.
Nature 459, 108-112 (7 May 2009) | doi:10.1038/nature07829; Received 17 October 2008; Accepted 26 January 2009; Published online 18 March 2009
Histone modifications at human enhancers reflect global cell-type-specific gene expression
http://www.nature.com/nature/journal/v459/n7243/full/nature07829.htmlThe human body is composed of diverse cell types with distinct functions. Although it is known that lineage specification depends on cell-specific gene expression, which in turn is driven by promoters, enhancers, insulators and other cis-regulatory DNA sequences for each gene1, 2, 3, the relative roles of these regulatory elements in this process are not clear. We have previously developed a chromatin-immunoprecipitation-based microarray method (ChIP-chip) to locate promoters, enhancers and insulators in the human genome4, 5, 6. Here we use the same approach to identify these elements in multiple cell types and investigate their roles in cell-type-specific gene expression. We observed that the chromatin state at promoters and CTCF-binding at insulators is largely invariant across diverse cell types. In contrast, enhancers are marked with highly cell-type-specific histone modification patterns, strongly correlate to cell-type-specific gene expression programs on a global scale, and are functionally active in a cell-type-specific manner. Our results define over 55,000 potential transcriptional enhancers in the human genome, significantly expanding the current catalogue of human enhancers and highlighting the role of these elements in cell-type-specific gene expression.
Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome
Nature Genetics 39, 311 - 318 (2007). Published online: 4 February 2007 | doi:10.1038/ng1966
Eukaryotic gene transcription is accompanied by acetylation and methylation of nucleosomes near promoters, but the locations and roles of histone modifications elsewhere in the genome remain unclear. We determined the chromatin modification states in high resolution along 30 Mb of the human genome and found that active promoters are marked by trimethylation of Lys4 of histone H3 (H3K4), whereas enhancers are marked by monomethylation, but not trimethylation, of H3K4. We developed computational algorithms using these distinct chromatin signatures to identify new regulatory elements, predicting over 200 promoters and 400 enhancers within the 30-Mb region. This approach accurately predicted the location and function of independently identified regulatory elements with high sensitivity and specificity and uncovered a novel functional enhancer for the carnitine transporter SLC22A5 (OCTN2). Our results give insight into the connections between chromatin modifications and transcriptional regulatory activity and provide a new tool for the functional annotation of the human genome.
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