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CpG island composition differences are a source of gene expression noise indicative of promoter responsiveness.

ABSTRACT: BACKGROUND:Population phenotypic variation can arise from genetic differences between individuals, or from cellular heterogeneity in an isogenic group of cells or organisms. The emergence of gene expression differences between genetically identical cells is referred to as gene expression noise, the sources of which are not well understood. RESULTS:In this work, by studying gene expression noise between multiple cell lineages and mammalian species, we find consistent evidence of a role for CpG islands as sources of gene expression noise. Variation in noise among CpG island promoters can be partially attributed to differences in island size, in which short islands have noisier gene expression. Building on these findings, we investigate the potential for short CpG islands to act as fast response elements to environmental stimuli. Specifically, we find that these islands are enriched amongst primary response genes in SWI/SNF-independent stimuli, suggesting that expression noise is an indicator of promoter responsiveness. CONCLUSIONS:Thus, through the integration of single-cell RNA expression profiling, chromatin landscape and temporal gene expression dynamics, we have uncovered a role for short CpG island promoters as fast response elements.

SUBMITTER: Morgan MD

PROVIDER: S-EPMC6020341 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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CpG island composition differences are a source of gene expression noise indicative of promoter responsiveness.

Morgan Michael D MD Marioni John C JC

Genome biology 20180626 1

<h4>Background</h4>Population phenotypic variation can arise from genetic differences between individuals, or from cellular heterogeneity in an isogenic group of cells or organisms. The emergence of gene expression differences between genetically identical cells is referred to as gene expression noise, the sources of which are not well understood.<h4>Results</h4>In this work, by studying gene expression noise between multiple cell lineages and mammalian species, we find consistent evidence of a ...[more]

PMID: 29945659

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Project description:Alpha-methylacyl-coenzyme A racemase (AMACR) regulates peroxisomal beta-oxidation of phytol-derived, branched-chain fatty acids from red meat and dairy products -- suspected risk factors for colon carcinoma (CCa). AMACR was first found overexpressed in prostate cancer but not in benign glands and is now an established diagnostic marker for prostate cancer. Aberrant expression of AMACR was recently reported in Cca; however, little is known about how this gene is abnormally activated in cancer. By using a panel of immunostained-laser-capture-microdissected clinical samples comprising the entire colon adenoma-carcinoma sequence, we show that deregulation of AMACR during colon carcinogenesis involves two nonrandom events, resulting in the mutually exclusive existence of double-deletion at CG3 and CG10 and deletion of CG12-16 in a newly identified CpG island within the core promoter of AMACR. The double-deletion at CG3 and CG10 was found to be a somatic lesion. It existed in histologically normal colonic glands and tubular adenomas with low AMACR expression and was absent in villous adenomas and all CCas expressing variable levels of AMACR. In contrast, deletion of CG12-16 was shown to be a constitutional allele with a frequency of 43% in a general population. Its prevalence reached 89% in moderately differentiated CCas strongly expressing AMACR but only existed at 14% in poorly differentiated CCas expressing little or no AMACR. The DNA sequences housing these deletions were found to be putative cis-regulatory elements for Sp1 at CG3 and CG10, and ZNF202 at CG12-16. Chromatin immunoprecipitation, siRNA knockdown, gel shift assay, ectopic expression, and promoter analyses supported the regulation by Sp1 and ZNF202 of AMACR gene expression in an opposite manner. Our findings identified key in vivo events and novel transcription factors responsible for AMACR regulation in CCas and suggested these AMACR deletions may have diagnostic/prognostic value for colon carcinogenesis.

Dataset Information

CpG island composition differences are a source of gene expression noise indicative of promoter responsiveness.

Publications

CpG island composition differences are a source of gene expression noise indicative of promoter responsiveness.

Similar Datasets

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