Unknown,Transcriptomics,Genomics,Proteomics

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A quantitative model of transcription regulation reveals the role of non-conserved enhancers

ABSTRACT: We identify sites of combinatorial control by performing high throughput ChIP experiments on p300, CREB-binding protein (CBP), the deacetylase SIRT1 and on multiple DNA-binding transcription factors in three different tissues. We present a quantitative model of transcriptional regulation that reveals the contribution of each binding site to tissue-specific gene expression in several mouse cell types. Binding to both evolutionarily conserved and non-conserved sequences is found to contribute significantly to transcriptional regulation. We demonstrate that binding location strongly predicts the expression level of nearby genes. Liver hepatocytes and cerebellum tissue were harvested from male C57BL/6J mice. RNA was extracted and hybridized to Affymetrix arrays. Examination of transcriptional regulator binding in three mouse tissues by ChIP-IP using tiling arrays. Examination of CBP binding in mouse liver and cerebellum by ChIP-seq.

ORGANISM(S): Mus musculus

SUBMITTER: Kenzie MacIsaac

PROVIDER: E-GEOD-17067 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A quantitative model of transcriptional regulation reveals the influence of binding location on expression.

MacIsaac Kenzie D KD Lo Kinyui A KA Gordon William W Motola Shmulik S Mazor Tali T Fraenkel Ernest E

PLoS computational biology 20100429 4

Understanding the mechanistic basis of transcriptional regulation has been a central focus of molecular biology since its inception. New high-throughput chromatin immunoprecipitation experiments have revealed that most regulatory proteins bind thousands of sites in mammalian genomes. However, the functional significance of these binding sites remains unclear. We present a quantitative model of transcriptional regulation that suggests the contribution of each binding site to tissue-specific gene ...[more]

PMID: 20442865

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Project description:Dioxin-like chemicals are well-known for their ability to upregulate expression of numerous genes via the AH receptor (AHR). However, recent transcriptomic analyses in several laboratories indicate that dioxin-like chemicals or AHR genotype itself also can downregulate levels of mRNAs encoded by numerous genes. The mechanism responsible for such downregulation is unknown. We hypothesized that microRNAs (miRNAs), which have emerged as powerful negative regulators of mRNA levels in several systems, might be responsible for mRNA downregulation in dioxin/AHR pathways. We conducted a thorough investigation to address the following questions: (1) does AHR genotype itself affect constitutive expression of microRNAs? (2) does TCDD affect microRNA levels and, if so, is this response dependent on the AHR? (3) does TCDD affect microRNA levels differently in animals that are sensitive to dioxin toxicity versus those that are dioxin-resistant? We used the Exiqon miRNA array platform as well as quantitative RT-PCR to measure miRNA levels in wildtype vs. Ahr-null mice. Treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in vivo caused few changes in miRNA levels in mouse livers and those changes that were statistically significant were of modest magnitude. AHR genotype had little effect on hepatic miRNA levels, either in constitutive expression or in response to TCDD M-bM-^@M-^S only a few miRNAs differed in expression between Ahr-null mice compared to mice with wildtype AHR. It is unlikely that mRNA downregulation by dioxins is mediated by miRNAs, nor are miRNAs likely to play a significant role in dioxin toxicity in adult mouse liver. Manuscript Submitted: Moffat ID, Boutros PC, Celius T, Pohjanvirta R & Okey AB. Micro-RNAs in rodent liver are refractory to dioxin treatment. Toxicological Sciences May, 2007. Keywords: miRNA expression, gene knockout, response to xenobiotics, genetic modification This was a two-factor, two-level design, the factors being genotype Ahr+/+ (WT) or Ahr-/- (KO) and treatment TCDD-treated (T) or vehicle control (C). Each total-RNA sample was separately labeled either with a Hy3- or a Hy5-fluorophore (Exiqon). Hy3- and Hy5-labeled samples were co-hybridized to an array. Dye-reversal was performed to eliminate dye bias. We tested 3 TCDD-treated and 3 control mice in the Ahr-/- groups and 4 TCDD-treated and 4 control mice in the Ahr+/+ groups. Technical replication of 1 TCDD-treated and 1 control mice in the Ahr-/- groups was performed. A loop design was used.

Dataset Information

A quantitative model of transcription regulation reveals the role of non-conserved enhancers

Publications

A quantitative model of transcriptional regulation reveals the influence of binding location on expression.

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