Dataset Information

Tissue- and stage-specific Wnt target gene expression is controlled subsequent to ?-catenin recruitment to cis-regulatory modules.

ABSTRACT: Key signalling pathways, such as canonical Wnt/?-catenin signalling, operate repeatedly to regulate tissue- and stage-specific transcriptional responses during development. Although recruitment of nuclear ?-catenin to target genomic loci serves as the hallmark of canonical Wnt signalling, mechanisms controlling stage- or tissue-specific transcriptional responses remain elusive. Here, a direct comparison of genome-wide occupancy of ?-catenin with a stage-matched Wnt-regulated transcriptome reveals that only a subset of ?-catenin-bound genomic loci are transcriptionally regulated by Wnt signalling. We demonstrate that Wnt signalling regulates ?-catenin binding to Wnt target genes not only when they are transcriptionally regulated, but also in contexts in which their transcription remains unaffected. The transcriptional response to Wnt signalling depends on additional mechanisms, such as BMP or FGF signalling for the particular genes we investigated, which do not influence ?-catenin recruitment. Our findings suggest a more general paradigm for Wnt-regulated transcriptional mechanisms, which is relevant for tissue-specific functions of Wnt/?-catenin signalling in embryonic development but also for stem cell-mediated homeostasis and cancer. Chromatin association of ?-catenin, even to functional Wnt-response elements, can no longer be considered a proxy for identifying transcriptionally Wnt-regulated genes. Context-dependent mechanisms are crucial for transcriptional activation of Wnt/?-catenin target genes subsequent to ?-catenin recruitment. Our conclusions therefore also imply that Wnt-regulated ?-catenin binding in one context can mark Wnt-regulated transcriptional target genes for different contexts.

SUBMITTER: Nakamura Y

PROVIDER: S-EPMC4920159 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β-catenin recruitment to cis-regulatory modules.

Nakamura Yukio Y de Paiva Alves Eduardo E Veenstra Gert Jan C GJ Hoppler Stefan S

Development (Cambridge, England) 20160411 11

Key signalling pathways, such as canonical Wnt/β-catenin signalling, operate repeatedly to regulate tissue- and stage-specific transcriptional responses during development. Although recruitment of nuclear β-catenin to target genomic loci serves as the hallmark of canonical Wnt signalling, mechanisms controlling stage- or tissue-specific transcriptional responses remain elusive. Here, a direct comparison of genome-wide occupancy of β-catenin with a stage-matched Wnt-regulated transcriptome reveal ...[more]

PMID: 27068107

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Project description:Researchers seeking to unlock the genetic basis of human physiology and diseases have been studying gene transcription regulation. The temporal and spatial patterns of gene expression are controlled by mainly non-coding elements known as cis-regulatory modules (CRMs) and epigenetic factors. CRMs modulating related genes share the regulatory signature which consists of transcription factor (TF) binding sites (TFBSs). Identifying such CRMs is a challenging problem due to the prohibitive number of sequence sets that need to be analyzed.We formulated the challenge as a supervised classification problem even though experimentally validated CRMs were not required. Our efforts resulted in a software system named CrmMiner. The system mines for CRMs in the vicinity of related genes. CrmMiner requires two sets of sequences: a mixed set and a control set. Sequences in the vicinity of the related genes comprise the mixed set, whereas the control set includes random genomic sequences. CrmMiner assumes that a large percentage of the mixed set is made of background sequences that do not include CRMs. The system identifies pairs of closely located motifs representing vertebrate TFBSs that are enriched in the training mixed set consisting of 50% of the gene loci. In addition, CrmMiner selects a group of the enriched pairs to represent the tissue-specific regulatory signature. The mixed and the control sets are searched for candidate sequences that include any of the selected pairs. Next, an optimal Bayesian classifier is used to distinguish candidates found in the mixed set from their control counterparts. Our study proposes 62 tissue-specific regulatory signatures and putative CRMs for different human tissues and cell types. These signatures consist of assortments of ubiquitously expressed TFs and tissue-specific TFs. Under controlled settings, CrmMiner identified known CRMs in noisy sets up to 1:25 signal-to-noise ratio. CrmMiner was 21-75% more precise than a related CRM predictor. The sensitivity of the system to locate known human heart enhancers reached up to 83%. CrmMiner precision reached 82% while mining for CRMs specific to the human CD4+ T cells. On several data sets, the system achieved 99% specificity.These results suggest that CrmMiner predictions are accurate and likely to be tissue-specific CRMs. We expect that the predicted tissue-specific CRMs and the regulatory signatures broaden our knowledge of gene transcription regulation.

Dataset Information

Tissue- and stage-specific Wnt target gene expression is controlled subsequent to ?-catenin recruitment to cis-regulatory modules.

Publications

Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β-catenin recruitment to cis-regulatory modules.

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