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Functional characteristics of novel pancreatic Pax6 regulatory elements.

ABSTRACT: Complex diseases, such as diabetes, are influenced by comprehensive transcriptional networks. Genome-wide association studies have revealed that variants located in regulatory elements for pancreatic transcription factors are linked to diabetes, including those functionally linked to the paired box transcription factor Pax6. Pax6 deletions in adult mice cause rapid onset of classic diabetes, but the full spectrum of pancreatic Pax6 regulators is unknown. Using a regulatory element discovery approach, we identified two novel Pax6 pancreatic cis-regulatory elements in a poorly characterized regulatory desert. Both new elements, Pax6 pancreas cis-regulatory element 3 (PE3) and PE4, are located 50 and 100 kb upstream and interact with different parts of the Pax6 promoter and nearby non-coding RNAs. They drive expression in the developing pancreas and brain and code for multiple pancreas-related transcription factor-binding sites. PE3 binds CCCTC-binding factor (CTCF) and is marked by stem cell identity markers in embryonic stem cells, whilst a common variant located in the PE4 element affects binding of Pax4, a known pancreatic regulator, altering Pax6 gene expression. To determine the ability of these elements to regulate gene expression, synthetic transcriptional activators and repressors were targeted to PE3 and PE4, modulating Pax6 gene expression, as well as influencing neighbouring genes and long non-coding RNAs, implicating the Pax6 locus in pancreas function and diabetes.

SUBMITTER: Buckle A

PROVIDER: S-EPMC6140780 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Functional characteristics of novel pancreatic Pax6 regulatory elements.

Buckle Adam A Nozawa Ryu-Suke RS Kleinjan Dirk A DA Gilbert Nick N

Human molecular genetics 20181001 19

Complex diseases, such as diabetes, are influenced by comprehensive transcriptional networks. Genome-wide association studies have revealed that variants located in regulatory elements for pancreatic transcription factors are linked to diabetes, including those functionally linked to the paired box transcription factor Pax6. Pax6 deletions in adult mice cause rapid onset of classic diabetes, but the full spectrum of pancreatic Pax6 regulators is unknown. Using a regulatory element discovery appr ...[more]

PMID: 30007277

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Project description:BackgroundCell and circadian cycles control a large fraction of cell and organismal physiology by regulating large periodic transcriptional programs that encompass anywhere from 15 to 80% of the genome despite performing distinct functions. In each case, these large periodic transcriptional programs are controlled by gene regulatory networks (GRNs), and it has been shown through genetics and chromosome mapping approaches in model systems that at the core of these GRNs are small sets of genes that drive the transcript dynamics of the GRNs. However, it is unlikely that we have identified all of these core genes, even in model organisms. Moreover, large periodic transcriptional programs controlling a variety of processes certainly exist in important non-model organisms where genetic approaches to identifying networks are expensive, time-consuming, or intractable. Ideally, the core network components could be identified using data-driven approaches on the transcriptome dynamics data already available.ResultsThis study shows that a unified set of quantified dynamic features of high-throughput time series gene expression data are more prominent in the core transcriptional regulators of cell and circadian cycles than in their outputs, in multiple organism, even in the presence of external periodic stimuli. Additionally, we observe that the power to discriminate between core and non-core genes is largely insensitive to the particular choice of quantification of these features.ConclusionsThere are practical applications of the approach presented in this study for network inference, since the result is a ranking of genes that is enriched for core regulatory elements driving a periodic phenotype. In this way, the method provides a prioritization of follow-up genetic experiments. Furthermore, these findings reveal something unexpected-that there are shared dynamic features of the transcript abundance of core components of unrelated GRNs that control disparate periodic phenotypes.

Dataset Information

Functional characteristics of novel pancreatic Pax6 regulatory elements.

Publications

Functional characteristics of novel pancreatic Pax6 regulatory elements.

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