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Identification of gene specific cis-regulatory elements during differentiation of mouse embryonic stem cells: An integrative approach using high-throughput datasets.

Accepted version
Peer-reviewed

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Authors

Vijayabaskar, MS 
Goode, Debbie K 
Obier, Nadine 
Lichtinger, Monika 

Abstract

Gene expression governs cell fate, and is regulated via a complex interplay of transcription factors and molecules that change chromatin structure. Advances in sequencing-based assays have enabled investigation of these processes genome-wide, leading to large datasets that combine information on the dynamics of gene expression, transcription factor binding and chromatin structure as cells differentiate. While numerous studies focus on the effects of these features on broader gene regulation, less work has been done on the mechanisms of gene-specific transcriptional control. In this study, we have focussed on the latter by integrating gene expression data for the in vitro differentiation of murine ES cells to macrophages and cardiomyocytes, with dynamic data on chromatin structure, epigenetics and transcription factor binding. Combining a novel strategy to identify communities of related control elements with a penalized regression approach, we developed individual models to identify the potential control elements predictive of the expression of each gene. Our models were compared to an existing method and evaluated using the existing literature and new experimental data from embryonic stem cell differentiation reporter assays. Our method is able to identify transcriptional control elements in a gene specific manner that reflect known regulatory relationships and to generate useful hypotheses for further testing.

Description

Keywords

Animals, Cell Differentiation, Chromatin, Databases, Genetic, Epigenesis, Genetic, Epigenomics, Gene Expression Regulation, Genome, High-Throughput Screening Assays, Macrophages, Mice, Mouse Embryonic Stem Cells, Myocytes, Cardiac, Promoter Regions, Genetic, Regulatory Elements, Transcriptional, Regulatory Sequences, Nucleic Acid, Transcription Factors

Journal Title

PLoS Comput Biol

Conference Name

Journal ISSN

1553-734X
1553-7358

Volume Title

15

Publisher

Public Library of Science (PLoS)

Rights

All rights reserved
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/I00050X/1)
Wellcome Trust (079895/Z/06/Z)
Wellcome Trust (203151/Z/16/Z)
Cancer Research UK (21762)
Medical Research Council (MC_PC_12009)
Wellcome Trust, BBSRC, CRUK