RT Journal Article
SR Electronic
T1 Temporal epigenomic profiling identifies AHR as dynamic super-enhancer controlled regulator of mesenchymal multipotency
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 183988
DO 10.1101/183988
A1 Deborah Gérard
A1 Florian Schmidt
A1 Aurélien Ginolhac
A1 Martine Schmitz
A1 Rashi Halder
A1 Peter Ebert
A1 Marcel H. Schulz
A1 Thomas Sauter
A1 Lasse Sinkkonen
YR 2017
UL http://biorxiv.org/content/early/2017/11/17/183988.abstract
AB Temporal data on gene expression and context-specific open chromatin states can improve identification of key transcription factors (TFs) and the gene regulatory networks (GRNs) controlling cellular differentiation. However, their integration remains challenging. Here, we delineate a general approach for data-driven and unbiased identification of key TFs and dynamic GRNs, called EPIC-DREM. We generated time-series transcriptomic and epigenomic profiles during differentiation of mouse multipotent bone marrow stromal cells (MSCs) towards adipocytes and osteoblasts. Using our novel approach we constructed time-resolved GRNs for both lineages. To prioritize the identified shared regulators, we mapped dynamic super-enhancers in both lineages and associated them to target genes with correlated expression profiles. We identified aryl hydrocarbon receptor (AHR) as a mesenchymal key TF controlled by a dynamic cluster of MSC-specific super-enhancers that become repressed in both lineages. AHR represses differentiation-induced genes such as Notch3 and we propose AHR to function as a guardian of mesenchymal multipotency.