Genome‐wide analysis of FOXO3 mediated transcription regulation through RNA polymerase II profiling

Molecular Systems Biology

Astrid Eijkelenboom²  Michal Mokry¹  Elzo de Wit¹  Lydia M Smits²  Paulien E Polderman²  Miranda H van Triest²  Ruben van Boxtel³  Almut Schulze⁴  Wouter de Laat¹  Edwin Cuppen¹ 

[1] Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Centre, Utrecht, The Netherlands;Department of Molecular Cancer Research, University Medical Centre, Utrecht, The Netherlands;Department of Cell Biology, University Medical Centre, Utrecht, The Netherlands;Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, London, UK

关键词: enhancer;    FOXO;    initiation;    RNA pol II;    transcription;   

DOI  :  10.1038/msb.2012.74

来源: Wiley

【 摘 要 】

Abstract

Forkhead box O (FOXO) transcription factors are key players in diverse cellular processes affecting tumorigenesis, stem cell maintenance and lifespan. To gain insight into the mechanisms of FOXO-regulated target gene expression, we studied genome-wide effects of FOXO3 activation. Profiling RNA polymerase II changes shows that FOXO3 regulates gene expression through transcription initiation. Correlative analysis of FOXO3 and RNA polymerase II ChIP-seq profiles demonstrates FOXO3 to act as a transcriptional activator. Furthermore, this analysis reveals a significant part of FOXO3 gene regulation proceeds through enhancer regions. FOXO3 binds to pre-existing enhancers and further activates these enhancers as shown by changes in histone acetylation and RNA polymerase II recruitment. In addition, FOXO3-mediated enhancer activation correlates with regulation of adjacent genes and pre-existence of chromatin loops between FOXO3 bound enhancers and target genes. Combined, our data elucidate how FOXOs regulate gene transcription and provide insight into mechanisms by which FOXOs can induce different gene expression programs depending on chromatin architecture.

Synopsis

By comparative analysis of RNA polymerase II and FOXO3 ChIP-sequencing, combined with 4C-sequencing and ChIPs on histone modifications, general mechanisms of FOXO3-mediated target gene regulation are identified.

• FOXO3 acts as a transcriptional activator, inducing target gene expression through RNA polymerase II recruitment.
• FOXO3 binds and activates a pre-existing network of distal enhancers.
• FOXO3 bound distant regulatory regions contribute to target gene regulation.
• Chromatin architecture could determine the cell type-specific effects of FOXO3 target gene regulation.

【 授权许可】

CC BY-NC-SA   
Copyright © 2013 EMBO and Macmillan Publishers Limited

Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.