4.8 Article

MyoD reprogramming requires Six1 and Six4 homeoproteins: genome-wide cis-regulatory module analysis

期刊

NUCLEIC ACIDS RESEARCH
卷 44, 期 18, 页码 8621-8640

出版社

OXFORD UNIV PRESS
DOI: 10.1093/nar/gkw512

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资金

  1. University of Paris VII
  2. 'Association Franc aise contre les Myopathies' (AFM)
  3. Agence National de la Recherche (ANR)
  4. Uehara Memorial Foundation
  5. JSPS Postdoctoral Fellowships for Research Abroad
  6. labex 'Who am I?' [ANR-11-LABX-0071, AN-R11-IDEX-0005-01]
  7. AFM [17167]
  8. Institut National de la Sante et de la Recherche Medicale (INSERM)
  9. Centre National de la Recherche Scientifique (CNRS)
  10. ANR [RPV09108KKA]
  11. Idex 'Sorbonne Paris Cite'
  12. INSERM
  13. Grants-in-Aid for Scientific Research [16H04729, 15K18468] Funding Source: KAKEN

向作者/读者索取更多资源

Myogenic regulatory factors of the MyoD family have the ability to reprogram differentiated cells toward a myogenic fate. In this study, we demonstrate that Six1 or Six4 are required for the reprogramming by MyoD of mouse embryonic fibroblasts (MEFs). Using microarray experiments, we found 761 genes under the control of both Six and MyoD. Using MyoD ChIPseq data and a genome-wide search for Six1/4 MEF3 binding sites, we found significant co-localization of binding sites for MyoD and Six proteins on over a thousand mouse genomic DNA regions. The combination of both datasets yielded 82 genes which are synergistically activated by Six and MyoD, with 96 associated MyoD+MEF3 putative cis-regulatory modules (CRMs). Fourteen out of 19 of the CRMs that we tested demonstrated in Luciferase assays a synergistic action also observed for their cognate gene. We searched putative binding sites on these CRMs using available databases and de novo search of conserved motifs and demonstrated that the Six/MyoD synergistic activation takes place in a feedforward way. It involves the recruitment of these two families of transcription factors to their targets, together with partner transcription factors, encoded by genes that are themselves activated by Six and MyoD, including Mef2, Pbx-Meis and EBF.

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