The embryonic subpallium generates neurons and glia which contribute to the functional diversity of the brain. Proper spatial and temporal generation of these cells relies on complex molecular mechanisms which control transcription through regulation of genome architecture. As the progeny of stem cells of the subpallium differentiate, the fate decision between neurons and glia is driven by expression of Dlx1/2 or Olig1/2 respectively, two sets of transcription factors (TFs) with a mutually repressive relationship. The mechanism by which TFs such as Dlx1/2 can repress alternative cell fates while simultaneously promoting transcription of genes required for differentiation, however, is not yet fully understood. Using immunoprecipitation in vitro and in vivo, we found that DLX1 interacts with the nucleosome remodeling complex NuRD through an interaction with RBBP4 and RBBP7. We observed that a reduction in the levels of RBBP4/7 in the developing telencephalon leads to a variety of developmental defects, including a reduction in cell division and interneuron production. ChIP-seq studies of genomic occupancy of DLX1 and six different members of the NuRD complex show that DLX1 and NuRD colocalize to putative regulatory elements (pREs) enriched near other transcription factors, and that loss of Dlx1/2 leads to dysregulation of genome accessibility at pREs near genes repressed by Dlx1/2. We identified an Olig2 pRE which has activity in the forebrain, remains accessible in Dlx1/2 mutants, and is bound by DLX1 and the NuRD complex. Consequently, heterozygosity of Dlx1/2 and Rbbp4 leads to an increase in the production of OLIG2+ cells. Together these findings suggest a mechanism by which Dlx1 cooperates with the NuRD complex to regulate transcription of target genes by altering the chromatin state of regulatory elements. These findings underscore the critical role of the NuRD complex during development and point to the interaction between TFs and chromatin remodelers as a mechanism underlying cell fate decisions.
|Advisor:||Black, Brian L.|
|Commitee:||Rubenstein, John L. R., Bruneau, Benoit G.|
|School:||University of California, San Francisco|
|School Location:||United States -- California|
|Source:||DAI-B 82/7(E), Dissertation Abstracts International|
|Subjects:||Developmental biology, Molecular biology|
|Keywords:||Basal ganglia, Chromatin, NuRD complex, Telencephalon|
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