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Nat Neurosci. 2015 May;18(5):647-56. doi: 10.1038/nn.3995. Epub 2015 Apr 6.

Regulation of chromatin accessibility and Zic binding at enhancers in the developing cerebellum.

Author information

1
1] Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA. [2] Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, USA.
2
Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA.
3
Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, USA.
4
1] Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, USA. [2] Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA.
5
1] Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, USA. [2] Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.
6
1] Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, USA. [2] Department of Pediatrics, Division of Molecular Genetics, Duke University Medical Center, Durham, North Carolina, USA.

Abstract

To identify chromatin mechanisms of neuronal differentiation, we characterized chromatin accessibility and gene expression in cerebellar granule neurons (CGNs) of the developing mouse. We used DNase-seq to map accessibility of cis-regulatory elements and RNA-seq to profile transcript abundance across postnatal stages of neuronal differentiation in vivo and in culture. We observed thousands of chromatin accessibility changes as CGNs differentiated, and verified, using H3K27ac ChIP-seq, reporter gene assays and CRISPR-mediated activation, that many of these regions function as neuronal enhancers. Motif discovery in differentially accessible chromatin regions suggested a previously unknown role for the Zic family of transcription factors in CGN maturation. We confirmed the association of Zic with these elements by ChIP-seq and found, using knockdown, that Zic1 and Zic2 are required for coordinating mature neuronal gene expression patterns. Together, our data reveal chromatin dynamics at thousands of gene regulatory elements that facilitate the gene expression patterns necessary for neuronal differentiation and function.

PMID:
25849986
PMCID:
PMC4414887
DOI:
10.1038/nn.3995
[Indexed for MEDLINE]
Free PMC Article

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