Chromatin Accessibility at a STAT3 Target Site Is Altered Prior to Astrocyte Differentiation

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  • Urayama Satoshi
    Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology Department of Biology, School of Medicine, Nara Medical University
  • Semi Katsunori
    Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology
  • Sanosaka Tsukasa
    Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology
  • Hori Yukina
    Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology
  • Namihira Masakazu
    Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology
  • Kohyama Jun
    Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology Department of Molecular and Medical Pharmacology Sciences, University of California, Los Angeles
  • Takizawa Takumi
    Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology Department of Pediatrics, Graduate School of Medicine, Gunma University
  • Nakashima Kinichi
    Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology

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Abstract

DNA demethylation of astrocyte-specific gene promoters and STAT3 activation in neural precursor cells (NPCs) are essential for astrogliogenesis in the developing brain. To date, it remains unclear whether DNA methylation is the sole epigenetic determinant responsible for suppressing astrocyte-specific genes. Here, we used mouse embryonic stem cells (TKO ESCs) that lacked all 3 DNA methyltransferase genes, Dnmt1, Dnmt3a, and Dnmt3b, and thereby exhibit complete demethylation of the astrocyte-specific glial fibrillary acidic protein (Gfap) gene promoter. We found that although the Gfap promoter was demethylated, STAT3 failed to bind to its cognate element to induce Gfap transcription, whereas it induced transcription of a different target gene, Socs3. Moreover, although the Gfap promoter region containing the STAT3-binding site (GSBS) is enriched with transcription-repressive histone modifications, such as methylation of H3 at lysine 9 (H3K9me3) and H3K27me3, the reduction of these modifications in TKO ESCs was not sufficient for binding of STAT3 at GSBS. Furthermore, GSBS was digested by micrococcal nuclease in late-gestational NPCs that express GFAP upon LIF stimulation, but not in cells that show no expression of GFAP even in the presence of LIF, indicating that STAT3 can access GSBS in the former cells. We further showed that expression of NF-1A, which is known to potentiate differentiation of mid-gestational NPCs into astrocytes, increased its accessibility. Taken together, our results suggest that chromatin accessibility of GSBS plays a critical role in the regulation of Gfap expression.

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