Methyl-CpG binding proteins are involved in restricting differentiation plasticity in neurons.
Neurons and astrocytes are generated from common neural precursors, yet neurogenesis precedes astrocytogenesis, which normally commences at later stages of development. We have previously reported that a particular cytosine residue within a STAT3-binding site in the astrocyte-specific marker glial fibrillary acidic protein (GFAP) gene promoter becomes demethylated in neuroepithelial cells as gestation proceeds. This demethylation correlates tightly with the onset of astrocyte differentiation, suggesting that a change in DNA methylation at cell-type-specific gene promoters controls the switch from neurogenesis to astrocytogenesis in the developing brain. Here, we show that late-gestation neuroepithelial cells, which have already lost the methylation in the STAT3-binding site within the GFAP promoter, can still give rise to neurons and that these neurons do not respond to a STAT3-activating cytokine to express GFAP. Members of a transcriptional repressor family, the methylated-CpG binding proteins (MBDs), including MeCP2, are predominantly expressed in neurons, and ectopic MeCP2 expression inhibited astrocyte differentiation of neuroepithelial cells. Moreover, we found that exon 1 of the GFAP gene remains hypermethylated even in neuroepithelial cells at a late developmental stage and in neurons differentiated from such neuroepithelial cells. We further demonstrate that MeCP2 actually binds to the highly methylated exon 1 of the GFAP gene in neurons. These results suggest that region-specific DNA methylation and MBDs play an important role in the regulation of differentiation plasticity in neurons.
Setoguchi
Hiroki
H
Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara, Japan. kin@bs.naist.jp
Namihira
Masakazu
M
Kohyama
Jun
J
Asano
Hirotsugu
H
Sanosaka
Tsukasa
T
Nakashima
Kinichi
K
D000818:Animals; D001253:Astrocytes / Q000737:chemistry; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000502:physiology; D004622:Embryo, Mammalian; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D051783:Methyl-CpG-Binding Protein 2 / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins / Q000378:metabolism; D046569:Neuroepithelial Cells / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D014162:Transfection / Q000379:methods; D014404:Tubulin / Q000378:metabolism
D016207:Cytokines; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; C489324:Mbd1 protein, rat; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D014404:Tubulin; C462941:beta3 tubulin, mouse