Epigenetic regulation of the stem cell mitogen Fgf-2 by Mbd1 in adult neural stem/progenitor cells.
Whether and how mechanisms intrinsic to stem cells modulate their proliferation and differentiation are two central questions in stem cell biology. Although exogenous basic fibroblast growth factor 2 (FGF-2/Fgf-2) is commonly used to expand adult neural stem/progenitor cells (NSPCs) in vitro, we do not yet understand the functional significance or the molecular regulation of Fgf-2 expressed endogenously by adult NSPCs. We previously demonstrated that methylated CpG binding protein 1 (MBD1/Mbd1) is a transcriptional repressor of Fgf-2 and is enriched in adult brains. Mbd1 deficiency in mice selectively affected adult neurogenesis and the differentiation of NSPCs. Here we show that an Mbd1 and DNA methylation-mediated epigenetic mechanism regulated the expression of stem cell mitogen Fgf-2 in adult NSPCs. Mbd1 bound to the Fgf-2 promoter and regulates its expression in adult NSPCs. In the absence of functional Mbd1, the Fgf-2 promoter was hypomethylated, and treatment with a DNA methylation inhibitor resulted in increased Fgf-2 expression in adult NSPCs. We further demonstrated that both acute knockdown of Mbd1 or overexpression of Fgf-2 in adult NSPCs inhibited their neuronal differentiation, which could be responsible for the neurogenic deficits observed in Mbd1-deficient mice. These data indicate that intrinsic epigenetic mechanisms play critical roles in the regulation of adult NSPC functions.
Li
Xuekun
X
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131 and the.
Barkho
Basam Z
BZ
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131 and the.
Luo
Yuping
Y
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131 and the.
Smrt
Richard D
RD
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131 and the.
Santistevan
Nicholas J
NJ
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131 and the.
Liu
Changmei
C
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131 and the.
Kuwabara
Tomoko
T
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California 92037.
Gage
Fred H
FH
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California 92037.
Zhao
Xinyu
X
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131 and the. Electronic address: xzhao@salud.unm.edu.
D053687:Adult Stem Cells; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008934:Mitogens / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D051381:Rats
D004268:DNA-Binding Proteins; C489323:Mbd1 protein, mouse; C489324:Mbd1 protein, rat; D008934:Mitogens; D016222:Fibroblast Growth Factor 2