The histone demethylase KDM5A is required for the repression of astrocytogenesis and regulated by the translational machinery in neural progenitor cells
- PMID: 29212818
- PMCID: PMC6266631
- DOI: 10.1096/fj.201700780R
The histone demethylase KDM5A is required for the repression of astrocytogenesis and regulated by the translational machinery in neural progenitor cells
Abstract
Histone demethylases are known to play important roles in the determination of the fate of stem cells and in cancer progression. In this study, we show that the lysine 4 of histone H3 (H3K4), lysine-specific demethylase 5A (KDM5A) is essential for the repression of astrocyte differentiation in neural progenitor cells (NPCs), and its expression is regulated by translational machinery. Knockdown of KDM5A in NPCs increased astrocytogenesis, and conversely, KDM5A overexpression reduced the transcriptional activity of the Gfap promoter. Induction of astrocytogenesis by ciliary neurotrophic factor (CNTF) or small interfering RNA-induced knockdown of KDM5A decreased KDM5A recruitment to the Gfap promoter and increased H3K4 methylation. The transcript level of Kdm5a was high, whereas KDM5A protein level was low in CNTF induced astrocytes. During astroglial differentiation, translational activity indicated by the phosphorylation of eukaryotic translation initiation factor (eIF)4E was decreased. Treatment of NPCs with the cercosporamide, a MAPK-interacting kinases inhibitor, reduced eIF4E phosphorylation and KDM5A protein expression, increased GFAP levels, and enhanced astrocytogenesis. These data suggest that KDM5A is a key regulator that maintains NPCs in an undifferentiated state by repressing astrocytogenesis and that its expression is translationally controlled during astrocyte differentiation. Thus, KDM5A is a promising target for the modulation of NPC fate.-Kong, S.-Y., Kim, W., Lee, H.-R., Kim, H.-J. The histone demethylase KDM5A is required for the repression of astrocytogenesis and regulated by the translational machinery in neural progenitor cells.
Keywords: H3K4 demethylase; MAPK-interacting kinase; NSC differentiation; eIF-4E; epigenetics.
Conflict of interest statement
This research was supported by the Chung-Ang University Excellent Student Scholarship and the National Research Foundation of Korea Grant NRF2017R1A1A1A05000876 (to H.J.K.), funded by the South Korean government. The Alabama Neuroscience Blueprint Core was supported by the U.S. National Institutes of Health, National Institute of Neurological Disorders and Stroke Grants NS39055 and NS057098. The authors declare no conflicts of interest.
Figures
References
-
- Gage F. H. (2000) Mammalian neural stem cells. Science 287, 1433–1438 - PubMed
-
- Kim H. J., McMillan E., Han F., Svendsen C. N. (2009) Regionally specified human neural progenitor cells derived from the mesencephalon and forebrain undergo increased neurogenesis following overexpression of ASCL1. Stem Cells 27, 390–398 - PubMed
-
- Reynolds B. A., Weiss S. (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255, 1707–1710 - PubMed
-
- Jepsen K., Solum D., Zhou T., McEvilly R. J., Kim H. J., Glass C. K., Hermanson O., Rosenfeld M. G. (2007) SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature 450, 415–419 - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous
