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.

Ribosome and Translational Control in Stem Cells

“…As previously described, 4EBP-dependent translational repression promotes NSC self-renewal and prevents differentiation [22]. However, it has been reported that MNK-mediated eIF4E phosphorylation is elevated in self-renewing neural progenitor cells (NPCs) and lost upon differentiation, in contrast to mTORC1 activity [33]. The effects of eIF4E phosphorylation on global translation in NPCs were not addressed but seem to strongly promote the expression of KDN5A, which is crucial for maintaining NPC stemness.…”

“…As described above, global translation in undifferentiated stem cells is generally maintained at a low level and needs to be tightly regulated. However, despite this dampening of global translational activity, stem cells need to sustain a proper expression level of key stemness factors in order to maintain their specific identities [7,[10][11][12]29,33]. Conversely, the expression of these factors must be repressed during differentiation while global protein synthesis increases.…”

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

“…KD of KDM5A in NPCs increases astrocytogenesis and GFAP synthesis. Conversely, KDM5A over-expression reduces the transcriptional activity of the GFAP promoter (Kong, Kim, Lee, & Kim, 2018).…”

“…KD of KDM5A in NPCs increases astrocytogenesis and GFAP synthesis. Conversely, KDM5A over‐expression reduces the transcriptional activity of the GFAP promoter (Kong, Kim, Lee, & Kim, ). Moreover, KDM4A and KDM4C are essential for proper differentiation of neural stem cells into neurons and astrocytes.…”

Functional Group-Dependent Induction of Astrocytogenesis and Neurogenesis by Flavone Derivatives

“…Endogenous NSCs are used for cell therapy due to their capacity to differentiate and restore the loss of neurons [2][3][4][5]. The fate of NSC is regulated by extrinsic factors and the culture environments in addition to intrinsic mechanisms [6][7][8][9][10][11][12][13][14]. For example, intrinsic factors such as the basic helix-loop-helix proteins, Mash1, and Neurogenin2, are involved in the acquisition of neuronal cell fate [15][16][17].…”