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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.

SUBMITTER: Kong SY

PROVIDER: S-EPMC6266631 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Patterns of methylation at lysine 4 and 27 of histone H3 have been associated with states of gene activation and repression that are developmentally regulated and are thought to underlie the establishment of lineage specific gene expression programs. Recent studies have provided fundamental insight into the problem of lineage specification by comparing global changes in chromatin and transcription between ES and neural stem (NS) cells, points respectively of departure and arrival for neural commitment. With these maps of the differentiated state in place, a central task is now to unravel the chromatin dynamics that enables these differentiation transitions. In particular, the observation that lineage-specific genes repressed in ES cells by Polycomb-mediated H3-K27 trimethylation (H3-K27me3) are demethylated and derepressed in differentiated cells posited the existence of a specific H3-K27 demethylase.In order to gain insight into the epigenetic transitions that enable lineage specification, we investigated the early stages of neural commitment using as model system the monolayer differentiation of mouse ES cells into neural stem (NS) cells. Starting from a comprehensive profiling of JmjC-domain genes, we report here that Jmjd3, recently identified as a H3-K27me3 specific demethylase, controls the expression of key regulators and markers of neurogenesis and is required for commitment to the neural lineage.Our results demonstrate the relevance of an enzymatic activity that antagonizes Polycomb regulation and highlight different modalities through which the dynamics of H3-K27me3 is related to transcriptional output. By showing that the H3-K27 demethylase Jmjd3 is required for commitment to the neural lineage and that it resolves the bivalent domain at the Nestin promoter, our work confirms the functional relevance of bivalent domain resolution that had been posited on the basis of the genome-wide correlation between their controlled resolution and differentiation. In addition, our data indicate that the regulation of H3-K27me3 is highly gene- and context- specific, suggesting that the interplay of methyltransferases and demethylases enables the fine-tuning more than the on/off alternation of methylation states.

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The histone demethylase KDM5A is required for the repression of astrocytogenesis and regulated by the translational machinery in neural progenitor cells.

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