Abstract
Polycomb group (PcG) proteins regulate the epigenetic status of transcription regulatory states during development. Progression from pluripotency to differentiation requires the sequential activation and repression of different PcG target genes, however, the relationship between early patterning signals, PcG expression, and the development of the central nervous system is still unclear. Using various models of neuronal differentiation, we provide evidence that CBX2 is a negative regulator of neuronal differentiation. Knock-down of CBX2 expression promotes neurite development, while overexpression of CBX2 inhibits neurite development. Further, we found that CBX2 is a direct target gene of miR-124. During neuronal differentiation, CBX2 was decreased while miR-124 was increased. Mechanistically, CBX2 directly interacts with the promoter region of several neuro-associated genes and regulates their expression. We found that the neuron-specific GAP-43 gene could contribute to the stimulating effect on neurite development associated with inhibition of CBX2.
Highlights
Cell differentiation is mainly achieved via repression of the important genes required for cell pluripotency, with simultaneously triggering of a cascade of epigenetic changes and de-repressing of the expression of lineage-specific genes (Camahort and Cowan, 2012)
In this study we identified CBX2 to be a novel regulator in neuronal differentiation and a direct target for miR-124dependent gene expression regulation (Figure 7)
We discovered a precise molecular pathway for this regulation, i.e., miR-124 suppressed CBX2 expression to stimulate neurite development by upregulating expression of GAP-43
Summary
Cell differentiation is mainly achieved via repression of the important genes required for cell pluripotency, with simultaneously triggering of a cascade of epigenetic changes and de-repressing of the expression of lineage-specific genes (Camahort and Cowan, 2012). First discovered in Drosophila (Jacobs and van Lohuizen, 1999), the Polycomb group (PcG) proteins were recognized as important regulators of differentiation and do so by forming and maintaining repressive chromatin states (Di Croce and Helin, 2013). The PcGs mainly form two protein complexes, the Polycomb repressive complex 2 (PRC2) and the Polycomb repressive complex 1 (PRC1). The PRC2 complex generally contains the Ezh1/2, Suz, and Eed. In the classical model, through its catalytic subunit EZH2, PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), thereby inhibiting the expression of its target genes (Cao et al, 2002). Once bound to H3K27me, the CBX proteins can recruit other components of PRC1 to chromatin via protein–protein interactions. Recruitment of PRC1 can further stimulate transcriptional inhibition through various mechanisms such as histone H2A ubiquitination (H2AK119Ub) and chromatin compaction (Francis et al, 2004; Eskeland et al, 2010; Gao et al, 2012)
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