Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex

Abstract

Multipotent progenitor cells of the cerebral cortex balance selfrenewal and differentiation to produce complex neural lineages in a fixed temporal order in a cell-autonomous manner. We studied the role of the polycomb epigenetic system, a chromatin-based repressive mechanism, in controlling cortical progenitor cell selfrenewal and differentiation. We found that the histone methyltransferase of polycomb repressive complex 2 (PCR2), enhancer of Zeste homolog 2 (Ezh2), is essential for controlling the rate at which development progresses within cortical progenitor cell lineages. Loss of function of Ezh2 removes the repressive mark of trimethylated histone H3 at lysine 27 (H3K27me3) in cortical progenitor cells and also prevents its establishment in postmitotic neurons. Removal of this repressive chromatin modification results in marked up-regulation in gene expression, the consequence of which is a shift in the balance between self-renewal and differentiation toward differentiation, both directly to neurons and indirectly via basal progenitor cell genesis. Although the temporal order of neurogenesis and gliogenesis are broadly conserved under these conditions, the timing of neurogenesis, the relative numbers of different cell types, and the switch to gliogenesis are all altered, narrowing the neurogenic period for progenitor cells and reducing their neuronal output. As a consequence, the timing of cortical development is altered significantly after loss of PRC2 function.development | epigenetics | stem cells | chromatin

REST and CoREST are transcriptional and epigenetic regulators of seminal neural fate decisions

“…62,63 REST and CoREST may also interact with other key factors involved in NSC fate decisions, such as the Polycomb group (PcG) proteins, Bmi1 and Ezh2, which are both implicated in regulating NSC maintenance and self-renewal. 90,91 It has been hypothesized that PcG complexes that contain these factors (i.e., PRC1 and PRC2) may be recruited to their genomic sites of action by REST. 8,92,93 However, an alternative explanation may be that these PcG proteins and REST can both be co-recruited to these genomic sites by lncRNAs.…”

Histone demethylase Jmjd3 is required for the development of subsets of retinal bipolar cells

“…Dynamic switches in polycomb targets that restrict pluripotency and define the developmental potential of progenitor cells have been demonstrated by differentiation of ES cells into Pax6-positive radial-glial neuronal progenitor cells (7). The role of H3K27 in defining the timing of neurogenesis and gliogenesis was shown in cortical neurons by ablating Ezh2 at different developmental stages (8)(9)(10). Jmjd3 (Kdm6b) and Utx (Kdm6a) are H3K27 demethylases (11,12).…”

Ikaros promotes early-born neuronal fates in the cerebral cortex

“…In fact, previous studies have shown that early excess neuronal differentiation results in a shortened period of deep layer genesis and a precocious switch to upper layer genesis, keeping the numbers of early-born neurons at normal levels (52). Given that at early stages of cortical development, the D6-Ikaros cortex contains more deep layer neurons than in littermate controls due to the increased early differentiation, it would be predicted that this would repress further genesis of deep layer neurons by negative feedback from postmitotic neurons, as occurs in the retina (53,54) and as has been proposed to operate in the cortex (55).…”

“…Fixation, cryosectioning, and immunohistochemistry were carried out as described (52), with minor modifications. For Ikaros immunostaining, fixation time was reduced to less than 3 h and freshly sectioned tissue was always used for staining.…”