Abstract
The polycomb group proteins (PcGs) are a group of epigenetic factors associated with gene silencing. They are found in several families of multiprotein complexes, including polycomb repressive complex 2 (PRC2). EZH2, EED and SUZ12 form the core components of the PRC2 complex, which is responsible for the mono, di- and trimethylation of lysine 27 of histone 3 (H3K27Me3), the chromatin mark associated with gene silencing. Loss-of-function studies of Ezh2, the catalytic subunit of PRC2, have shown that PRC2 plays a role in regulating developmental transitions of neuronal progenitor cells (NPCs); from self-renewal to differentiation and the neurogenic-to-gliogenic fate switch. To further address the function of EZH2 and H3K27me3 during neuronal development, we generated a conditional mutant in which Ezh2 was removed in the mammalian isthmic (mid-hindbrain) region from E10.5 onward. Loss of Ezh2 changed the molecular coding of the anterior ventral hindbrain leading to a fate switch and the appearance of ectopic dopaminergic (DA) neurons. The correct specification of the isthmic region is dependent on the signaling factors produced by the Isthmic organizer (IsO), located at the border of the mid- and hindbrain. We propose that the change of cellular fate is a result of the presence of Otx2 in the hindbrain of Ezh2 conditional knock-outs (cKOs) and a dysfunctional IsO, as represented by the loss of Fgf8 and Wnt1. Our work implies that next to controlling developmental transitions, EZH2 mediated gene silencing is important for specification of the isthmic region by influencing IsO functioning and repressing Otx2 in the hindbrain.
Highlights
In recent years, it has become apparent that next to transcription factors, gene regulation via epigenetics plays an important part in the development of a multicellular organism (Bernstein et al, 2006; Mikkelsen et al, 2007; Mohn et al, 2008)
The polycomb repressive complex 2 (PRC2) mediates the mono, di and tri-methylation of lysine 27 of histone 3 (H3K27me1, 2 and 3; Shen et al, 2008) and consists of three core subunits: enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development (EED) and suppressor of zeste 12 (SUZ12), that are all crucial for the catalytic activity of the complex (Corley and Kroll, 2015)
We show that the En1Cre driven deletion of Ezh2 and a consequential loss of H3K27me3 leads to a disorganized Isthmic Organizer (IsO) and ectopic expression of the transcription factor Otx2 in the hindbrain
Summary
It has become apparent that next to transcription factors, gene regulation via epigenetics plays an important part in the development of a multicellular organism (Bernstein et al, 2006; Mikkelsen et al, 2007; Mohn et al, 2008). When Ezh or Eed were removed during neurogenesis, the neurogenic phase was prolonged at the expense of the onset of astrogenesis (Hirabayashi et al, 2009) These data suggest that PRC2 plays a role in regulating developmental transitions in cortical progenitor cells; from self-renewal to differentiation and the neurogenic-to-gliogenic switch (Hirabayashi et al, 2009; Pereira et al, 2010). Our data suggest that next to transcription factors, gene repression via EZH2 and H3K27me are required for the repression of Otx in the hindbrain, maintenance of the IsO and the correct fate-determination of the isthmic area
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