Frontiers in Neuroscience (May 2022)

EZH2-Mediated H3K27me3 Targets Transcriptional Circuits of Neuronal Differentiation

  • Serena Buontempo,
  • Pasquale Laise,
  • James M. Hughes,
  • Sebastiano Trattaro,
  • Sebastiano Trattaro,
  • Sebastiano Trattaro,
  • Vivek Das,
  • Chantal Rencurel,
  • Giuseppe Testa,
  • Giuseppe Testa,
  • Giuseppe Testa

DOI
https://doi.org/10.3389/fnins.2022.814144
Journal volume & issue
Vol. 16

Abstract

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The Polycomb Repressive Complex 2 (PRC2) plays important roles in the epigenetic regulation of cellular development and differentiation through H3K27me3-dependent transcriptional repression. Aberrant PRC2 activity has been associated with cancer and neurodevelopmental disorders, particularly with respect to the malfunction of sits catalytic subunit EZH2. Here, we investigated the role of the EZH2-mediated H3K27me3 apposition in neuronal differentiation. We made use of a transgenic mouse model harboring Ezh2 conditional KO alleles to derive embryonic stem cells and differentiate them into glutamatergic neurons. Time course transcriptomics and epigenomic analyses of H3K27me3 in absence of EZH2 revealed a significant dysregulation of molecular networks affecting the glutamatergic differentiation trajectory that resulted in: (i) the deregulation of transcriptional circuitries related to neuronal differentiation and synaptic plasticity, in particular LTD, as a direct effect of EZH2 loss and (ii) the appearance of a GABAergic gene expression signature during glutamatergic neuron differentiation. These results expand the knowledge about the molecular pathways targeted by Polycomb during glutamatergic neuron differentiation.

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