Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration

Abstract

Normal brain function depends on the interaction between highly specialized neurons that operate within anatomically and functionally distinct brain regions. Neuronal specification is driven by transcriptional programs that are established during early neuronal development and remain in place in the adult brain. The fidelity of neuronal specification depends on the robustness of the transcriptional program that supports the neuron type-specific gene expression patterns. Here we show that PRC2, which supports neuron specification during differentiation, contributes to the suppression of a transcriptional program that is detrimental for adult neuron function and survival. We show that PRC2 deficiency in striatal neurons leads to the de-repression of selected, predominantly bivalent PRC2 target genes that are dominated by self-regulating transcription factors normally suppressed in these neurons. The transcriptional changes in PRC2-deficient neurons lead to progressive and fatal neurodegeneration in mice. Our results point to a key role of PRC2 in protecting neurons against degeneration.

Switch-Like Roles for Polycomb Proteins from Neurodevelopment to Neurodegeneration

“…Remarkably, PcG proteins safeguard bivalent domains also in mature neurons and prevent the switch-on of self-reinforcing transcriptional circuits that repress cell-type specific genes. De-repression of these networks in the absence of PCR2's catalytic subunits triggers in turn the progressive neurodegeneration of MSN and Purkinje cells [104] (Figure 6). By contrast to chromatin bivalency in ESC and NPCs, PcG binding in adult MSNs does not position target genes for rapid switch-like expression, but maintains constitutive silencing in order to prevent neurodegeneration.…”

“…Expression of the PCR2 subunits Ezh1, Ezh2, Suz12, and Jarid2b, persists in adult neurons, and points to a role in gene regulation even after completion of neuronal differentiation [104]. Likewise, the H3K27me3 specific demethylases Kdm6b and Utx (ubiquitously transcribed tetratricopeptide repeat, X alias Kdm6a) continue to be expressed in adult neurons.…”

“…To obtain more direct evidence for PRC2's function in adult neurons, von Schimmelmann et al [104] investigated mice with null mutations in Ezh1 and 2 in medium spiny neurons (MSNs, a highly specialized population of striatal cells) and cerebellar Purkinje cells. Both cell types fulfil an important role in motor control and are commonly affected in various neurodegenerative diseases.…”

“…These responders encoded predominantly TFs that were normally expressed during development, particularly, Hox genes that are switched off during early MSN development or non-MSN and non-neuronal cell lineage expressed genes together with several cell death promoting genes ( Figure 6B). About one-quarter of these transcriptional regulators belonged to self-regulatory transcriptional networks that could underpin their robust upregulation in the absence of Ezh1 and 2 [104]. Surprisingly though, this up-regulation failed in inducing neuronal programs that were unrelated to MSNs.…”

Structure of the PRC2 complex and application to drug discovery

“…More recently, PRC2 has been reported to support neuron specification during differentiation through silencing genes responsible for neurodegeneration [75] , suggesting an important role for PRC2 in protecting neurons against degeneration.…”