A cytosolic Ezh1 isoform modulates a PRC2–Ezh1 epigenetic adaptive response in postmitotic cells

Abstract

The evolution of chromatin-based epigenetic cell memory may be driven not only by the necessity for cells to stably maintain transcription programs, but also by the need to recognize signals and allow plastic responses to environmental stimuli. The mechanistic role of the epigenome in adult postmitotic tissues, however, remains largely unknown. In vertebrates, two variants of the Polycomb repressive complex (PRC2-Ezh2 and PRC2-Ezh1) control gene silencing via methylation of histone H3 on Lys27 (H3K27me). Here we describe a reversible mechanism that involves a novel isoform of Ezh1 (Ezh1β). Ezh1β lacks the catalytic SET domain and acts in the cytoplasm of skeletal muscle cells to control nuclear PRC2-Ezh1 activity in response to atrophic oxidative stress, by regulating Eed assembly with Suz12 and Ezh1α (the canonical isoform) at their target genes. We report a novel PRC2-Ezh1 function that utilizes Ezh1β as an adaptive stress sensor in the cytoplasm, thus allowing postmitotic cells to maintain tissue integrity in response to environmental changes.

Genome‐wide occupancy of histone H3K27 methyltransferases CURLY LEAF and SWINGER in Arabidopsis seedlings

“…It might also imply that CLF/SWN and FIE probably have distinct functions, although the clf swn double mutants share similar phenotypes with the fie mutants (Bouyer et al., ; Chanvivattana et al., ). In mammals, similarly, a partial overlap between the occupancy of H3K27 methyltransferases EZH1 and EED has been reported recently (Bodega et al., ).…”

How Polycomb‐Mediated Cell Memory Deals With a Changing Environment

“…Ezh1 remains the predominant, if not the exclusive H3K27‐HMTase expressed in differentiated tissues. In a recent study we reported that PRC2‐Ezh1 has a key repressive adaptive function specifically exerted in response to oxidative stress . We discovered a novel Ezh1 coding alternative splicing isoform expressed in healthy skeletal muscle fibers, lacking the catalytic SET domain, (Ezh1β).…”

“…Following ROS stress, phosphorylation by MAPK (mitogen activated protein kinase) negatively controls Bmi‐1 triggering its detachment from chromatin . Conversely, in skeletal muscle cells, oxidative stress induces increase of intra‐nuclear Eed level driving genome‐wide activation of PCR2‐Ezh1 complex and silencing of specific muscle gene networks . In Cardiac hypertrophy generated upon stress or hormone stimulation, the interaction between the lncRNA Chaer and PRC2, inhibits Ezh2 repressive function at hypertrophic genes leading to their induction …”

“…In response to atrophic stimuli Ezh1β is degraded, allowing cytoplasmic Eed to enter the nucleus and form an active PRC2–Ezh1α complex instrumental for adaptive stress response (Figure ). Importantly, as stress stimuli cease, chromatin state reverts to the previous state …”

“…Indeed, extensive ChIP‐seq data obtained on a variety of model systems (e.g., ENCODE Consortium) demonstrate that high levels of H3K27me3 mark can be bona fide predictive of a repressed state. However, ChIP‐seq data on PcG proteins, revealed that the sole presence of individual PcG components at promoters or other cis ‐elements may not be diagnostic of silenced state, but instead of the competence to silence in response to environmental stimuli or other functions including transcriptional activation and alternative splicing . This scenario appears to be particularly relevant in post‐mitotic cells where chromatin‐based cell memory systems do not operate to ensure transmission through cell division but rather to fix ranges of plasticity in tissue specific gene expression programs.…”