# Prion-like Properties of Short Isoforms of Human Chromatin Modifier PHC3

## TL;DR

Short versions of the PHC3 protein can form prion-like aggregates, affecting gene regulation and chromatin structure.

## Contribution

Short PHC3 isoforms exhibit prion-like behavior and influence chromatin modification in human cells.

## Key findings

- Short N-terminal PHC3 isoforms form prion-like aggregates in yeast and E. coli assays.
- Aggregates sequester full-length PHC3, altering its localization and transcriptional activity.
- Aggregation of short PHC3 isoforms may downregulate PRC1 activity, promoting open chromatin.

## Abstract

The formation of self-perpetuating protein aggregates such as amyloids is associated with various diseases and provides a basis for transmissible (infectious or heritable) protein isoforms (prions). Many human proteins involved in the regulation of transcription contain potentially amyloidogenic regions. Here, it is shown that short N-terminal isoforms of the human protein PHC3, a component of the chromatin-modifying complex PRC1 (Polycomb repressive complex 1), can form prion-like aggregates in yeast assays, exhibit amyloid properties in the E. coli-based C-DAG assay, and produce detergent-resistant aggregates when ectopically expressed in cultured human cells. Moreover, aggregates of short isoforms can sequester the full-length PHC3 protein, causing its accumulation in the cytosol instead of the nucleus. The introduction of an aggregating short PHC3 isoform alters the transcriptional profile of cultured human cells. It is proposed that the aggregation of short isoforms is involved in the feedback downregulation of PRC1 activity, leading to more open chromatin configuration.