PALI1 facilitates DNA and nucleosome binding by PRC2 and triggers an allosteric activation of catalysis

Qi Zhang,Brady M Owen,Samuel C Agius,Chen Davidovich,Michael Uckelmann,Sarena F Flanigan,Vitalina Levina

doi:10.1038/s41467-021-24866-3

Abstract

The polycomb repressive complex 2 (PRC2) is a histone methyltransferase that maintains cell identities. JARID2 is the only accessory subunit of PRC2 that known to trigger an allosteric activation of methyltransferase. Yet, this mechanism cannot be generalised to all PRC2 variants as, in vertebrates, JARID2 is mutually exclusive with most of the accessory subunits of PRC2. Here we provide functional and structural evidence that the vertebrate-specific PRC2 accessory subunit PALI1 emerged through a convergent evolution to mimic JARID2 at the molecular level. Mechanistically, PRC2 methylates PALI1 K1241, which then binds to the PRC2-regulatory subunit EED to allosterically activate PRC2. PALI1 K1241 is methylated in mouse and human cell lines and is essential for PALI1-induced allosteric activation of PRC2. High-resolution crystal structures revealed that PALI1 mimics the regulatory interactions formed between JARID2 and EED. Independently, PALI1 also facilitates DNA and nucleosome binding by PRC2. In acute myelogenous leukemia cells, overexpression of PALI1 leads to cell differentiation, with the phenotype altered by a separation-of-function PALI1 mutation, defective in allosteric activation and active in DNA binding. Collectively, we show that PALI1 facilitates catalysis and substrate binding by PRC2 and provide evidence that subunit-induced allosteric activation is a general property of holo-PRC2 complexes.

Highlights

The polycomb repressive complex 2 (PRC2) is a histone methyltransferase that maintains cell identities
We analysed multiple publicly available liquid chromatography with tandem mass spectrometry (LC-MS/MS) data originating from Affinity purification mass spectrometry (AP-MS) experiments, where PRC2 subunits were used as baits[15,26,27,28,29] (Fig. 1a and Supplementary Data 1)
Our data indicate that the PRC2-interacting domain of PALI1 is sufficient to enhance the histone methyltransferase (HMTase) activity of PRC2 by two independent mechanisms: (i) allosteric activation of catalysis (Fig. 2) and (ii) DNA binding (Figs. 6 and 7)

Summary

Introduction

The polycomb repressive complex 2 (PRC2) is a histone methyltransferase that maintains cell identities. JARID2 is the only accessory subunit of PRC2 that known to trigger an allosteric activation of methyltransferase. We provide functional and structural evidence that the vertebratespecific PRC2 accessory subunit PALI1 emerged through a convergent evolution to mimic JARID2 at the molecular level. PRC2 methylates PALI1 K1241, which binds to the PRC2-regulatory subunit EED to allosterically activate PRC2. We show that PALI1 facilitates catalysis and substrate binding by PRC2 and provide evidence that subunit-induced allosteric activation is a general property of holo-PRC2 complexes. The polycomb repressive complex 2 (PRC2) is a histone methyltransferase complex that is required for the maintenance of cell identity in all multicellular organisms. Most of the accessory subunits of the vertebrate PRC2 emerged through gene duplication and some are vertebrate specific, with the latter poorly understood mechanistically

Methods

Results

Conclusion