H3.3K27M-induced chromatin changes drive ectopic replication through misregulation of the JNK pathway in C. elegans

Kamila Delaney,Florian A Steiner,Joanna M Wenda,Maude Strobino,Andrzej Pankowski

doi:10.1038/s41467-019-10404-9

Kamila Delaney, Florian A Steiner + Show 3 more

Open Access

https://doi.org/10.1038/s41467-019-10404-9

Copy DOI

Abstract

Substitution of lysine 27 with methionine in histone H3.3 is a recently discovered driver mutation of pediatric high-grade gliomas. Mutant cells show decreased levels and altered distribution of H3K27 trimethylation (H3K27me3). How these chromatin changes are established genome-wide and lead to tumorigenesis remains unclear. Here we show that H3.3K27M-mediated alterations in H3K27me3 distribution result in ectopic DNA replication and cell cycle progression of germ cells in Caenorhabditis elegans. By genetically inducing changes in the H3.3 distribution, we demonstrate that both H3.3K27M and pre-existing H3K27me3 act locally and antagonistically on Polycomb Repressive Complex 2 (PRC2) in a concentration-dependent manner. The heterochromatin changes result in extensive gene misregulation, and genetic screening identified upregulation of JNK as an underlying cause of the germcell aberrations. Moreover, JNK inhibition suppresses the replicative fate in human tumor-derived H3.3K27M cells, thus establishing C. elegans as a powerful model for the identification of potential drug targets for treatment of H3.3K27M tumors.

Highlights

Substitution of lysine 27 with methionine in histone H3.3 is a recently discovered driver mutation of pediatric high-grade gliomas
In wild-type C. elegans germ lines, germ cells derive from a distal stem cell, undergo a few cycles of replication and mitotic division and mature through meiotic phases in an assembly line fashion into oocytes that are arrested in diakinesis of meiosis I until fertilization (Fig. 1b, left panel)
Our results demonstrate that H3.3K27M-mediated redistribution of H3K27me[3] directly results in gene expression changes, but that the aberrant oocyte replication and endomitosis is driven by misregulation of specific serine/threonine kinases such as Jun amino-terminal kinase (JNK)

Summary

Introduction

Substitution of lysine 27 with methionine in histone H3.3 is a recently discovered driver mutation of pediatric high-grade gliomas. Mutant cells show decreased levels and altered distribution of H3K27 trimethylation (H3K27me[3]) How these chromatin changes are established genome-wide and lead to tumorigenesis remains unclear. Histones can carry epigenetic information, either through post-translational modifications (PTMs) of the N-terminal tails or through the incorporation of histone variants These chromatin signatures are indispensable for many crucial cellular processes like DNA replication, transcription, cell division or differentiation[1,2]. One notable example is the recently discovered replacement of lysine 27 with methionine in histone H3 or, more commonly, H3.3 that acts as a driver mutation of specific types of pediatric diffuse intrinsic pontine gliomas (DIPGs)[9] and some cases of acute myeloid leukemia[10]. H3K27 methylation is deposited, recognized and propagated by the Polycomb repressive complex 2 (PRC2), a multiprotein complex responsible for maintaining the silent state of the genes during development and cell differentiation[15,16]

Objectives

Methods

Results

Conclusion