Dynamic methylation of histone H3K18 in differentiating Theileria parasites

Kevin Cheeseman,Franck Letourneur,Teresa Calegari-Silva,Nelly Lourenço,Jérémy Berthelet,Jonathan B Weitzman,Guillaume Jannot,Marie Villares,Juliette Hamroune,Fernando Rodrigues-Lima

doi:10.1038/s41467-021-23477-2

Abstract

Lysine methylation on histone tails impacts genome regulation and cell fate determination in many developmental processes. Apicomplexa intracellular parasites cause major diseases and they have developed complex life cycles with fine-tuned differentiation events. Yet, apicomplexa genomes have few transcription factors and little is known about their epigenetic control systems. Tick-borne Theileria apicomplexa species have relatively small, compact genomes and a remarkable ability to transform leucocytes in their bovine hosts. Here we report enriched H3 lysine 18 monomethylation (H3K18me1) on the gene bodies of repressed genes in Theileria macroschizonts. Differentiation to merozoites (merogony) leads to decreased H3K18me1 in parasite nuclei. Pharmacological manipulation of H3K18 acetylation or methylation impacted parasite differentiation and expression of stage-specific genes. Finally, we identify a parasite SET-domain methyltransferase (TaSETup1) that can methylate H3K18 and represses gene expression. Thus, H3K18me1 emerges as an important epigenetic mark which controls gene expression and stage differentiation in Theileria parasites.

Highlights

Lysine methylation on histone tails impacts genome regulation and cell fate determination in many developmental processes
To initiate a study of epigenetic regulation in Theileria parasites, we examined parasite histones focusing on H3
We observed similar parasite-specific staining for H3K18me[1], but not for H3K18Ac, in T. annulata-infected macrophages TaC12 (Fig. 1c, d) and in lymphocytes infected with related T. parva parasites (Supplementary Fig. 2)

Summary

Introduction

Lysine methylation on histone tails impacts genome regulation and cell fate determination in many developmental processes. When Theileria-infected cells are treated in vitro with Buparvaquone, the intracellular parasite diminishes in the host leucocytes, which lose the transformed phenotype, but drug resistance in the field is an emerging concern for disease control. While previous studies have focused on the host signaling pathways activated by intracellular parasites[6,15], very little is known about the regulation of the parasite genome and the mechanisms that orchestrate parasite differentiation and its complex life cycle. Numerous reports of misregulation of KMTs and KDMs in cancer drove an intense search for specific small-molecular inhibitors[21] Despite these advances, relatively little is known about the role of epigenetic proteins (methylation Writers or Erasers) in infectious diseases or in infection-induced cancers[25,26]. In this work we describe the role of methylation of histone H3K18 as an important gene regulatory event during the differentiation of Theileria parasites and identify the first parasite methyltransferase capable of methylating H3K18

Methods

Results

Conclusion