Histone Modifications and Other Facets of Epigenetic Regulation in Trypanosomatids: Leaving Their Mark

Abstract

Histone posttranslational modifications (PTMs) modulate several eukaryotic cellular processes, including transcription, replication, and repair. Vast arrays of modifications have been identified in conventional eukaryotes over the last 20 to 25 years. While initial studies uncovered these primarily on histone tails, multiple modifications were subsequently found on the central globular domains as well. Histones are evolutionarily conserved across eukaryotes, and a large number of their PTMs and the functional relevance of these PTMs are largely conserved. Trypanosomatids, however, are early diverging eukaryotes. Although possessing all four canonical histones as well as several variants, their sequences diverge from those of other eukaryotes, particularly in the tails. Consequently, the modifications they carry also vary. Initial analyses almost 15 years ago suggested that trypanosomatids possessed a smaller collection of histone modifications. However, exhaustive high resolution mass spectrometry analyses in the last few years have overturned this belief, and it is now evident that the “histone code” proposed by Allis and coworkers in the early years of this century is as complex in these organisms as in other eukaryotes. Trypanosomatids cause several diseases, and the members of this group of organisms have varied lifestyles, evolving diverse mechanisms to evade the host immune system, some of which have been found to be principally controlled by epigenetic mechanisms. This minireview aims to acquaint the reader with the impact of histone PTMs on trypanosomatid cellular processes, as well as other facets of trypanosomatid epigenetic regulation, including the influence of three-dimensional (3D) genome architecture, and discusses avenues for future investigations.

Protein Lactylation Critically Regulates Energy Metabolism in the Protozoan Parasite Trypanosoma brucei

“…Furthermore, the Kla sites on H3 and H4 were observed to be localized to the N- and C-terminal tails, which bear numerous PTM sites with various modifications such as hyperacetylation. H3K23 and H3K32 ( Supplementary Figure 3C ) in T. brucei may be synonymous with the universal H3K27 and H3K36 residues and might represent an ancient basal repertoire of histone modifications ( Saha, 2020 ). H3K27La was previously identified in both human and mouse ( Zhang et al, 2019 ), while H3K32La in T. brucei is probably a species-specific modification.…”

“…PTMs, such as protein acylation or phosphorylation, play critical roles in cellular metabolism and signal transduction, and can modulate protein conformation, stability, and function ( Heinemann and Sauer, 2010 ). These modifications can alter the stability or function of the modified proteins, especially histones and their variants, and frequently work in concert to influence fundamental cellular processes, including gene expression ( Kouzarides, 2007 ; Croken et al, 2012 ; Saha, 2020 ). Several studies have implicated PTMs in multiple aspects of trypanosome biology, especially in the modulation of parasite development and viability ( Nett et al, 2009 ; Urbaniak et al, 2013 ; Moretti et al, 2018 ; Zhang et al, 2020 ).…”

Impact of Genetic Diversity and Genome Plasticity of Leishmania spp. in Treatment and the Search for Novel Chemotherapeutic Targets

“…All genes are constitutively expressed, mainly by RNA polymerase II; however, the start of transcription is not well understood because canonical promoter sequences have not yet been found in these parasites ( Martínez-Calvillo et al., 2003 ; Martínez-Calvillo et al., 2004 ; Thomas et al., 2009 ; Iantorno et al., 2017 ). Epigenetic mechanisms appear to play a role in Leishmania transcription initiation by influencing DNA accessibility ( Thomas et al., 2009 ; Chandra et al., 2017 ; Saha, 2020 ; Grünebast et al., 2021 ). Transcription termination occurs at the end of each polycistronic transcription unit and is determined by the presence of the base J ( van Luenen et al., 2012 ; Reynolds et al., 2016 ; Kieft et al., 2020 ).…”

Protein acetylation in the critical biological processes in protozoan parasites

“…The MYST family of KATs are named for the first identified proteins of this group (MOZ, Ybf2/ Sas3, Sas2, Tip60). While T. gondii and P. falciparum contain more GNAT family KATs, trypanosomes have many MYST KATs [24] (Figure 1 and Table S1). The third group of KATs is similar to Hat1, the first identified histone acetyltransferase in yeast [25].…”