Abstract
Epigenetic regulatory mechanisms are central to the development and survival of all eukaryotic organisms. These mechanisms critically depend on the marking of chromatin domains with distinctive histone tail modifications (PTMs) and their recognition by effector protein complexes. Here we used quantitative proteomic approaches to unveil interactions between PTMs and associated reader protein complexes of Plasmodium falciparum, a unicellular parasite causing malaria. Histone peptide pull-downs with the most prominent and/or parasite-specific PTMs revealed the binding preference for 14 putative and novel reader proteins. Amongst others, they highlighted the acetylation-level-dependent recruitment of the BDP1/BDP2 complex and identified an PhD-finger protein (PHD 1, PF3D7_1008100) that could mediate a cross-talk between H3K4me2/3 and H3K9ac marks. Tagging and interaction proteomics of 12 identified proteins unveiled the composition of 5 major epigenetic complexes, including the elusive TBP-associated-factor complex as well as two distinct GCN5/ADA2 complexes. Furthermore, it has highlighted a remarkable degree of interaction between these five (sub)complexes. Collectively, this study provides an extensive inventory of PTM-reader interactions and composition of epigenetic complexes. It will not only fuel further explorations of gene regulation amongst ancient eukaryotes, but also provides a stepping stone for exploration of PTM-reader interactions for antimalarial drug development.
Highlights
Malaria is caused by unicellular, eukaryotic parasites from the Plasmodium genus
We present the first large-scale characterisation of the interaction between histone tail modifications and associated reader proteins in P. falciparum using histone peptide pull-down coupled to quantitative mass-spectrometry (Figure 1)
Our analysis revealed that many of these reader proteins reside in multiprotein complexes, containing ‘writers’ of histone modifications or chromatin remodelling enzymes (Figure 4)
Summary
Malaria is caused by unicellular, eukaryotic parasites from the Plasmodium genus. Plasmodium falciparum parasites have an intricate lifecycle between their mosquito vector and human host, where all disease symptoms are associated with the asexual replication of the parasites within red blood cells [1]. Pioneering proteomic analysis of histone extracts identified more than forty posttranslational histone modifications (PTMs) and four different histone variants These PTMs include methylation, acetylation, phosphorylation, ubiquitinoylation, formylation, crotonylation, amongst which acetyl modifications are the most numerous and abundant epigenetic marks [9]. Genome-wide mapping of some of these PTMs and histone variants revealed the basic layout of the Plasmodium epigenome and revealed the key role for histone variants/modifications in dividing the genome into functionally distinct domains
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