Clipped histone H3 is integrated into nucleosomes ofDNAreplication genes in the human malaria parasitePlasmodium falciparum

Abstract

Post‐translational modifications of histone H3 N‐terminal tails are key epigenetic regulators of virulence gene expression and sexual commitment in the human malaria parasite Plasmodium falciparum . Here, we identify proteolytic clipping of the N‐terminal tail of nucleosome‐associated histone H3 at amino acid position 21 as a new chromatin modification. A cathepsin C‐like proteolytic clipping activity is observed in nuclear parasite extracts. Notably, an ectopically expressed version of clipped histone H3, PfH3p‐ HA , is targeted to the nucleus and integrates into mononucleosomes. Furthermore, chromatin immunoprecipitation and next‐generation sequencing analysis identified PfH3p‐ HA as being highly enriched in the upstream region of six genes that play a key role in DNA replication and repair: In these genes, PfH3p‐ HA demarcates a specific 1.5 kb chromatin island adjacent to the open reading frame. Our results indicate that, in P. falciparum , the process of histone clipping may precede chromatin integration hinting at preferential targeting of pre‐assembled PfH3p‐containing nucleosomes to specific genomic regions. The discovery of a protease‐directed mode of chromatin organization in P. falciparum opens up new avenues to develop new anti‐malarials.

Plasmodium falciparum GCN5 acetyltransferase follows a novel proteolytic processing pathway that is essential for its function

“…In a recent study, we have shown that the replication protein PfORC2 goes through an ER-associated proteolytic processing pathway to attain its mature form (Sharma et al, 2018). Another study on histone H3 shows that PfH3 protein is 'clipped' by a nuclear protease in asexual blood stage and this cleaved H3 form is enriched at the upstream regions of few DNA replication/repair genes (Herrera-Solorio et al, 2019). However, cleaving of a nuclear protein by a food vacuole protease is unique to parasites and does not generally occur in eukaryotic organisms.…”

Malaria Parasite Stress Tolerance Is Regulated by DNMT2-Mediated tRNA Cytosine Methylation

“…Malaria pathogens rely on multiple layers of epigenetics in order to regulate gene expression across their complex life cycle (for review, see reference 2 ). This fast-evolving research field has recently revealed several unprecedented epigenetic mechanisms in P. falciparum such as histone clipping ( 3 ), the role of noncoding RNAs in regulating virulence gene expression and sexual commitment ( 4 , 5 ) as well as the role of the RNA exosome-linked RNase (Rrp6) in ncRNA decay regulation ( 6 ). Furthermore, the detection of an unusual DNA cytosine modification has been recently linked to P. falciparum gene expression ( 7 ).…”

The tropical coral Pocillopora acuta displays an unusual chromatin structure and shows histone H3 clipping plasticity upon bleaching

“…Cleavage activity is induced under conditions of nutrient deprivation and sporulation ( Santos-Rosa et al , 2009 ). In the human parasite Plasmodium falciparum , H3 clipping occurs after Ala21 and is abundant in genes regulating DNA replication of the pathogen ( Herrera‐Solorio et al , 2019 ). H3 cleavage was also observed in vertebrates where it is cell type-dependent and plays multiple important biological functions ( Azad et al , 2018 ).…”