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Actin-related protein Arp4 regulates euchromatic gene expression and development by H2A.Z deposition in blood-stage Plasmodium falciparum [Arp4/6 ChIP-seq]

ABSTRACT: Chromatin structure is a basal epigenetic mechanism that determines cellular fate by organizing the dynamic gene expression during the cell development and proliferation. The nuclear members of the evolutionarily conserved actin-related protein (ARPs) superfamily are major components of nucleosome remodeling complexes in the nucleus. In the human malaria parasites, Plasmodium falciparum, comparative genome analysis reveals that two canonical actins and three orthologues of ARPs including PfArp1, PfArp4, and PfArp6 are encoded in the genome of this parasite. However, little is known about the biological functions of the two nuclear PfArp4 and PfArp6 proteins. Here, by Pfarp4 gene knockdown and comparative transcriptome analysis, we uncovered that PfArp4 correlated positively with the dynamic expression of eukaryotic genes. Genome-wide distribution analysis by ChIP-seq revealed that PfArp4 protein colocalized with the histone 2A variant H2A.Z and euchromatic marker H3K9ac in the intergenic regions. Inducible downregulation of PfArp4 resulted in the depletion of H2A.Z and lower H3K9ac level at the upstream regions of eukaryotic genes, thereby repressing the transcriptional abundances. Moreover, we found a significant enrichment of PfArp4 at the flanking sites of centromeres, which likely shapes the H2A.Z-enriched centromeric chromatin microenvironment as a boundary marker. PfArp4 depletion triggered loss of H2A.Z at the entire centromere regions, and arrested the blood-stage development probably through interference with the schizogony process. Finally, PfArp6 was detected as an interactor of PfArp4 in the nucleus. Taken together, our finding indicates that the nuclear PfArp4/6regulates the cell cycles through controlling H2A.Z deposition and centromere biology, which will contribute to understanding the complex epigenetic regulation of gene expression and development of the malaria parasites.

ORGANISM(S): Plasmodium falciparum

PROVIDER: GSE143898 | GEO | 2020/06/24

REPOSITORIES: GEO

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Project description:Protein-coding genes in kinetoplastid protists are transcribed from polycistronic arrays, yielding RNA precursors which are processed to form mature transcripts bearing a 5M-bM-^@M-^Y spliced leader (SL) and 3M-bM-^@M-^Y poly(A) tract. Regions of transcription initiation and termination lack known eukaryotic promoter and terminator elements, and current data suggest that transcription is instead regulated predominantly through epigenetic mechanisms. Several epigenetic marks, including histone modifications, histone variants, and an atypical DNA modification known as base J have been localized to regions of transcription initiation or termination in Trypanosoma brucei, Trypanosoma cruzi, and/or Leishmania major. Despite this conservation, the phenotypes of base J mutants vary significantly across trypanosomatids, suggesting that the specific epigenetic networks governing transcription initiation and termination have diverged significantly during evolution. In this light, we sought to characterize and compare the roles of the histone variants H2A.Z, H2B.V, and H3.V in L. major. As in T. brucei, the histone variants H2A.Z and H2B.V were shown to be essential in L. major using a powerful quantitative plasmid segregation-based test. In contrast and again similar to T. brucei, H3.V is not essential in Leishmania as H3.V-null lines grew normally, resembled WT, and remained infectious. Using SL-primed RNA-seq, we found that H3.V-null parasites have steady-state transcript levels comparable to WT parasites and display no defects in the efficiency of transcription termination at convergent strand switch regions (SSRs). Our results show a conservation of histone variant phenotypes between L. major and T. brucei, in contrast to the phenotypes associated with the epigenetic DNA base J modification. Total RNA from Four LmjF samples were analyzed using RNA-Seq. One of them is wildtype parasites, one is single knockout for H3V gene and two independent double knockouts for H3V gene.

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Actin-related protein Arp4 regulates euchromatic gene expression and development by H2A.Z deposition in blood-stage Plasmodium falciparum [Arp4/6 ChIP-seq]

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