A Plasmodium falciparum MORC protein complex modulates epigenetic control of gene expression through interaction with heterochromatin

Singh, Maneesh Kumar; Bonnell, Victoria Ann; Tojal Da Silva, Israel; Santiago, Verônica Feijoli; Moraes, Miriam Santos; Adderley, Jack; Doerig, Christian; Palmisano, Giuseppe; Llinas, Manuel; Garcia, Celia RS

doi:10.7554/elife.92201

Cited by 3 publications

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Transcriptome analysis reveals a novel DNA element that may interact with chromatin-associated proteins inPlasmodium bergheiduring erythrocytic development

Okafor,

Adam,

Brors

et al. 2024

Preprint

View full text Add to dashboard Cite

Background: The life cycle of Plasmodium parasites is intricate and multistage, alternating between dynamic environments. Temporal regulation of transcription by stage-specific transcription factor binding at particular regulatory regions within gene promoters facilitates its progression. As a result, each new developmental stage is endowed with its unique gene sets, whose just-in-time expression enables the parasite to completely adapt to the necessary circumstances. Our understanding of these transcriptome-level regulatory processes is limited, and more so, a thorough examination of the entire life cycle in the experimentally tractable rodent model organism P. berghei is lacking. Results: We performed a genome-wide analysis of RNA-Seq data from different developmental stages of P. berghei. Integrated data from the human malaria parasites P. falciparum and P. vivax demonstrated that Plasmodium parasites have a unique transcriptional signature. We identified the sets of genes differentially expressed at each stage, clustered them based on similarities of their expression profiles, and predicted the regulatory motifs governing their expression. We interpreted the motifs using known binding sites for established eukaryotic transcription factors, including those of the ApiAP2s, and identified eight potentially novel motifs. Additionally, we expanded the annotation of another motif, AGGTAA, found in genes exclusive to erythrocytic development and identified members of the PfMORC and GCN5 complexes among its possible interacting proteins. Conclusion: This study provides new insights into gene usage and its regulation during P. berghei development. Keywords: Plasmodium berghei, RNA-Seq, ApiAP2s, regulatory motifs, Plasmodium falciparum, Plasmodium vivax

show abstract

Transcriptome analysis reveals a novel DNA element that may interact with chromatin-associated proteins inPlasmodium bergheiduring erythrocytic development

Okafor,

Adam,

Brors

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

PfMORC protein regulates chromatin accessibility and transcriptional repression in the human malaria parasite, Plasmodium falciparum

Chahine,

Gupta,

Lenz

et al. 2024

eLife

View full text Add to dashboard Cite

The environmental challenges the human malaria parasite, Plasmodium falciparum, faces during its progression into its various lifecycle stages warrant the use of effective and highly regulated access to chromatin for transcriptional regulation. Microrchidia (MORC) proteins have been implicated in DNA compaction and gene silencing across plant and animal kingdoms. Accumulating evidence has shed light into the role MORC protein plays as a transcriptional switch in apicomplexan parasites. In this study, using CRISPR/Cas9 genome editing tool along with complementary molecular and genomics approaches, we demonstrate that PfMORC not only modulates chromatin structure and heterochromatin formation throughout the parasite erythrocytic cycle, but is also essential to the parasite survival. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) experiments suggest that PfMORC binds to not only sub-telomeric regions and genes involved in antigenic variation but is also most likely a key modulator of stage transition. Protein knockdown experiments followed by chromatin conformation capture (Hi-C) studies indicate that downregulation of PfMORC induces the collapse of the parasite heterochromatin structure leading to its death. All together these findings confirm that PfMORC plays a crucial role in chromatin structure and gene regulation, validating this factor as a strong candidate for novel antimalarial strategies.

show abstract

PfMORC protein regulates chromatin accessibility and transcriptional repression in the human malaria parasite, Plasmodium falciparum

Chahine,

Gupta,

Lenz

et al. 2024

eLife

View full text Add to dashboard Cite

The environmental challenges the human malaria parasite, Plasmodium falciparum, faces during its progression into its various lifecycle stages warrant the use of effective and highly regulated access to chromatin for transcriptional regulation. Microrchidia (MORC) proteins have been implicated in DNA compaction and gene silencing across plant and animal kingdoms. Accumulating evidence has shed light on the role MORC protein plays as a transcriptional switch in apicomplexan parasites. In this study, using the CRISPR/Cas9 genome editing tool along with complementary molecular and genomics approaches, we demonstrate that PfMORC not only modulates chromatin structure and heterochromatin formation throughout the parasite erythrocytic cycle, but is also essential to the parasite survival. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) experiments suggests that PfMORC binds to not only sub-telomeric regions and genes involved in antigenic variation but may also play a role in modulating stage transition. Protein knockdown experiments followed by chromatin conformation capture (Hi-C) studies indicate that downregulation of PfMORC impairs key histone marks and induces the collapse of the parasite heterochromatin structure leading to its death. All together these findings confirm that PfMORC plays a crucial role in chromatin structure and gene regulation, validating this factor as a strong candidate for novel antimalarial strategies.

show abstract

A Plasmodium falciparum MORC protein complex modulates epigenetic control of gene expression through interaction with heterochromatin

Cited by 3 publications

References 80 publications

Transcriptome analysis reveals a novel DNA element that may interact with chromatin-associated proteins inPlasmodium bergheiduring erythrocytic development

Transcriptome analysis reveals a novel DNA element that may interact with chromatin-associated proteins inPlasmodium bergheiduring erythrocytic development

PfMORC protein regulates chromatin accessibility and transcriptional repression in the human malaria parasite, Plasmodium falciparum

PfMORC protein regulates chromatin accessibility and transcriptional repression in the human malaria parasite, Plasmodium falciparum

Contact Info

Product

Resources

About