Biology subjects

Petter, M.

Publications and source records attributed to Petter, M..

4 recordsLinked to original sources

bioRxiv2025

Protein landscape of the chromatin states in the malaria parasite Plasmodium falciparum

Epigenetic regulation is essential for development and adaptation across eukaryotes. However, a comprehensive overview of the molecular framework of chromatin-mediated regulation, particularly in non-model organisms, is lacking. Here, we present a systematic proteomic characterization of the chromatin states in P. falciparum, an ancient human pathogen with unique genome composition and epigenetic blueprint. We adapted and systematically employed three proximity-labelling approaches to provide a high-confidence and comprehensive proteome of heterochromatin, euchromatin and (peri)centromeric chromatin comprised of 214 proteins, including both expected and new chromatin components. Characterization of 20 proteins validated our approach and i) uncovered a protein influencing parasite transmission, ii) defined complexes relevant for histone variant exchange and chromatin-RNA interactions and iii) provided evidence for the so far believed to be absent spindle assembly checkpoint and the corresponding Bub1-like kinase. This study hence offers a reference proteome of the chromatin states and a resource to uncover novel chromatin biology.

cell biology↗

bioRxiv2025

A novel inhibitor against the bromodomain PfBDP1 of the malaria pathogen Plasmodium falciparum

The rise of drug resistances in malaria necessitates the exploration of novel therapeutic strategies. Targeting epigenetic pathways could open new, promising treatment avenues. In this study, we focus on PfBDP1, an essential bromodomain protein in P. falciparum. Utilizing the pan-selective bromodomain inhibitor MPM6, we identified a potent initial hit and subsequently developed it into a nanomolar binder. Through a combination of virtual docking, isothermal titration calorimetry, and X-ray crystallography, we elucidated the molecular interactions of the new inhibitors with PfBD1. Our findings include the first cocrystallized structures of PfBD1 and PvBD1 with these inhibitors, providing insights into their binding mechanisms. Further validation using conditional knockdown of PfBDP1 in P. falciparum demonstrated parasite sensitivity to the inhibitor, underscoring its potential as a targeted therapeutic approach against malaria.

biochemistry↗

bioRxiv2021

Constant rate of Plasmodium falciparum sexual commitment promotes variable gametocyte proportions as infection progresses over time

Plasmodium falciparum infections persist through long dry seasons at low parasitaemia without causing malaria symptoms and thus remain untreated. In asymptomatic children, increased circulation of infected erythrocytes without adhering to the vascular endothelium is observed during the dry months, compared to febrile malaria in the wet season. However, alterations of parasite sexual commitment and gametocytogenesis have not been investigated. Here, we compared the expression of genes related to sexual commitment and gametocytogenesis, the proportion and density of P. falciparum gametocytes, and the blood concentration of phospholipids in dry season asymptomatic individuals versus symptomatic subjects in the wet season. Additionally, we adapted a within-host mathematical model considering asexual and sexually-committed parasites and gametocytes to understand the dynamics of gametocyte number and proportion as infections progress. Compared to clinical malaria cases, transcripts of late-stage gametocytes were predominantly upregulated in the dry season, associating with increased proportions of mature gametocytes; while transcription of genes related to parasite sexual commitment was unaltered throughout the year. Our data suggest that gametocyte density and proportion diverge as infections progress from recent transmission to chronic carriage, without alterations in the sexual commitment rate over time.

microbiology↗

bioRxiv2017

Integrated transcriptomic, proteomic and epigenomic analysis of Plasmodium vivax salivary-gland sporozoites

Plasmodium vivax is the key obstacle to malaria elimination in Asia and Latin America, largely attributed to its ability to form resilient hypnozoites (sleeper-cells) in the host liver that escape treatment and cause relapsing infections. The decision to form hypnozoites is made early in the liver infection and may already be set in sporozoites prior to invasion. To better understand these early stages of infection, we undertook a comprehensive transcriptomic and histone epigenetic characterization of P. vivax sporozoites. The salivary-gland sporozoite transcriptome is heavily composed of transcripts associated with functions needed for early infection of the vertebrate host and development within hepatocytes. Through comparisons to recently published proteome data for the P. vivax sporozoite, our study finds that although highly transcribed, these transcripts are not detectable as proteins and may be regulated through translational repression; a finding we test for a small subset of transcripts and proteins through immunofluorescent microscopy of sporozoites and liver stages in humanized mice. We identify differential transcription between the sporozoite and published transcriptomes of asexual blood-stages and mixed versus hypnozoite-enriched liver stages. These comparisons point to multiple layers of transcriptional, post-transcriptional and post-translational control that appear active in sporozoites and to a lesser extent hypnozoites, but largely absent in replicating liver schizonts or mixed blood-stages. Common transcripts up-regulated in sporozoites and hypnozoites compared to mixed (i.e., schizont) liver-stages identify genes linked to dormancy/persistence in bacteria, amoebae and plants. We also characterise histone epigenetic modifications in the P. vivax sporozoite and explore their role in regulating transcription. Collectively, these data support the hypothesis that the sporozoite as a tightly programmed stage primed to infect the human host and identifies potential mechanisms for hypnozoite-formation that may be further explored in liver stage models.

microbiology↗