Abstract:During red-blood-cell-stage infection of Plasmodium falciparum, the parasite undergoes repeated rounds of replication, egress, and invasion. Erythrocyte invasion involves specific interactions between host cell receptors and parasite ligands and coordinated expression of genes specific to this step of the life cycle. We show that a parasite-specific bromodomain protein, PfBDP1, binds to chromatin at transcriptional start sites of invasion-related genes and directly controls their expression. Conditional PfBDP1… Show more
“…3a), and BDP1-knockdown parasites consistently failed to invade new erythrocytes. BDP1 also appears to act as a recruitment platform for other effector proteins such as BDP2 and members of the apicomplexan AP2 (ApiAP2) transcription factor family [31]. Fig.…”
Section: Parasite Genomicsmentioning
confidence: 99%
“…1Major advances in omics-related fields. This figure highlights landmark studies providing key insights into parasite makeup, development, and pathogenesis ( yellow boxes ) as well as crucial technical advances ( blue boxes ) since the first Plasmodium genomes were published in 2002 [2, 5, 12, 13, 27, 29, 31, 39, 40, 42, 43, 48–50, 53, 54, 57, 66, 114, 115, 151, 153–178]. AID auxin-inducible degron, ART artemisinin, cKD conditional knockdown, CRISPR clustered regularly interspaced short palindromic repeats, DD destabilization domain, K13 kelch13, Pb P. berghei , Pf P. falciparum , TSS transcription start site, TF transcription factor, ZNF zinc finger nuclease…”
Malaria continues to impose a significant disease burden on low- and middle-income countries in the tropics. However, revolutionary progress over the last 3 years in nucleic acid sequencing, reverse genetics, and post-genome analyses has generated step changes in our understanding of malaria parasite (Plasmodium spp.) biology and its interactions with its host and vector. Driven by the availability of vast amounts of genome sequence data from Plasmodium species strains, relevant human populations of different ethnicities, and mosquito vectors, researchers can consider any biological component of the malarial process in isolation or in the interactive setting that is infection. In particular, considerable progress has been made in the area of population genomics, with Plasmodium falciparum serving as a highly relevant model. Such studies have demonstrated that genome evolution under strong selective pressure can be detected. These data, combined with reverse genetics, have enabled the identification of the region of the P. falciparum genome that is under selective pressure and the confirmation of the functionality of the mutations in the kelch13 gene that accompany resistance to the major frontline antimalarial, artemisinin. Furthermore, the central role of epigenetic regulation of gene expression and antigenic variation and developmental fate in P. falciparum is becoming ever clearer. This review summarizes recent exciting discoveries that genome technologies have enabled in malaria research and highlights some of their applications to healthcare. The knowledge gained will help to develop surveillance approaches for the emergence or spread of drug resistance and to identify new targets for the development of antimalarial drugs and perhaps vaccines.
“…3a), and BDP1-knockdown parasites consistently failed to invade new erythrocytes. BDP1 also appears to act as a recruitment platform for other effector proteins such as BDP2 and members of the apicomplexan AP2 (ApiAP2) transcription factor family [31]. Fig.…”
Section: Parasite Genomicsmentioning
confidence: 99%
“…1Major advances in omics-related fields. This figure highlights landmark studies providing key insights into parasite makeup, development, and pathogenesis ( yellow boxes ) as well as crucial technical advances ( blue boxes ) since the first Plasmodium genomes were published in 2002 [2, 5, 12, 13, 27, 29, 31, 39, 40, 42, 43, 48–50, 53, 54, 57, 66, 114, 115, 151, 153–178]. AID auxin-inducible degron, ART artemisinin, cKD conditional knockdown, CRISPR clustered regularly interspaced short palindromic repeats, DD destabilization domain, K13 kelch13, Pb P. berghei , Pf P. falciparum , TSS transcription start site, TF transcription factor, ZNF zinc finger nuclease…”
Malaria continues to impose a significant disease burden on low- and middle-income countries in the tropics. However, revolutionary progress over the last 3 years in nucleic acid sequencing, reverse genetics, and post-genome analyses has generated step changes in our understanding of malaria parasite (Plasmodium spp.) biology and its interactions with its host and vector. Driven by the availability of vast amounts of genome sequence data from Plasmodium species strains, relevant human populations of different ethnicities, and mosquito vectors, researchers can consider any biological component of the malarial process in isolation or in the interactive setting that is infection. In particular, considerable progress has been made in the area of population genomics, with Plasmodium falciparum serving as a highly relevant model. Such studies have demonstrated that genome evolution under strong selective pressure can be detected. These data, combined with reverse genetics, have enabled the identification of the region of the P. falciparum genome that is under selective pressure and the confirmation of the functionality of the mutations in the kelch13 gene that accompany resistance to the major frontline antimalarial, artemisinin. Furthermore, the central role of epigenetic regulation of gene expression and antigenic variation and developmental fate in P. falciparum is becoming ever clearer. This review summarizes recent exciting discoveries that genome technologies have enabled in malaria research and highlights some of their applications to healthcare. The knowledge gained will help to develop surveillance approaches for the emergence or spread of drug resistance and to identify new targets for the development of antimalarial drugs and perhaps vaccines.
“…Considering our general lack of understanding of transcriptional regulation in malaria parasites, this family should serve as fertile ground for deciphering important regulatory pathways; however, to date only a single member of the family has been characterized in any depth, the probable ortholog to the yeast protein GCN5 (Fan et al, 2004). In this issue, Josling and colleagues (Josling et al, 2015) utilize an elegant genetic and biochemical approach to characterize a second member of the family, a protein called PfBDP1, and show that it plays a crucial role in regulating the expression of a large cohort of genes involved in red blood cell invasion by parasites. The findings are consistent with bromodomain-containing proteins serving as regulators of transcriptional programs, in this case coordinating the expression of a large suite of genes associated with host cell invasion.…”
mentioning
confidence: 96%
“…List of Bromodomain-Containing Proteins Encoded in the Genome of the Malaria Parasite Plasmodium falciparum Coordinates expression of genes involved in red blood cell invasionJosling et al, 2015 …”
Malaria parasites must express a large contingent of invasion-related genes to propagate within host red blood cells. In this issue of Cell Host & Microbe, Josling et al. (2015) identify a bromodomain protein that serves as a transcriptional activator required to coordinate expression of these genes and enable parasite proliferation.
“…Consequently, pathogenic parasites rely on epigenetic control mechanisms to fine-tune gene expression, facilitating adaptation to different hosts/tissues or stressful environments. Emerging evidence has suggested that bromodomain-containing proteins are important mediators of gene expression that may represent novel drug targets in protozoal pathogens (3)(4)(5). This review discusses the various bromodomain proteins in representative parasites from the Apicomplexa and Euglenozoa phyla, providing novel insight into the evolution of this protein family and how it may contribute to parasite biology in the context of lysine acetylation signaling.…”
SUMMARY
Parasitic infections remain one of the most pressing global health concerns of our day, affecting billions of people and producing unsustainable economic burdens. The rise of drug-resistant parasites has created an urgent need to study their biology in hopes of uncovering new potential drug targets. It has been established that disrupting gene expression by interfering with lysine acetylation is detrimental to survival of apicomplexan (Toxoplasma gondii and Plasmodium spp.) and kinetoplastid (Leishmania spp. and Trypanosoma spp.) parasites. As “readers” of lysine acetylation, bromodomain proteins have emerged as key gene expression regulators and a promising new class of drug target. Here we review recent studies that demonstrate the essential roles played by bromodomain-containing proteins in parasite viability, invasion, and stage switching and present work showing the efficacy of bromodomain inhibitors as novel antiparasitic agents. In addition, we performed a phylogenetic analysis of bromodomain proteins in representative pathogens, some of which possess unique features that may be specific to parasite processes and useful in future drug development.
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