Unravelling molecular mechanisms of transcriptional regulation by Plasmodium falciparum bromodomain proteins

The malaria parasite Plasmodium falciparum infects and multiplies inside human red blood cells. Like all living organisms, malaria parasites need to tightly regulate their genes to produce proteins important for physiological processes such as the invasion of their host cells at the correct point in time. Gene regulation involves epigenetic mechanisms mediated by the dynamic structure and composition chromatin, which consist of repetitive units of DNA wrapping around an octamer of histone proteins. The N-terminal tails of histones can be reversibly modified with small chemical moieties to create a highly dynamic platform of docking stations for various protein complexes that can modify the structure of chromatin and control gene expression in a temporal and spatial fashion. One important modification is the addition of an acetyl-group to lysine residues in histones, which can be bound by proteins that contain a module called a bromodomain. Due to their central role in gene regulation and the fact that potent inhibitors have been developed, bromodomain proteins have recently become topical drug targets in HIV, cancer, and inflammation and could be promising as targets for novel anti-malarials. A unique P. falciparum bromodomain protein has been recently identified, PfBDP1, as a histone acetyl-lysine binding protein that is essential for parasite growth. PfBDP1 binds to histones in the promoter of genes involved in erythrocyte invasion and coordinates their expression. However, the molecular mechanisms by which PfBDP1 controls transcription are unclear. Bromodomain proteins in other organisms regulate gene expression through interactions with specific transcription factors and the Mediator complex, a flexible multi-subunit complex critical for several steps. These interactions induce local changes in chromatin and ultimately lead to transcription by RNA Polymerase II. Evidence has been found that PfBDP1 may act in a similar way in malaria parasites. 

Emerging genome-editing tools will be used and employ genome-wide RNA- and Chromatin-sequencing (ChIPseq) as well as proteomics approaches to uncover fundamental molecular mechanisms of gene regulation mediated by PfBDP1 in the malaria parasite. More specifically, the project will interrogate the functional relationship of PfBDP1 with a candidate co-activator of the ApiAP2 transcription factor family (aim1), the effect of PfBDP1 depletion on components of the basal transcription machinery will be examined (aim 2), and a putative novel chromatin protein that interacts with PfBDP1 will be functionally characterized (aim 3). Together, these studies will contribute to a much improved understanding of how malaria parasites regulate the genes that allow them to infect and survive in their human host.

Project details

Basic Science

Jan 2017 — Dec 2021

Germany