Unravelling molecular mechanisms of transcriptional regulation by Plasmodium falciparum bromodomain proteins
Final Report Abstract
The human malaria parasite Plasmodium falciparum is a protozoan parasite that multiplies asexually inside red blood cells. For its transmission, the parasite differentiates into sexual stages, male and female gametocytes, which are taken up by female Anopheles mosquitos. After fertilization and the development of a new generation of infective parasites, these are injected by the mosquito into a new human being during a blood meal, thereby reinitiating the infectious cycle. The virulence of the disease is modulated by the expression pattern of single members of variant surface antigens exported to the red blood cell surface, which are encoded in multigene families in the parasite’s genome. Both, the differentiation and the virulence of the parasite rely on the epigenetic regulation of gene expression, which is mediated by posttranslational modifications of the histone proteins that package the genome. The genome wide pattern of histone acetylation is critical for correct gene transcription. Histone acetylations are bound by bromodomain proteins, which act like adapter proteins that interact with chromatin remodelling proteins and transcription factors to modulate gene expression. Our previous work demonstrated that the bromodomain protein 1, PfBDP1, is essential for the expression of genes that mediate invasion of the parasite into red blood cells. Here we further investigated the molecular mechanisms of gene regulation by PfBDP1. We functionally characterized the PfBDP1 interacting bromodomain protein PfBDP7 and demonstrated that it co-regulates virulence genes together with PfBDP1. While in mature schizont stage parasites PfBDP1 and PfBDP7 are mostly bound to acetylated histones at invasion genes and are critical for their correct activation, we discovered that in earlier parasite stages, both proteins are enriched at genes coding for variant surface antigens and suppress their activation. Further, we showed that PfBDP1 is critical for the development of gametocytes. Depletion of PfBDP1 resulted in a cascade of gene misexpression, leading to the formation of abnormal gametocytes. Mapping genome wide binding sites of PfBDP1 and correlating these with the gene expression changes after PfBDP1 knock down revealed that PfBDP1 directly regulates a transcription factor that acts as a suppressor of stage-inappropriate genes. Collectively, our studies demonstrate that P. falciparum bromodomain proteins are critical regulators of parasite development and virulence and make them interesting candidates for further exploration as novel anti-malaria drug target.
Publications
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(2019) ApiAP2 Transcription Factors in Apicomplexan Parasites. Pathogens, 8
Jeninga, M.D., Quinn, J.E. and Petter, M.
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(2020) Histone modifications associated with gene expression and genome accessibility are dynamically enriched at Plasmodium falciparum regulatory sequences. Epigenetics Chromatin. 2020 Nov 23;13(1):50
Tang J, Chisholm S.A., Yeoh L.M., Gilson P.R., Papenfuss A.T., Day K.P., Petter M, Duffy M.F.
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(2022) The putative bromodomain protein PfBDP7 of the human malaria parasite Plasmodium falciparum cooperates with PfBDP1 in the silencing of variant surface antigen expression. Front Cell Dev Biol, 10, 816558
Quinn, J.E., Jeninga, M.D., Limm, K., Pareek, K., Meissgeier, T., Bachmann, A., Duffy, M.F. and Petter, M.
