Malaria parasite harbors a unique protein lysine methyltransferase targeting both chromatin and motility machinery - PROJECT SUMMARY
Epigenetics machinery has been used as important therapeutic drug targets evident by the
successful inhibitors for cancer treatment. Although the malaria parasite harbors many epigenetic
regulators, it remains a great challenge to discover unique ones diverse from those in the human
host. Based on previous studies and our recent preliminary data, PfSET7, one of ten SET-domain
containing lysine (K) methyltransferases (KMTs) in Plasmodium falciparum, is discovered to be a
Plasmodium-specific KMT with unique structures and functions. PfSET7 does not belong to any
known SET family in model organisms because it contains a unique motif II in the SET domain.
PfSET7 was found localized at the apical tip of merozoite and downregulation of PfSET7 by ~35%
using our newly developed CRISPR interference (CRISPRi) resulted in defects in merozoite
egress and invasion, reminiscent of the findings that Toxoplasma gondii apical complex KMT
(TgAKMT) is also localized at the apical tip before egress and disruption of TgAKMT led to defects
in parasite egress and invasion due to impaired motility. However, TgAKMT’s mode of action,
especially its substrates, is still unknown. Remarkably, PfSET7 was found also localized in the
gametocyte cytoplasm and nucleus, and downregulation of PfSET7 by ~26% also led to defects
in gametocyte development, coincidentally with the findings that PfSET7 has peak expression in
gametocytes and many distinct methylated lysines were identified in gametocyte histones.
Notably, PfSET7 contains four Plasmodium-specific regions and is only ~41% identical to
TgAKMT, indicating PfSET7 harbors malaria-specific structures. Based on these findings, we
hypothesize that PfSET7 is a Plasmodium-specific KMT and has a dual function in the regulation
of gametocyte gene expression and merozoite motility during egress/invasion by targeting histone
and non-histone proteins, respectively. To decipher the critical function and substrate specificity
of PfSET7, we will apply advanced new technologies including a stronger CRISPRi KD with
optimized gRNAs and a conditional knockout for gene functional study, and quantitative
methylome for substrate identification. It is anticipated that this study will lay a solid foundation for
understanding PfSET7’s mechanism of action and the development of novel apicomplexan-
specific epigenetic drugs.
