Dynamic Chromatin Structure and Epigenetics Control the Fate of Malaria Parasites

Abstract

Multiple hosts and various life cycle stages prompt the human malaria parasite, Plasmodium falciparum, to acquire sophisticated molecular mechanisms to ensure its survival, spread, and transmission to its next host. To face these environmental challenges, increasing evidence suggests that the parasite has developed complex and complementary layers of regulatory mechanisms controlling gene expression. Here, we discuss the recent developments in the discovery of molecular components that contribute to cell replication and differentiation and highlight the major contributions of epigenetics, transcription factors, and nuclear architecture in controlling gene regulation and life cycle progression in Plasmodium spp.

Keywords: Plasmodium; chromatin architecture; epigenetics; malaria; transcription factor.

Figure 1.. Life cycle of P. falciparum.

An infected mosquito injects sporozoites into the human during a blood meal. After invading the hepatocytes, parasites replicate multiple times to generate thousands of merozoites, which then invade red blood cells and initiate the intraerythrocytic developmental cycle (IDC). In P. vivax and P. ovale, a dormant stage, hypnozoite, is able to persist in the liver for months, sometime years, before being reactivated and released into the blood stream. During IDC, a parasite multiplies asexually and undergoes several rounds of DNA replication resulting in the formation of 16 to 32 new merozoites. These merozoites reinvade new RBCs after bursting out of the host cells. During this cycle, a number of these parasites differentiate into male and female gametocytes and are taken up by a mosquito. The formed zygote develops into an ookinete, then an oocyst in the Anopheles midgut. The oocyst grows and divides into thousands of sporozoites which migrate to the salivary glands to ensure a new full cycle. The mosquito stages are represented in blue and human stages in red.

Figure 2.. Chromatin remodeling and sexual commitment in Plasmodium.

(A) Nucleosome occupancy, histone variants, and epigenetic marks participate in the chromatin remodeling at a given promoter and lead to the accessibility of the transcription machinery. LncRNAs and chromatin modifying enzymes are also involved in the regulation of gene expression. (B) Cellular and molecular mechanisms implied in the gametocyte commitment. Dynamic chromatin structure and epigenetic factors are crucial in the control of the master regulator of gametocytogenesis, AP2-G.

Figure 3.. Dynamic chromatin organization across different stages of P. falciparum.

Telomere regions (black spheres) as well as inactive var genes (red spheres) are located within the repressive cluster at the periphery of the nucleus, while centromeres (green spheres) form a cluster on the opposite side. The active var gene is represented by a blue sphere. Throughout the life cycle, extensive remodeling of the chromatin occurs and provides essential modulation of gene expression during parasite development.