Disruption of the Plasmodium falciparum Life Cycle through Transcriptional Reprogramming by Inhibitors of Jumonji Demethylases.

Little is known about the role of the three Jumonji C (JmjC) enzymes in Plasmodium falciparum (Pf). Here, we show that JIB-04 and other established inhibitors of mammalian JmjC histone demethylases kill asexual blood stage parasites and are even more potent at blocking gametocyte development and gamete formation. In late stage parasites, JIB-04 increased levels of trimethylated lysine residues on histones, suggesting the inhibition of P. falciparum Jumonji demethylase activity. These epigenetic defects coincide with deregulation of invasion, cell motor, and sexual development gene programs, including gene targets coregulated by the PfAP2-I transcription factor and chromatin-binding factor, PfBDP1. Mechanistically, we demonstrate that PfJmj3 converts 2-oxoglutarate to succinate in an iron-dependent manner consistent with mammalian Jumonji enzymes, and this catalytic activity is inhibited by JIB-04 and other Jumonji inhibitors. Our pharmacological studies of Jumonji activity in the malaria parasite provide evidence that inhibition of these enzymatic activities is detrimental to the parasite.

The house fly Y Chromosome is young and minimally differentiated from its ancient X Chromosome partner.

Canonical ancient sex chromosome pairs consist of a gene rich X (or Z) Chromosome and a male-limited (or female-limited) Y (or W) Chromosome that is gene poor. In contrast to highly differentiated sex chromosomes, nascent sex chromosome pairs are homomorphic or very similar in sequence content. Nascent sex chromosomes can arise if an existing sex chromosome fuses to an autosome or an autosome acquires a new sex-determining locus/allele. Sex chromosomes often differ between closely related species and can even be polymorphic within species, suggesting that nascent sex chromosomes arise frequently over the course of evolution. Previously documented sex chromosome transitions involve changes to both members of the sex chromosome pair (X and Y, or Z and W). The house fly has sex chromosomes that resemble the ancestral fly karyotype that originated ∼100 million yr ago; therefore, the house fly is expected to have X and Y Chromosomes with different gene content. We tested this hypothesis using whole-genome sequencing and transcriptomic data, and we discovered little evidence for genetic differentiation between the X and Y in house fly. We propose that the house fly has retained the ancient X Chromosome, but the ancestral Y was replaced by an X Chromosome carrying a new male determining gene. Our proposed hypothesis provides a mechanism for how one member of a sex chromosome pair can experience evolutionary turnover while the other member remains unaffected.