Dziedziech, A. | Search bioRxiv

bioRxiv2020

Bab2 activates JNK signaling to reprogram Drosophila wing disc development

In response to cellular stress and damage, certain tissues are able to regenerate and to restore tissue homeostasis. In Drosophila imaginal wing discs, dying cells express mitogens that induce compensatory proliferation in the surrounding tissue. Here we report that high levels of the BTB/POZ transcription factor Bab2 in the posterior compartment of wing discs activates c-Jun N-terminal kinase (JNK) signaling and local, cell-autonomous apoptotic cell death. This in turn triggered the upregulation of the Dpp mitogen and cellular proliferation in the anterior compartment in a JNK-dependent manner. In the posterior compartment, however, dpp expression was suppressed, most likely by direct transcriptional repression by Bab2. This dual-mode of JNK-signaling, autocrine pro-apoptotic signaling and paracrine pro-proliferative signaling, led to opposite effects in the two compartments and reprogramming of the adult wing structure. We establish Bab2 as a regulator of wing disc development, with the capacity to reprogram development via JNK activation in a cell-autonomous and non-cell-autonomous manner. Summary statementZhao et al. shows that the BTB/POZ transcription factor Bab2 is a potent activator of JNK signaling, apoptosis and compensatory proliferation, thereby driving both pro-tumorigenic and anti-tumorigenic processes.

developmental biology↗

bioRxiv2019

A histone methyltransferase inhibitor can reverse epigenetically acquired drug resistance in the malaria parasite Plasmodium falciparum

Malaria parasites invade and replicate within red blood cells (RBCs), extensively modifying their structure and gaining access to the extracellular environment by placing the plasmodial surface anion channel (PSAC) into the RBC membrane. Expression of members of the cytoadherence linked antigen gene 3 (clag3) family is required for PSAC activity, a process that is regulated epigenetically. PSAC is a well-established route of uptake for large, hydrophilic antimalarial compounds and parasites can acquire resistance by silencing clag3 gene expression, thereby reducing drug uptake. We found that exposure to sub-IC50 concentrations of the histone methyltransferase inhibitor chaetocin caused substantial changes in both clag3 gene expression and RBC permeability, reversing acquired resistance to the antimalarial compound blasticidin S that is transported through PSAC. Chaetocin treatment also altered progression of parasites through their replicative cycle, presumably by changing their ability to modify chromatin appropriately to enable DNA replication. These results indicate that targeting histone modifiers could represent a novel tool for reversing epigenetically acquired drug resistance in P. falciparum.\n\nImportanceDrug resistance is a major concern for the treatment of infectious diseases throughout the world. For malaria, a novel mechanism of resistance was recently described in which epigenetic modifications led to a resistance phenotype that is rapidly reversible, thus reducing the fitness cost that is often associated with genetic mutations that lead to resistance. The possibility of this type of resistance arising in a natural setting is particularly troubling since parasites could rapidly switch to and from a resistant phenotype, thus making it especially difficult to combat. Here we show that application of a histone methyltransferase inhibitor can rapidly reverse the epigenetic changes that lead to drug resistance, thereby causing parasites to revert to a drug sensitive phenotype. This is a novel application of drugs that target epigenetic modifiers and lends additional support for ongoing efforts to develop drugs against malaria that target the histone modifiers of the parasite.

microbiology↗