PRMT5-mediated regulation of developmental myelination

Oligodendrocytes (OLs) are the myelin-forming cells of the central nervous system. They are derived from differentiation of oligodendrocyte progenitors through a process requiring cell cycle exit and histone modifications. Here we identify the histone arginine methyl-transferase PRMT5, a molecule catalyzing symmetric methylation of histone H4R3, as critical for developmental myelination. PRMT5 pharmacological inhibition, CRISPR/cas9 targeting, or genetic ablation decrease p53-dependent survival and impair differentiation without affecting proliferation. Conditional ablation of Prmt5 in progenitors results in hypomyelination, reduced survival and differentiation. Decreased histone H4R3 symmetric methylation is followed by increased nuclear acetylation of H4K5, and is rescued by pharmacological inhibition of histone acetyltransferases. Data obtained using purified histones further validate the results obtained in mice and in cultured oligodendrocyte progenitors. Together, these results identify PRMT5 as critical for oligodendrocyte differentiation and developmental myelination by modulating the cross-talk between histone arginine methylation and lysine acetylation

Immune-factors regulating the development of experimental cerebral malaria in mice infected or coinfected with Plasmodium spp.

During malaria infection, innate responses are triggered to limit the maximum parasite density when it crosses certain threshold. Toll-like receptors signaling pathway, mononuclear phagocytes and NK cell-mediated cytotoxicity are known to have important roles in activation of protective innate immunity to malaria. Therefore, we first assessed role in experimental cerebral malaria (ECM) pathogenesis of molecules (TRIF and IRF3) involved in innate immunity signal transduction. TRIF-deficient mice infected with PbAluc were susceptible to ECM and displayed increased parasite biomass, although peripheral parasitemia was comparable to WT mice. Conversely, mice infected with another parasite strain, PbA-BdS, did not develop ECM despite having similar parasitemia to WT group. IRF3-deficient mice infected with either PbAluc or PbA-BdS were ECM-resistant. Lastly, macrophages and NK cells role in suppression of PbA growth and ECM in mice coinfected with Plasmodium spp. was elucidated. Using transgenic mouse model, MaFIA, which allows conditional ablation of myeloid cells, we showed that depletion of these cells protected coinfected mice against ECM and decreased total parasitemia due to an effect on Py 17X 1.1 growth. However, it had no effect on PbA suppression. Similarly, conditional ablation of NK cells in NKDTR mice excluded involvement of NK cells in PbA suppression, although these mice did not develop ECM.Bachelor of Science in Biological Science

Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth

MDM4 is a promising target for cancer therapy, as it is undetectable in most normal adult tissues but often upregulated in cancer cells to dampen p53 tumor-suppressor function. The mechanisms that underlie MDM4 upregulation in cancer cells are largely unknown. Here, we have shown that this key oncogenic event mainly depends on a specific alternative splicing switch. We determined that while a nonsense-mediated, decay-targeted isoform of MDM4 (MDM4-S) is produced in normal adult tissues as a result of exon 6 skipping, enhanced exon 6 inclusion leads to expression of full-length MDM4 in a large number of human cancers. Although this alternative splicing event is likely regulated by multiple splicing factors, we identified the SRSF3 oncoprotein as a key enhancer of exon 6 inclusion. In multiple human melanoma cell lines and in melanoma patient-derived xenograft (PDX) mouse models, antisense oligonucleotide-mediated (ASO-mediated) skipping of exon 6 decreased MDM4 abundance, inhibited melanoma growth, and enhanced sensitivity to MAPK-targeting therapeutics. Additionally, ASO-based MDM4 targeting reduced diffuse large B cell lymphoma PDX growth. As full-length MDM4 is enhanced in multiple human tumors, our data indicate that this strategy is applicable to a wide range of tumor types. We conclude that enhanced MDM4 exon 6 inclusion is a common oncogenic event and has potential as a clinically compatible therapeutic targe

PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis

PRDM (PRDI-BF1 and RIZ homology domain containing) family members are sequence-specific transcriptional regulators involved in cell identity and fate determination, often dysregulated in cancer. The PRDM15 gene is of particular interest, given its low expression in adult tissues and its overexpression in B-cell lymphomas. Despite its well characterized role in stem cell biology and during early development, the role of PRDM15 in cancer remains obscure. Herein, we demonstrate that while PRDM15 is largely dispensable for mouse adult somatic cell homeostasis in vivo, it plays a critical role in B-cell lymphomagenesis. Mechanistically, PRDM15 regulates a transcriptional program that sustains the activity of the PI3K/AKT/mTOR pathway and glycolysis in B-cell lymphomas. Abrogation of PRDM15 induces a metabolic crisis and selective death of lymphoma cells. Collectively, our data demonstrate that PRDM15 fuels the metabolic requirement of B-cell lymphomas and validate it as an attractive and previously unrecognized target in oncology