Discovery of Novel Cross-Talk between Protein Arginine Methyltransferase Isoforms and Design of Dimerization Inhibitors

Protein arginine methyltransferase, PRMT, is a family of epigenetic enzymes that methylate arginine residues on histone and nonhistone substrates which result in a monomethylation, symmetric dimethylation or asymmetric dimethylation via the transfer of a methyl group from S-adenosyl-L-methionine (SAM). We discovered a novel interaction between two PRMT isoforms: PRMT1 interacts and methylates PRMT6. In this study site-directed mutagenesis was performed on selected arginines identified from tandem mass spectrometric analysis to investigate major methylation sites of PRMT6 by PRMT1. In combination with radiometric methyltransferase assays, we determined two major methylation sites. Methylations at these sites have significant effects on the nascent enzymatic activity of PRMT6 in H4 methylation. PRMTs have the ability to homodimerize which have been linked to methyltransferase activity. We designed dimerization inhibitors (DMIs) to further investigate the need for dimerization for enzyme activity. Preliminary results suggest that the monomeric form of PRMT1 retains methyltransferase activity comparable to that of the uninhibited PRMT1

Late veneer and late accretion to the terrestrial planets

It is generally accepted that silicate-metal (`rocky') planet formation relies on coagulation from a mixture of sub-Mars sized planetary embryos and (smaller) planetesimals that dynamically emerge from the evolving circum-solar disc in the first few million years of our Solar System. Once the planets have, for the most part, assembled after a giant impact phase, they continue to be bombarded by a multitude of planetesimals left over from accretion. Here we place limits on the mass and evolution of these planetesimals based on constraints from the highly siderophile element (HSE) budget of the Moon. Outcomes from a combination of N-body and Monte Carlo simulations of planet formation lead us to four key conclusions about the nature of this early epoch. First, matching the terrestrial to lunar HSE ratio requires either that the late veneer on Earth consisted of a single lunar-size impactor striking the Earth before 4.45 Ga, or that it originated from the impact that created the Moon. An added complication is that analysis of lunar samples indicates the Moon does not preserve convincing evidence for a late veneer like Earth. Second, the expected chondritic veneer component on Mars is 0.06 weight percent. Third, the flux of terrestrial impactors must have been low ( <=10^(-6) M_earth/Myr) to avoid wholesale melting of Earth's crust after 4.4~Ga, and to simultaneously match the number of observed lunar basins. This conclusion leads to an Hadean eon which is more clement than assumed previously. Last, after the terrestrial planets had fully formed, the mass in remnant planetesimals was ~10^(-3) M_earth, lower by at least an order of magnitude than most previous models suggest. Our dynamically and geochemically self-consistent scenario requires that future N-body simulations of rocky planet formation either directly incorporate collisional grinding or rely on pebble accretion.Comment: Accepted for publication in Earth and Planetary Science Letter

Non-Alcoholic Fatty Liver and Hepatocarcimona Attenuation by Specific CD98 Down-Regulation Via Nanovectors

CD98 is a multifunctional glycoprotein that is involved in various biological processes such as amino acid transport and cell adhesion, diffusion, and proliferation. Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid hepatic accumulation. The role of CD98 in NAFLD has not thoroughly been examined and there are limited reports in the literature with regards CD98 relation to liver disease. Here, we investigated whether a reduction of CD98 expression mediated by CD98 siRNA-loaded nanoparticles (NPs) and plant derived nanovesicles could attenuate liver disease markers in a mouse model of NAFLD. The nanoparticles strongly decreased all markers of NAFLD, including the blood levels of ALT and lipids accumulation, fibrosis evidence and pro-inflammatory cytokines. Treatment with the plant nanovesicles attenuated inflammation and steatosis in the mouse NAFLD model. In conclusion, our results indicate that CD98 appears to function as a key actor/inducer in NAFLD, and that our NPs approach may offer a new targeted therapeutic for this disease. Exosomes are nanovesicles that are secreted by cells and participate in intercellular communication via exchange of cargo such as oligonucleotides, lipids, proteins, and peptides. Lately the role of tumor derived exosomes has been questioned for aiding metastasis as some tumor derived exosomes participate in developing cellular environments that support metastasis in various organs. Patients suffering from colorectal cancer commonly develop liver metastasis, thus the role of exosomes from colorectal cancer could participate in the development of metastasis in the liver. Our results demonstrated that exosomes derived from Caco2 BBe can increase integrin signaling which can contribute to metastasis or more tumorigenic phenotype