Using liver miRNA profiles to predict chemical hepatocarcinogenesis

Industrial, agricultural, and pharmaceutical requirements drive the development of a plethora of new chemical entities each year, many of which - for example drugs, pesticides, and food additives - have to be assessed for potential human health hazard. The current benchmark for risk assessement is the lifetime rodent bioassay which is expensive, time-consuming, laborious, requires the sacrifice of numerous animals, and is often irrelevant to humans. Hence alternative strategies to the rodent lifetime bioassay for prediction of chemical carcinogens are being pursued, especially for the liver which is an organ frequently affected by exogenous chemicals due to its detoxifying and metabolic roles. Numerous studies in recent years support the important role of microRNAs in cancer development, including hepatocellular carcinoma. The principal hypothesis of this project was that hepatic microRNA signatures can contribute to the earlier prediction of chemical hepatocarcinogens. Examination of livers from male Fischer rats treated with six chemical hepatocarcinogens, with diverse mode of actions for 90 days revealed that all the tested hepatocarcinogens affected the liver miRNAome from that early stage. Interestingly, a small set of microRNAs were identified whose expression was frequently deregulated by the hepatocarcinogens. Bioinformatic analysis indicates that these microRNAs can regulate pathways which are important in hepatocellular carcinoma. A more detailed investigation of one of those hepatocarcinogens, phenobarbital, showed that its effects on liver microRNAs were both dose and time dependent, with a progressive induction of specific microRNA clusters.Thus this study was the first to investigate in depth the effects of chemical hepatocarcinogens on the liver miRNAome and supports the potential usefulness of hepatic microRNA signatures in risk assessment

Repression of hedgehog signal transduction in T-lineage cells increases TCR-induced activation and proliferation

Hedgehog proteins signal for differentiation, survival and proliferation of the earliest thymocyte progenitors, but their functions at later stages of thymocyte development and in peripheral T-cell function are controversial. Here we show that repression of Hedgehog (Hh) pathway activation in T-lineage cells, by expression of a transgenic repressor form of Gli2 (Gli2DeltaC2), increased T-cell differentiation and activationin response to TCR signalling. Expression of the Gli2DeltaC2 transgene increased differentiation from CD4(+)CD8(+) to single positive thymocyte, and increased peripheral T cell populations. Gli2DeltaC2 T-cells were hyper-responsive to activation by ligation of CD3 and CD28: they expressed cell surface activation markers CD69 and CD25 more quickly, and proliferated more than wild-type T-cells. These data show that Hedgehog pathway activation in thymocytes and T-cells negatively regulates TCR-dependent differentiation and proliferation. Thus, as negative regulators of TCR-dependent events, Hh proteins provide an environmental influence on T-cell fate

Modulation of the Genome and Epigenome of Individuals Susceptible to Autism by Environmental Risk Factors

Diverse environmental factors have been implicated with the development of autism spectrum disorders (ASD). Genetic factors also underlie the differential vulnerability to environmental risk factors of susceptible individuals. Currently the way in which environmental risk factors interact with genetic factors to increase the incidence of ASD is not well understood. A greater understanding of the metabolic, cellular, and biochemical events involved in gene x environment interactions in ASD would have important implications for the prevention and possible treatment of the disorder. In this review we discuss various established and more alternative processes through which environmental factors implicated in ASD can modulate the genome and epigenome of genetically-susceptible individuals

Modulation of the Genome and Epigenome of Individuals Susceptible to Autism by Environmental Risk Factors

Diverse environmental factors have been implicated with the development of autism spectrum disorders (ASD). Genetic factors also underlie the differential vulnerability to environmental risk factors of susceptible individuals. Currently the way in which environmental risk factors interact with genetic factors to increase the incidence of ASD is not well understood. A greater understanding of the metabolic, cellular, and biochemical events involved in gene x environment interactions in ASD would have important implications for the prevention and possible treatment of the disorder. In this review we discuss various established and more alternative processes through which environmental factors implicated in ASD can modulate the genome and epigenome of genetically-susceptible individuals

Protein interaction and functional data indicate MTHFD2 involvement in RNA processing and translation

Abstract Background The folate-coupled metabolic enzyme MTHFD2 is overexpressed in many tumor types and required for cancer cell proliferation, and is therefore of interest as a potential cancer therapeutic target. However, recent evidence suggests that MTHFD2 has a non-enzymatic function which may underlie the dependence of cancer cells on this protein. Understanding this non-enzymatic function is important for optimal targeting of MTHFD2 in cancer. Methods To identify potential non-enzymatic functions of MTHFD2, we defined its interacting proteins using co-immunoprecipitation and mass spectrometry and integrated this information with large-scale co-expression analysis, protein dynamics, and gene expression response to MTHFD2 knockdown. Results We found that MTHFD2 physically interacts with a set of nuclear proteins involved in RNA metabolism and translation, including components of the small ribosomal subunit and multiple members of the RNA-processing hnRNP family. Interacting proteins were also in general co-expressed with MTHFD2 in experiments that stimulate or repress proliferation, suggesting a close functional relationship. Also, unlike other folate one-carbon enzymes, the MTHFD2 protein has a short half-life and responds rapidly to serum. Finally, shRNA against MTHFD2 depletes several of its interactors and yields an overall transcriptional response similar to targeted inhibition of certain ribosomal subunits. Conclusions Taken together, our findings suggest a novel function of MTHFD2 in RNA metabolism and translation

Using liver miRNA profiles to predict chemical hepatocarcinogenesis

Industrial, agricultural, and pharmaceutical requirements drive the development of a plethora of new chemical entities each year, many of which - for example drugs, pesticides, and food additives - have to be assessed for potential human health hazard. The current benchmark for risk assessement is the lifetime rodent bioassay which is expensive, time-consuming, laborious, requires the sacrifice of numerous animals, and is often irrelevant to humans. Hence alternative strategies to the rodent lifetime bioassay for prediction of chemical carcinogens are being pursued, especially for the liver which is an organ frequently affected by exogenous chemicals due to its detoxifying and metabolic roles. Numerous studies in recent years support the important role of microRNAs in cancer development, including hepatocellular carcinoma. The principal hypothesis of this project was that hepatic microRNA signatures can contribute to the earlier prediction of chemical hepatocarcinogens. Examination of livers from male Fischer rats treated with six chemical hepatocarcinogens, with diverse mode of actions for 90 days revealed that all the tested hepatocarcinogens affected the liver miRNAome from that early stage. Interestingly, a small set of microRNAs were identified whose expression was frequently deregulated by the hepatocarcinogens. Bioinformatic analysis indicates that these microRNAs can regulate pathways which are important in hepatocellular carcinoma. A more detailed investigation of one of those hepatocarcinogens, phenobarbital, showed that its effects on liver microRNAs were both dose and time dependent, with a progressive induction of specific microRNA clusters.Thus this study was the first to investigate in depth the effects of chemical hepatocarcinogens on the liver miRNAome and supports the potential usefulness of hepatic microRNA signatures in risk assessment.EThOS - Electronic Theses Online ServiceBBSRCGBUnited Kingdo