I am pleased to see the Friday Science Review back online, and very much look forward to contributing to the Cross-Border Biotech Blog. This week I will play a little catch up and provide details on a number of publications from the Canadian research realm spanning the last month or so. Future posts will of course focus on weekly hits. So without further delay..
Early Epigenetic Experience: Some of the earliest adverse events humans experience may occur even before we are born. Roughly 15% of mothers suffer mood disturbances while pregnant, and an increasing amount of evidence is implicating maternal depression and anxiety in the development of neurobehavioural disturbances during childhood. A reduced concentration of the neurotransmitter serotonin (5-HT) in the brain has long been associated with depression, and can be directly linked to weak expression of the transmembrane serotonin transporter 5-HTT. A study led by Dr. Tim Oberlander of the Department of Pediatrics at the University of British Columbia shows that maternal depression during the 2nd trimester is associated with a decrease in both maternal and neonatal methylation in the 5-HTT promoter region. These findings suggest that maternal mood can alter epigenetic patterns in newborns, and may to some extent “program” infant and childhood behaviour.
A Sensitive Subject: As male fertility in the human population continues to decline, researchers are pressed to investigate links between environmental factors and the development of spermatozoa. New findings implicate environmental-epigenetic modification in the regulation of two key stem cell genes involved in spermatogenesis. Using the chromatin modifying drugs tranylcypromine and trichostatin, researchers were able to show that increases in histone H3 methylation and acetylation led to activation of the genes Pou51 and Gfra1. Chemicals with chromatin modifying capabilities may be able to influence the expression of genes necessary for normal and healthy spermatogenesis, and illustrates the sensitivity of these precious cells to chemical cues in our environment. The study was led by Dr. Sarah Kimmins from the Department of Animal Science at McGill University.
One Gene, Many Proteins: The lethality of different cancer cell types is often directly related to their ability to metastasize, or move from their place of origin to distant sites in the body. A study led by Dr. Jacek Majewski from the Department of Human Genetics at McGill University, suggests there could be an intimate relationship between alternative splicing and the metastatic abilities of breast cancer cells. Using splicing-sensitive microarray technology (Affymetrix Exon Microarrays), researchers analyzed genome-wide mRNA isoforms derived from three mouse mammary carcinoma cell lines with varying propensities to metastasize. What they found was a large group of genes, 2623 to be exact, that underwent gene expression variations specific to metastatic characteristics. This research, published in PLoS, suggests that metastasis of breast cancer cells may be facilitated by splicing variations or splicing defects that affect a number of biological processes including cell adhesion, migration, apoptosis, and proliferation.
Biomimicry: The transcriptional and translational factor YB-1 (Y-box binding protein-1) has been known to exacerbate breast cancer by binding DNA and enhancing the expression of several genes related to drug resistance and tumour growth including EGFR and HER-2. Dr. Sandra Dunn and her colleagues in the Laboratory for Oncogenic Research at UBC recently identified a kinase, RSK, that activates YB-1 by phosphorylation allowing it to bind DNA. Their solution? A molecular decoy protein. In this recent study in PLoS, researchers design a cell permeable peptide (CPP) that mimics the activation site of YB-1, thus competing for RSK’s attention. The result was a drastic reduction in phosphorylation of YB-1 and concomitant reduction in the expression of EGFR and HER-2. The beauty of this approach is that YB-1 has been broadly implicated in cancers including those of the bone, lung, colon, and brain. The findings also give hope to patients with the most aggressive form of breast cancer that fail to respond to other therapeutics such as trastuzumab; the decoy protein was found to reduce growth in a dose-dependent manner in an incurable model of breast cancer (triple-negative, HER-2+).