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Tag Archives: University of Alberta

Friday Science Review: March 4, 2011

The Origin of Meier-Gorlin Syndrome

Dalhousie University ♦ University of Montreal ♦ University of British Columbia

Published in Nature Genetics, Feb. 27, 2011

Researchers have mapped a locus for Meier-Gorlin syndrome (MGS), a rare genetic condition characterized by short stature, small ears, and reduced or absent kneecaps. A mutation in the ORC4 gene seems to be at the root of the disorder. ORC4 is a component of the eukaryotic origin recognition complex.

To map the locus responsible for MGS researchers performed high density genome-wide SNP genotyping using a panel of 600,000 markers provided by Illumina. The next stop involved PLINK, a whole genome analysis toolset, which was able to identify a haplotype on chromosome 2 within a number of affected individuals. Sequencing of coding exons located in the ORC4 gene led to the identification of a missense mutation that causes a tyrosine (residue 174) to cysteine switch in the ORC4 protein. The tyrosine residue affected in MGS is completely conserved across eukaryotes suggesting it has an important function; the amino acid is also believed to interact with a conserved arginine residue on a nearby helix motif in the protein structure. In the absence of this interaction the structural integrity of the protein could be compromised in part.

The origin recognition complex consists of six proteins in humans and is essential for DNA replication. It plays a critical role in recognizing origin sites on DNA and in the formation of DNA replication forks. This is the first report of an inherited mutation in any gene of the origin recognition complex in the vertebrate literature.

The Human Serum Metabolome

University of Alberta ♦ National Institute of Nanotechnology

Published in PLoS ONE, Feb. 16, 2011

Human biofluids are very important from a clinical standpoint given the insight they can provide into the disease conditions of a human being. The study of metabolomics attempts to identify, on a large scale, the composition of metabolites found in these biofluids. The advent of advanced analytical techniques along with mounting pressures for scientists in the metabolomics community to document the entire human metabolome, led to the development of the Human Metabolome Project. The project is supported by Genome Alberta and Genome Canada, the latter of which is a private, non-profit, corporation that received $600 million in funding from the Canadian government to develop and implement a national strategy in genomics and proteomics.

The most recent contribution to the project is a comprehensive multicentre study led by Dr. David Wishart at the University of Alberta. Using a diversity of metabolomics platforms researchers were able to identify, and quantify, metabolites found in human serum. The use of different methods, including nuclear magnetic resonance (NMR), and various mass-spectrometry platforms (GC-MS, LC-MS), increased the overall coverage of the serum metabolome. Data gathered via these platforms was linked to computer-aided literature mining which allowed for the development of a virtually complete set of metabolites. In total the group found 4,229 metabolites, but this number may increase in coming years as more powerful characterization techniques are developed.

Dr. Wishart and his colleagues previously characterized the human cerebrospinal fluid metabolome.

Friday Science Review: February 25, 2011

Fusion Construct Promotes Erythropoietic Development from Human Embryonic Stem Cells

McMaster University ♦ The Ottawa Hospital ♦ British Columbia Cancer Agency

Published in Stem Cells, Feb. 15, 2011

The homeobox (Hox) genes encode a group of highly conserved transcription factors that have been known to regulate hematopoietic differentiation. As a result of their involvement in hematopoietic proliferation and lineage commitment, Hox genes have also been implicated in leukemogenesis. Researchers from Dr. Mick Bhatia’s lab have created a fusion construct that alters the hematopoietic differentiation program of human embryonic stem cells (hESCs). They chose the homeobox gene HOXA10, and partnered this with NUP98, a gene that is often found fused to Hox genes in human leukemias. After introduction of the fusion construct into undifferentiated hESCs or early-stage blood progenitors there was a marked increase in the level of erythroid progenitors founds in culture. Introduction of the construct to later-stage cells already committed to the hematopoietic lineage had no effect on the yield of erythropoietic cells. Apparently, unlike some of the fusion constructs observed in leukemias, the combination of HOXA10 and NUP98 does not lead to malignant expansion. Given the interest Dr. Bhatia and his group have in the production of blood cells, it is foreseeable that this fusion construct could be used in future differentiation protocols to bias the differentiation of hESCs towards the erythropoietic lineage.

Ubiquitination Factor E4B, A Novel Target for Brain Cancer

University of Alberta ♦ Published in Nature Medicine, Feb. 13, 2011

The tumour supressor gene TP53 and its protein product p53 are at the root of many cancers. TP53 is inactivated in 50% of human tumours. The resulting deficiency in p53 allows fledgling cancer cells to circumvent apoptotic programs and proliferate wildly. Deficiency in p53 protein may result from a mutation in the TP53 gene, or as is more frequently the case, inactivation of the p53 protein. Inactivation is often the result of ubiquitination. A specific class of enzymes in the body has the ability to add ubiquitin to proteins which marks them for degradation by other protein machinery. However, the molecular mechanisms behind inactivation of p53 in the brain remain largely understood.  Dr. Roger Leng and his team at the University of Alberta have identified a novel mechanism of inactivation in brain tumours: a ubiquitination factor (UBE4B) that directly interacts with the p53 protein destabilizing it and marking it for destruction. The factor was found to interact with an enzyme (Hdm2) that is also involved in ubiquitination. Silencing UBE4B in xenotransplanted tumours led to impaired tumour growth while over-expression of the factor was associated with amplification of its gene suggestive of a positive feedback mechanism. This discovery elucidates a potential target for treating medulloblastoma and ependymoma, two brain cancer types that exhibit inactivation of the p53 protein.


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