Thursday, February 27, 2014

Research Highlights

I've decided to try my hand at writing some short research highlights, like you'd find in Nature.  These basically summarize new research to try and get people excited about it!  These are quite jargony, so I apologize to my non-scientific audience, and I promise I'll be back with something new and exciting as soon as I submit my thesis.

The expression of genes that are required for the proliferation and differentiation of cell types are tightly controlled by a combination of transcription regulators and epigenetic modifications such as chromatin remodeling.  Haematopoeisis, the formation of blood cell components, is guided by a specific type of chromatin regulating factors, including Mll and Bmi1, that mediate the differentiation of haematopoetic stem cells into mature blood cells.  Huang and colleagues used a large-scale in vivo reverse genetic screen which targeted zebrafish gene orthologues to 425 human chromatin regulating factors to help decode the epigenetic determinants of blood cell differentiation.

The resulting 34 chromatin regulating factors that were identified included 15 that were involved in the regulation of primitive haematopoeisis, and 29 that regulates definitive haematopoeisis, including many chromatin factors that had not been previously identified.  This screen identified a number of chromatin factor complexes with distinct functions with respect to the regulation of haematopoeisis, including previously unidentified members of the ISWI complex such as smarca1, chrac1, and rsf1b.  Future in vivo studies will help elucidate the function of these chromatin factor complexes in the broader transcriptional network of gene regulation in blood development.

Calcium (Ca2+) maintains cellular function by playing a key role in a wide array of cellular processes, including signal transduction, muscle contraction, and gene expression.  In animals, calcium is sequestered in the mitochondria; however, the influx of large amounts of calcium into the mitochondria through the calcium-mediated opening of the permeatibility transition pore (PTP) can lead to cell death.  The import of calcium into the mitochondria is accomplished by the recently discovered mitochondrial calcium uniporter (MCU).  The study of MCU and the dynamics of mitochondrial calcium levels may elucidate its role in cell death, potentially leading to the development of MCU inhibitors with implications for the management of a number of clinically important disease processes such as ischaemia and neurodegeneration.

Using mice lacking MCU (MCU-/-), Pan et al. were able to confirm the role of MCU in mitochondrial calcium transport, as well as the effects of MCU on normal mitochondrial metabolism.  Despite a normal phenotype, the skeletal muscle of MCU-/- mice had a 75% decrease in calcium uptake levels, and displayed alterations in the phosphorylation and activity of pyruvate dehydrogenase.  As a result, MCU-/- mice had significantly impaired muscle strength and endurance, and showed no evidence of calcium-induced PTP opening, though this did not have a protective effect against cell death.  These results illustrate one of the mechanisms of calcium-mediated regulation of mitochondrial metabolism and animal physiology.

Polymorphism is a biological process in which differential gene expression leads to phenotypic changes.  This process is related to biodiversity, genetic variation, and adaptation, yet the effect of these polymorphisms on gene expression dynamics during development remains elusive.  This study used the model species C. elegans at different developmental stages, to examine the fluctuation in the timing, rate, and magnitude of gene expression by expression quantitative trait loci (eQTL).

By using eQTL mapping, the authors identified 900 cis-eQTL and 10 clusters of trans-eQTL able to regulate gene expression in the worms over a 12-hour period.  Genes significantly affected by cis-eQTL contained higher variation in their untranslated regions (UTR), suggesting that these regions are responsible for the alterations in gene expression.  Cis-eQTL were found to be involved in increasing or decreasing gene expression, while trans-eQTL clusters affected gene expression via the alteration of gene expression timing.  The approach used in this study could also be applied to the genetic analysis of more complex systems, and may be useful for characterizing the effect of genetic variation on physiology and disease progression in humans.

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