Cancer Genetics

HIF-1α induces genetic instability by transcriptionally downregulating MutSα expression.. Koshiji, M. et al. Mol. Cell 17, 793–803 (2005)

HIF-1α, a transcription factor responsible for the cellular response to hypoxia, now seems to control the expression of proteins that are involved in DNA mismatch repair. The authors show that, during oxygen-starvation conditions, HIF-1α is a transcriptional repressor of MSH2 and MSH6 (Escherichia coli MutS homologues), which safeguard the integrity of the genome. Although HIF-1α overexpression is frequently observed in human cancers, whether hypoxia-associated genetic instability caused by HIF-1α contributes to tumour formation is unknown.

Human Genetics

Regulatory variation at glypican-3 underlies a major growth QTL in mice.. Oliver, F. et al. PLoS Biol. 3, e135 (2005)

Of the ∼2,000 QTLs that have been identified in rodents, few have been characterized at the molecular level. The authors extend their previous work on a single QTL that is associated with body-size variation in mice, and show that differences in the transcript levels of glypican-3 are responsible for this phenotype. Because mutations in glypican-3 cause Simpson–Golabi–Behmel syndrome in humans, these findings show that a gene linked to a Mendelian growth disorder in humans can contribute to quantitative variation in mice.

Evolution

The transcriptional consequences of mutation and natural selection in Caenorhabditis elegans. Denver, D. R. et al. Nature Genet. 24 April 2005 (10.1038/ng1554)

Divergent species differ in their gene-transcription profiles, but what do these differences mean? Are they neutral, as some claim, or do they have an adaptive purpose? These authors used microarrays to examine the transcription-variation patterns of two types of Caenorhabditis elegans population — mutation-accumulation lines and natural isolates — and show that, for thousands of expressed sequences, transcription evolution is governed by stabilizing selection.

Epigenetics

Genomic characterization reveals a simple histone H4 acetylation code.. Dion, M. F. et al. Proc. Natl Acad. Sci. USA 102, 5501–5506 (2005)

Histone modifications have been proposed to provide a complex combinatorial code that can cause variation in gene expression. Dion et al. made yeast strains that carry all possible combinations of mutations in the four histone H4 lysine residues that undergo acetylation, and examined the effects on genome-wide gene expression. Only one of the acetylation sites had specific effects on gene expression, whereas mutations in the other three had non-specific, cumulative effects. Acetylation on histone H4 therefore provides a relatively simple transcriptional code.