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PNAS Papers on Gene Expression Noise, Breast Cancer Tumorigenesis, Drosophila Genome Stability

Editor's Note: Some of the articles described below are not yet available at the PNAS site but are scheduled to be posted this week.

Researchers from Rutgers University and the University of Delaware describe a strategy for dampening down "noisy" bursts of expression for some genes in human cells by boosting the accessibility of a given gene locus. Using ATAC-seq, single-molecule fluorescence in situ hybridization, nascent messenger RNA imaging, and other approaches, the team followed the activity of histone acetyl transferase genes tethered to nuclease-deficient forms of Cas9 in a human cell line, which led to local chromatin architecture shifts that enhanced accessibility and diminished gene expression variability at loci of interest. "Because of the increased accessibility of the promoter to transcription factors, the transcription from two genes became less noisy, even when the average levels of expression [in nuclei] did not change," the authors report. "In addition to providing evidence for chromatin accessibility as a determinant of the noise in gene expression, our study offers a mechanism for controlling gene expression noise which is otherwise unavoidable."

A team from China and the US explores a role for a calcium-binding protein called calreticulin (CALR) in breast cancer development and progression. Along with higher-than-usual levels of CALR in breast cancer samples or breast cell lines compared to their matched normal sample counterparts, the investigators relied on chromatin immunoprecipitation, reporter assays, mammosphere assays, gene knockdown experiments, and other methods to show that hypoxic breast cancer cells growing in low oxygen conditions had enhanced levels of the hypoxia-inducible factor 1 (HIF-1) that, in turn, corresponded to increased CALR expression and Wnt/beta-catenin signaling — effects that were particularly common in cells with breast cancer stem cell (BCSC) features and in biopsy samples from breast cancer patients with poor outcomes. "Taken together," they write, "our results demonstrate that CALR facilitates [breast cancer] progression by promoting the BCSC phenotype through Wnt/beta-catenin signaling in an HIF-1-dependent manner and suggest that CALR may represent a target for [breast cancer] therapy."

University of Massachusetts, University of Vermont, and Mayo Clinic researchers outline the histone nuclear factor P (Hinfp) transcription factor's contribution to somatic genome stability in a Drosophila fruit fly model. Based on their Hinfp loss of function, transposable element inhibition, transgenic histone expression, and other experiments, they suggest that Hinfp protects the genome from somatic changes by repressing transposable elements. From these and other experiments, the authors conclude that "Hinfp is a physiological regulator of Histone1-dependent silencing of most transposable elements, as well as many host genes, and serves as a venue for studying genome instability, cancer progression, neurodegeneration, and aging."