Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline

The Euchromatic and Heterochromatic Landscapes Are Shaped by Antagonizing Effects of Transcription on H2A.Z Deposition

A role for variant histone H2A.Z in gene expression is now well established but little is known about the mechanisms by which it operates. Using a combination of ChIP–chip, knockdown and expression profiling experiments, we show that upon gene induction, human H2A.Z associates with gene promoters and helps in recruiting the transcriptional machinery. Surprisingly, we also found that H2A.Z is randomly incorporated in the genome at low levels and that active transcription antagonizes this incorporation in transcribed regions. After cessation of transcription, random H2A.Z quickly reappears on genes, demonstrating that this incorporation utilizes an active mechanism. Within facultative heterochromatin, we observe a hyper accumulation of the variant histone, which might be due to the lack of transcription in these regions. These results show how chromatin structure and transcription can antagonize each other, therefore shaping chromatin and controlling gene expression

Type-2 airway inflammation in mild asthma patients with high blood eosinophils and high fractional exhaled nitric oxide.

Abstract Type‐2 (T2) inflammation is a characteristic feature of asthma. Biological therapies have been developed to target T2‐inflammation in asthma. IL‐13 is a key component of T2‐inflammation in asthma, driving mucus hypersecretion, IgE‐induction, and smooth muscle contraction. Early phase clinical trials for treatments that target T2‐inflammation require biomarkers to assess pharmacological effects. The aim of this study was to examine levels of IL‐13 inducible biomarkers in the airway epithelium of patients with mild asthma compared to healthy controls. Ten patients with mild asthma with high blood eosinophil and high fractional exhaled nitric oxide (FeNO) were recruited, and six healthy subjects. Blood eosinophil and FeNO reproducibility was assessed prior to bronchoscopy. Epithelial brushings were collected and assessed for IL‐13 inducible gene expression. Blood eosinophil and FeNO levels remained consistent in both patients with asthma and healthy subjects. Of the 11 genes assessed, expression levels of 15LOX1, POSTN, CLCA1, SERPINB2, CCL26, and NOS2 were significantly higher in patients with asthma compared to healthy controls. These six genes, present in patients with mild asthma with T2 inflammation, have the potential to be used in translational early phase asthma clinical trials of novel therapies as bronchial epithelial biomarkers