Mouse HP1γ regulates TRF1 expression and telomere stability.

AIMS: Telomeric repeat-containing RNAs are long non-coding RNAs generated from the telomeres. TERRAs are essential for the establishment of heterochromatin marks at telomeres, which serve for the binding of members of the heterochromatin protein 1 (HP1) protein family of epigenetic modifiers involved with chromatin compaction and gene silencing. While HP1γ is enriched on gene bodies of actively transcribed human and mouse genes, it is unclear if its transcriptional role is important for HP1γ function in telomere cohesion and telomere maintenance. We aimed to study the effect of mouse HP1γ on the transcription of telomere factors and molecules that can affect telomere maintenance. MAIN METHODS: We investigated the telomere function of HP1γ by using HP1γ deficient mouse embryonic fibroblasts (MEFs). We used gene expression analysis of HP1γ deficient MEFs and validated the molecular and mechanistic consequences of HP1γ loss by telomere FISH, immunofluorescence, RT-qPCR and DNA-RNA immunoprecipitation (DRIP). KEY FINDINGS: Loss of HP1γ in primary MEFs led to a downregulation of various telomere and telomere-accessory transcripts, including the shelterin protein TRF1. Its downregulation is associated with increased telomere replication stress and DNA damage (γH2AX), effects more profound in females. We suggest that the source for the impaired telomere maintenance is a consequence of increased telomeric DNA-RNA hybrids and TERRAs arising at and from mouse chromosomes 18 and X. SIGNIFICANCE: Our results suggest an important transcriptional control by mouse HP1γ of various telomere factors including TRF1 protein and TERRAs that has profound consequences on telomere stability, with a potential sexually dimorphic nature.

A wearable motion capture suit and machine learning predict disease progression in Friedreich's ataxia.

Friedreich's ataxia (FA) is caused by a variant of the Frataxin (FXN) gene, leading to its downregulation and progressively impaired cardiac and neurological function. Current gold-standard clinical scales use simplistic behavioral assessments, which require 18- to 24-month-long trials to determine if therapies are beneficial. Here we captured full-body movement kinematics from patients with wearable sensors, enabling us to define digital behavioral features based on the data from nine FA patients (six females and three males) and nine age- and sex-matched controls, who performed the 8-m walk (8-MW) test and 9-hole peg test (9 HPT). We used machine learning to combine these features to longitudinally predict the clinical scores of the FA patients, and compared these with two standard clinical assessments, Spinocerebellar Ataxia Functional Index (SCAFI) and Scale for the Assessment and Rating of Ataxia (SARA). The digital behavioral features enabled longitudinal predictions of personal SARA and SCAFI scores 9 months into the future and were 1.7 and 4 times more precise than longitudinal predictions using only SARA and SCAFI scores, respectively. Unlike the two clinical scales, the digital behavioral features accurately predicted FXN gene expression levels for each FA patient in a cross-sectional manner. Our work demonstrates how data-derived wearable biomarkers can track personal disease trajectories and indicates the potential of such biomarkers for substantially reducing the duration or size of clinical trials testing disease-modifying therapies and for enabling behavioral transcriptomics.

Transcription elongation and tissue-specific somatic CAG instability.

The expansion of CAG/CTG repeats is responsible for many diseases, including Huntington's disease (HD) and myotonic dystrophy 1. CAG/CTG expansions are unstable in selective somatic tissues, which accelerates disease progression. The mechanisms underlying repeat instability are complex, and it remains unclear whether chromatin structure and/or transcription contribute to somatic CAG/CTG instability in vivo. To address these issues, we investigated the relationship between CAG instability, chromatin structure, and transcription at the HD locus using the R6/1 and R6/2 HD transgenic mouse lines. These mice express a similar transgene, albeit integrated at a different site, and recapitulate HD tissue-specific instability. We show that instability rates are increased in R6/2 tissues as compared to R6/1 matched-samples. High transgene expression levels and chromatin accessibility correlated with the increased CAG instability of R6/2 mice. Transgene mRNA and H3K4 trimethylation at the HD locus were increased, whereas H3K9 dimethylation was reduced in R6/2 tissues relative to R6/1 matched-tissues. However, the levels of transgene expression and these specific histone marks were similar in the striatum and cerebellum, two tissues showing very different CAG instability levels, irrespective of mouse line. Interestingly, the levels of elongating RNA Pol II at the HD locus, but not the initiating form of RNA Pol II, were tissue-specific and correlated with CAG instability levels. Similarly, H3K36 trimethylation, a mark associated with transcription elongation, was specifically increased at the HD locus in the striatum and not in the cerebellum. Together, our data support the view that transcription modulates somatic CAG instability in vivo. More specifically, our results suggest for the first time that transcription elongation is regulated in a tissue-dependent manner, contributing to tissue-selective CAG instability.

Context is everything: activators can also repress.

Maintenance of genome integrity, cell division and gene expression have all been shown to be regulated by the condensation of DNA into heterochromatin. In a study published in this issue, Bulut-Karslioglu et al. reveal a new heterochromatin function for transcription factors in a mammalian system. They show that instead of activating gene expression, in the context of heterochromatic repeats, specific transcription factors are necessary for the maintenance of transcriptional repression and heterochromatin.

An investigation of visual contour integration ability in relation to writing performance in primary school students.

A previous study found a visual deficit in contour integration in English readers with dyslexia (Simmers & Bex, 2001). Visual contour integration may play an even more significant role in Chinese handwriting particularly due to its logographic presentation (Lam, Au, Leung, & Li-Tsang, 2011). The current study examined the relationship between children's performance in visual contour (VC) integration and Chinese handwriting. Twenty students from grade 3 to grade 6 were recruited (M=9.51, SD=1.02) from a mainstream primary school using the convenience sampling method. Ten students were identified by teachers as having handwriting problems, and the other 10 were typical students. Participants performed the VC tasks and their handwriting performance was assessed by a Chinese Handwriting Assessment Tool (CHAT) in a classroom setting. Correlation analyses revealed that VC accuracy was significantly and negatively correlated with on paper time and total writing duration. t-Test analyses revealed statistically significant differences in VC accuracy between students with typical and poor handwriting, with consistently better VC accuracy performance in all conditions in the typical handwriting group. The results may have important implications for interventions aiming at improving children's handwriting.

Comparison of monitor unit calculations performed with a 3D computerized planning system and independent "hand" calculations: results of three years clinical experience.

A comparison of the monitor unit calculations of a commercial 3D computerized treatment planning system (TPS) with "hand" calculations from lookup tables was made for a large number of clinical cases (greater than 13 500 treatment fields). Differences were analyzed by treatment site for prostate, rectum, cranium, and breast. The 3D TPS monitor unit calculation was systematically higher than the "hand" calculation by an amount that depended on the complexity of the treatment geometry. For simple geometries the mean difference was 1% and was as high as 3% for more complicated geometries. The higher value was attributed to an accumulation of differences introduced by multiple factors in the monitor unit calculation. Careful attention to factors such as patient contour could reduce the mean difference. "Hand" calculations were shown to be an accurate and useful tool for verification of TPS monitor unit calculations.