Transcriptional activation of pericentromeric satellite repeats and disruption of centromeric clustering upon proteasome inhibition

Heterochromatinisation of pericentromeres, which in mice consist of arrays of major satellite repeats, are important for centromere formation and maintenance of genome stability. The dysregulation of this process has been linked to genomic stress and various cancers. Here we show in mice that the proteasome binds to major satellite repeats and proteasome inhibition by MG132 results in their transcriptional de-repression; this de-repression is independent of cell-cycle perturbation. The transcriptional activation of major satellite repeats upon proteasome inhibition is accompanied by delocalisation of heterochromatin protein 1 alpha (HP1α) from chromocentres, without detectable change in the levels of histone H3K9me3, H3K4me3, H3K36me3 and H3 acetylation on the major satellite repeats. Moreover, inhibition of the proteasome was found to increase the number of chromocentres per cell, reflecting destabilisation of the chromocentre structures. Our findings suggest that the proteasome plays a role in maintaining heterochromatin integrity of pericentromeres

PREDICT-PD: Identifying risk of Parkinson's disease in the community: methods and baseline results

To present methods and baseline results for an online screening tool to identify increased risk for Parkinson's disease (PD) in the UK population

PREDICT-PD: Identifying risk of Parkinson's disease in the community: methods and baseline results

This work was supported by Parkinson’s UK (Innovation Grant reference number K-1006: £35 000)

Case report: A novel biallelic variant causing multisystem anomalies with severe epilepsy, widening the spectrum of syndrome

The fat mass and obesity-associated gene ( FTO ) codes for a DNA/RNA demethylase. Pathological variants in this gene are rare, with only three reports in the literature, all with mutations in the catalytic domain. We report the first biallelic human variant in fat mass and obesity-associated gene (c.287G>C, p.Arg96Pro/R96P) outside the catalytic site, causing numerous abnormalities across multiple organ systems, affecting respiratory, cardiovascular, and neurological function. Biochemical assays of cells with the patient’s variant were performed to further quantify the effect of the variant on function. Loss-of-function resulting from the patient’s R96P missense variant was demonstrated with in vitro biochemical characterization of demethylase activity, resulting in a 90% reduction in function of the fat mass and obesity-associated protein compared to wild-type. Our findings demonstrate a novel fat mass and obesity-associated gene non-catalytic site variant with a unique patient phenotype of bilateral multifocal epilepsy and multisystem congenital anomalies