Biology subjects

Sadikovic, B.

Publications and source records attributed to Sadikovic, B..

2 recordsLinked to original sources

bioRxiv2025

Identification of genetic and non-genetic modifiers of genomic imprinting through whole genome screening in humans

Genomic imprinting is required for normal development, and abnormal methylation of differentially methylated regions (iDMRs) controlling the parent of origin-dependent expression of the imprinted genes has been found in constitutional disorders affecting growth, metabolism, neurobehavior, and in cancer. In most of these cases the cause of the imprinting abnormalities is unknown. Also, these studies have generally been performed on a limited number of CpGs, and a systematic investigation of iDMR methylation in the general population is lacking. By analysing the iDMRs in a large number of peripheral blood DNA methylation array datasets of unaffected individuals and patients with rare disorders, we determined the most common iDMR methylation profiles and identified many genetic and non-genetic factors contributing to their variability. We found that methylation variability is not homogeneous within the iDMRs and that the CpGs closer to the ZFP57 binding sites are less susceptible to methylation changes. We demonstrated the methylation polymorphism of three iDMRs and the atypical behaviour of several others, and reported the association of 25 disease- and 47 non-disease-complex traits, including blood cell type composition, as well as 15 mendelian or chromosomal disorders, with iDMR methylation changes in blood DNA. These findings identify several genetic and non-genetic factors associated with genomic imprinting maintenance in humans, which may have a role in the aetiology of the diseases associated with imprinting abnormalities and have clear implications in molecular diagnostics.

genetics↗

bioRxiv2019

Screening for genes that accelerate the epigenetic ageing clock in humans reveals a role for the H3K36 methyltransferase NSD1

BackgroundEpigenetic clocks are mathematical models that predict the biological age of an individual using DNA methylation data, and which have emerged in the last few years as the most accurate biomarkers of the ageing process. However, little is known about the molecular mechanisms that control the rate of such clocks. Here, we have examined the human epigenetic clock in patients with a variety of developmental disorders, harbouring mutations in proteins of the epigenetic machinery. ResultsUsing the Horvath epigenetic clock, we performed an unbiased screen for epigenetic age acceleration (EAA) in the blood of these patients. We demonstrate that loss-of-function mutations in the H3K36 histone methyltransferase NSD1, which cause Sotos syndrome, substantially accelerate epigenetic ageing. Furthermore, we show that the normal ageing process and Sotos syndrome share methylation changes and the genomic context in which they occur. Finally, we found that the Horvath clock CpG sites are characterised by a higher Shannon methylation entropy when compared with the rest of the genome, which is dramatically decreased in Sotos syndrome patients. ConclusionsThese results suggest that the H3K36 methylation machinery is a key component of the epigenetic maintenance system in humans, which controls the rate of epigenetic ageing, and this role seems to be conserved in model organisms. Our observations provide novel insights into the mechanisms behind the epigenetic ageing clock and we expect will shed light on the different processes that erode the human epigenetic landscape during ageing.

genomics↗