Biology subjects

Hoeijmakers, J.

Publications and source records attributed to Hoeijmakers, J..

4 recordsLinked to original sources

bioRxiv2025

RNA sequence analysis of somatic mutations in aging and Parkinson's Disease

Parkinsons Disease (PD) is an age-related neurodegenerative disorder that has been associated with increased DNA damage. To test if PD is associated with increased somatic mutations, we analyzed RNA-seq data in whole blood from 5 visits of the Parkinsons Progression Markers Initiative for clonally amplified somatic variants. Comprehensive analysis of RNA-sequencing data revealed a total of 5,927 somatic variants (2.4 variants per sample on average). Mutation frequencies were significantly elevated in PD subjects as compared to age-matched controls at the time of the last visit. This was confirmed by RNA analysis of substantia nigra. By contrast, the fraction of carriers with clonal hematopoiesis, was significantly reduced in old PD patients as compared to old healthy controls. These results indicate that while the overall mutation rate is higher in PD, specific clonally amplified mutations are protective against PD, as has been found for Alzheimers Disease.

genetics↗

bioRxiv2024

Mathematical model of transcription loss due to accumulated DNA damage

We offer a simple mathematical model of gene transcription loss due to accumulated DNA damage in time based on widely agreed biological axioms. Closed form formulae characterizing the distribution of the underlying stochastic processes representing the transcription loss upon specified number of DNA damages are obtained. Moreover, the asymptotic behavior of the stochastic process was analyzed. Finally, the distribution of the first hitting time of transcription loss to specified biologically relevant levels was studied both analytically and computationally on mice data.

systems biology↗

bioRxiv2022

The regulatory landscapes of human ovarian ageing

Summary paragraphThe ovary is the first organ to age in the human body, affecting both fertility and overall health in women1-8. However, the biological mechanisms underlying human ovarian ageing remain poorly understood. Here we performed single-nuclei multi-omics analysis of young and reproductively aged human ovaries to understand the molecular and cellular basis of ovarian ageing in humans. Our analysis reveals coordinated changes in transcriptomic output and chromatin accessibility across cell types during ageing, including elevated mTOR and MAPK signaling, decreased activity of the oxidative phosphorylation and DNA damage repair pathways, and an increased signature of cellular senescence. By constructing cell type-specific regulatory networks, we uncover enhanced activity of the transcription factor CEBPD across cell types in the aged ovary, with a corresponding significant loss of activity of most cell identity-associated transcription factors. Moreover, by performing integrative analyses of our single-nuclei multi-omics data with common genetic variants associated with age at natural menopause (ANM) from genome-wide association studies, we demonstrate a global impact of functional variants on changes in gene regulatory networks across ovarian cell types. Finally, we nominate about a dozen of functional non-coding variants, their target genes and cell types and regulatory mechanisms that underlie genetic association with ANM. This work provides a comprehensive multimodal landscape of human ovarian ageing and mechanistic insights into inherited variation of ANM.

genomics↗

bioRxiv2017

Deficiency of global genome nucleotide excision repair explains mutational signature observed in cancer

Nucleotide excision repair (NER) is one of the main DNA repair pathways that protect cells against genomic damage. Disruption of this pathway can contribute to the development of cancer and accelerate aging. Tumors deficient in NER are more sensitive to cisplatin treatment. Characterization of the mutational consequences of NER-deficiency may therefore provide important diagnostic opportunities. Here, we analyzed the somatic mutational profiles of adult stem cells (ASCs) from NER-deficient Ercc1-/{Delta} mice, using whole-genome sequencing analysis of clonally derived organoid cultures. Our results indicate that NER-deficiency increases the base substitution load in liver, but not in small intestinal ASCs, which coincides with a tissue-specific aging-pathology observed in these mice. The mutational landscape changes as a result of NER-deficiency in ASCs of both tissues and shows an increased contribution of Signature 8 mutations, which is a pattern with unknown etiology that is recurrently observed in various cancer types. The scattered genomic distribution of the acquired base substitutions indicates that deficiency of global-genome NER (GG-NER) is responsible for the altered mutational landscape. In line with this, we observed increased Signature 8 mutations in a GG-NER-deficient human organoid culture in which XPC was deleted using CRISPR-Cas9 gene-editing. Furthermore, genomes of NER-deficient breast tumors show an increased contribution of Signature 8 mutations compared with NER-proficient tumors. Elevated levels of Signature 8 mutations may therefore serve as a biomarker for NER-deficiency and could improve personalized cancer treatment strategies.

molecular biology↗