Sex chromosome dosage in ageing and age-related disease

1 PhD project offered in the IPP summer call 2021

This project is part of the Science of Healthy Ageing Research Programme (SHARP).

Scientific background

On average lifespan is about 7 years longer for women than men worldwide and overall women show less age-associated cognitive decline than men during ageing. While a lot is known about hormonal contribution to differences between sexes, the extent by which genetics and the chromosome complement is contributing to it is unclear.

Aneuploidy and haploinsufficiency are two forms of gene-dosage alteration, where transcriptional and cellular changes ultimately result in a diseased state. Chromosome copy number alterations are for example observed during ageing, where older individuals display an increased rate of chromosome losses that most frequently affect the sex chromosomes. Cellular hallmarks of ageing include genomic instability, epigenome alterations, a breakdown in tissue homeostasis, stem cell dysfunction and increased susceptibility to diseases.

PhD project: Cellular dynamics upon sex chromosome elimination

Because chromosome losses arise spontaneously, current experimental analyses of this phenomenon are scarce and limited to a static “snapshot” of rare cells among a population of diploids. Therefore, the prevalence, physiological relevance and dynamic cellular response mechanisms associated with spontaneous chromosome loss during ageing remain largely unclear.

In this project, the PhD student will develop a novel cellular tool allowing the inducible loss of a specific chromosome. For this, the selected candidate will establish a proof of principle in mouse embryonic stem cells. The student will perform molecular cloning and CRISPR engineering. Cells will be characterized using live and fixed confocal imaging, karyotyping, allele-specific analyses, multi-omics and biochemical assays. The student will dissect the cellular responses upon chromosome losses in stem cells and in terminally differentiated tissues. In collaboration with the University Medical Center (UMC) Mainz, the project will involve translational work, where cells and samples from healthy and diseased human individuals will be analyzed. Ultimately, the studies are aimed at generating complex murine study models.

We are looking for a student with a strong interest in mechanisms of gene regulation and developmental cell biology. Your passion to work at the bench is driven by an “engineering” mindset and the curiosity to unravel molecular mechanisms relevant to human physiology and disease. You will be mentored by and working in a collaborative team (Dr. Claudia Keller Valsecchi and Dr. M. Felicia Basilicata at the IMB, Prof. Susann Schweiger and Prof. Benedikt Berninger at the UMC), which requires enthusiasm to move your project forward in a multidisciplinary environment. If you are a team player and show a high degree of motivation and excitement for science, you will be the right person to join our group.

If you are interested in this project, please select Claudia Keller-Valsecchi as your group preference in the IPP application platform.

Publications relevant to this project

Valsecchi CIK, Basilicata MF, Semplicio G, GeorgievP, Gutierrez NM and  Akhtar A (2018) Facultative Dosage Compensation of Developmental Genes on Autosomes in Drosophila and Mouse Embryonic Stem Cells. Nature Communications, 9(1):3626 Link

Basilicata MF, Bruel AL, Semplicio G, Valsecchi CIK, Aktaş T, Duffourd Y, et al (2018) De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation. Nat Genet, 50:1442–1451 Link

Wijchers PJ, Yandim C, Panousopoulou E, Ahmad M, Harker N, Saveliev A, et al. (2010) Sexual dimorphism in mammalian autosomal gene regulation is determined not only by Sry but by sex chromosome complement as well. Dev Cell, 19:477–484 Link

Davis EJ, Broestl L, Abdulai-Saiku S, Worden K, Bonham LW, Miñones-Moyano E, et al. (2020) A second X chromosome contributes to resilience in a mouse model of Alzheimer’s disease. Sci Transl Med,12(558):eaaz5677 Link

Machiela MJ, Zhou W, Karlins E, Sampson JN, Freedman ND, Yang Q, et al. (2016) Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome. Nat Commun, 7:11843 Link

Valsecchi CIK, Felicia Basilicata M, Georgiev P, Gaub A, Seyfferth J, Kulkarni T, et al. (2021) RNA nucleation by MSL2 induces selective X chromosome compartmentalization. Nature, 589:137-142 Link

Contact

Dr Claudia Keller-Valsecchi (If you are interested in this project, please select Claudia Keller-Valsecchi as your group preference in the IPP application platform.)

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Dr M Felicia Basilicata

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Prof. Susann Schweiger

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Prof. Benedikt Berninger

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