The two female XX chromosomes and their role in providing sex-specific resilience and protective strength

1 PhD project offered in the IPP summer call 2021

Consortium: Peter Baumann, Joan Barau, M. Felicia Basilicata, Claudia Keller Valsecchi

Scientific background

Women are less frequently affected by neurodevelopmental disorders, have a more efficient immune-response and live substantially longer than man. Many of these differences have been attributed to the changes in physiology that coincide with male development. However, males and females also differ in their chromosome complements, as males harbor a single X chromosome, whereas females have two. To counteract gene expression imbalances, X chromosome dosage compensation is achieved by a chromosome-wide, random inactivation of one X chromosome in every cell during embryonic development in females. Interestingly, it has recently been found that inactivation can be reversed in certain conditions and for certain genes. The consequences of this X chromosome reactivation in females and its link to the gender bias in disease manifestation are only poorly understood.

PhD project: Epigenetic mechanisms for X chromosome reactivation in neurodevelopment and immune responses

Exciting new data shows that an intriguing group of X-linked genes can escape inactivation in a tissue- and stimulus-specific fashion. We hypothesize that those genes provide a genetic reservoir of variation that is specific to females and can be unlocked under certain conditions. We are looking for a PhD candidate to embrace the exciting opportunity to use cutting edge genomics and cell biological tools to unveil the roles of X-inactivation escape for female robustness, resilience and plasticity. During your PhD, you will tackle key questions related to the mechanisms that lead to X-inactivation escape and its consequences. You will use human induced pluripotent stem cells (iPSCs) and models of differentiation into neural progenitor cells (NPCs) and brain organoids to investigate those novel escapees.

We are looking for a student with a strong interest in mechanisms of gene regulation and developmental cell biology. While this is not a strict requirement, candidates should be equally interested in wet lab approaches and computational data analysis. This position is part of a larger network of scientists from the IMB, the Johannes-Gutenberg University and the University Medicine in Mainz. To be successful in this highly interdisciplinary environment, excellent organizational and communication skills are essential. In addition, our preferred candidate exhibits kindness, courage as well as enthusiasm to unravel molecular mechanisms relevant to human physiology and disease.

If you are interested in this project, please select Peter Baumann (Consortium) as your group preference in the IPP application platform.

Publications relevant to the project

Tukiainen, T., Villani, AC., Yen, A. et al. (2017) Landscape of X chromosome inactivation across human tissues. Nature, 550:244–248 Link         

Arnold AP (2014) Conceptual frameworks and mouse models for studying sex differences in physiology and disease: why compensation changes the game. Exp Neurol, 259:2-9 Link                                          

Khramtsova EA, Davis LK, Stranger BE (2019) The role of sex in the genomics of human complex traits. Nat Rev Genet, 20:173–190 Link

Barau J, Teissandier A, Zamudio N, Roy S, Nalesso V, Hérault Y, Guillou F, Bourc’his D (2016) The DNA methyltransferase DNMT3C protects male germ cells from transposon activity. Science, 354:909–912 Link

Basilicata MF, Bruel AL*, Semplicio G*, Keller Valsecchi CI*, Aktaş T*, Duffourd Y, Rumpf T, Morton J, Bache I, Szymanski WG, Gilissen C, Vanakker O, Õunap K, Mittler G, van der Burgt I, El Chehadeh S, Cho MT, Pfundt R, Tan TY, Kirchhoff M, Menten B, Vergult S, Lindstrom K, Reis A, Johnson DS, Fryer A, McKay V, Fisher RB, Thauvin-Robinet C, Francis D, Roscioli T, Pajusalu S, Radtke K, Ganesh J, Brunner HG, Wilson M, Faivre L, Kalscheuer VM, Thevenon J# and Akhtar A# (2018) De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylationNat Genet, 50:1442–1451 (*indicates joint contribution, #indicates joint correspondence) Link           

Keller Valsecchi CI*, Basilicata MF*, Georgiev P, Gaub A, Seyfferth J, Kulkarni T, Panhale A, Semplicio G, Manjunath V, Holz H, Dasmeh P and Akhtar A (2020) RNA nucleation by MSL2 induces selective X chromosome compartmentalizationNature, doi: 10.1038/s41586-020-2935-z (*indicates joint contribution) Link        

 

Contact

Prof. Peter Baumann (If you are interested in this project, please select Peter Baumann (Consortium) as your group preference in the IPP application platform.)

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Dr Joan Barau

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Dr M Felicia Basilicata

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Dr Claudia Keller-Valsecchi

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