PhD Position in Stem Cell and Developmental Epigenetics

Catholic University of Leuven

 
In mammals, the genetic information encoded in DNA contains coating of chemical marks, predominantly in the form of methylation at cytosine-guanine dinucleotides. Changes in DNA methylation regulate gene expression and phenotype without altering the DNA sequence, constituting an important part of “epigenetics” research. DNA methylation patterns can change dramatically during fetal development, with additional influences from genetics, nutritional and environmental factors. Whether aberrant DNA methylation events in early development predispose to diseases later in life is an important question with implications for future public health management. Here, we study the Tet-Eleven-Translocation (TET) family of DNA dioxygenases, which have gained attention as the “DNA demethylases” sought after in mammalian development. Using transgenic mouse models, we have recently discovered that knock-out of TET1 in embryos can lead to a group of severe congenital disorders called neural tube defects (NTDs), which are among the most common human congenital malformations. Interestingly, the severity of these disorders in Tet1-deficient embryos varies remarkably in different genetic backgrounds, suggesting that additional modifying factors can influence the phenotype. Our current projects aim to understand how the molecular interactions of TET1 with its regulatory loci and signalling environment can be influenced by folate one-carbon metabolism, vitamin co-factors, and genetic variants to tip the balance between health and disease during development. Moreover, dysregulation of the DNA methylome caused by TET deficiency, even when not causing NTDs, can remain as latent modifications that affect cell function later in post-natal life. Therefore, insights from our studies may have additional relevance for other neurological diseases, such as autism, in which aberrant DNA methylation during gestation may play a significant role. These studies are critical to inform new therapeutic strategies to prevent NTDs and a broad spectrum of neurodevelopmental disorders.

Project

We use complementary genetic and epigenetic approaches in mouse models, in order to discover genetic variants in noncoding regions of the genome underlying the etiologies of Tet1-dependent neurulation disorders, or the epigenetic dysregulation related to non-genetic factors, or the combination of both. Studies using transgenic mouse strains generated in the laboratory will be complemented with in vitro studies using mouse and human pluripotent stem cell cultures. Bulk and single-cell multiomics approaches will be used to investigate epigenetic mechanisms regulating chromatin accessibility, gene expression and DNA methylation in neurulation and cell fate reprogramming.

Web links:
• www.kuleuven.be/samenwerking/scil/paperkian2020
• www.news-medical.net/news/20170518/KU-Leuven-researchers-identify-vital-role-of-TET1-protein-in-earliest-stages-of-embryonic-development.aspx.

Selected Publications:
 Luo X, van der Veer BK, Sun L, Bartoccetti M, Boretto M, Vankelecom H, Khoueiry R. Koh KP (2020). Coordination of germ-layer lineage choice by TET1 during primed pluripotency. Genes & Development 34(7-8), 598-618.

 Bartoccetti M, van der Veer BK, Luo X, Khoueiry R, She P, Bajaj M, Xu J,  Janiszewski A, Thienpont B, Pasque V and Koh KP (2020). Regulatory dynamics of Tet1 and Oct4 resolve stages of global DNA demethylation and transcriptomic changes in pluripotency. Cell Reports 30(7), 2150-2169.

 Khoueiry R, Sohni A, Thienpont B, Luo XL, Vande Velde J, Bartoccetti M, Boeck B, Zwijsen A, Rao A, Lambrechts D, Koh KP (2017). Lineage-specific functions of TET1 in the post-implantation mouse embryo. Nature Genetics 49, 1061-1072.

 Koh KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J, Laiho A, Tahiliani M, Sommer CA, Mostoslavsky G, Lahesmaa R, Orkin SH, Rodig SJ, Daley GQ, Rao A (2011). Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8, 200-213.

Profile

• You have a Bachelor Honors or Master’s degree from one of the countries of the EU, the EER, the UK or Switzerland, in molecular and cellular biology, biochemistry or a related biomedical field with excellent grades.
• You have good command of written and spoken English and are motivated to read and write manuscripts and research proposals.
• You have a passion for science and can thrive in an ambitious and highly interdisciplinary environment.

Offer

You will be paid salary and benefits based on KU Leuven employment guidelines. Scholarship is available for 4 years upon satisfactory evaluation during the first year. The successful candidate must also be competitive for Belgium national fellowships.

Interested?

The application file must include:
- Cover letter containing statement of motivation
- CV (summarizing education, positions and academic work, scientific publications if any)
- Copies of educational certificates and grades
- Name and contact details of 1-2 referees.

For more information please contact Kian Koh, mail: kian.koh@kuleuven.be.

You can apply for this job no later than December 01, 2020 via the
KU Leuven seeks to foster an environment where all talents can flourish, regardless of gender, age, cultural background, nationality or impairments. If you have any questions relating to accessibility or support, please contact us at diversiteit.HR@kuleuven.be.
  • Employment percentage: Voltijds
  • Location: Leuven
  • Apply before: December 1, 2020
  • Tags: Ontwikkeling en Regeneratie