(ref. BAP-2020-170)Laatst aangepast : 14/04/2020
In the early development of a mammal, cells of the embryo generate the first three germ layers of endoderm, mesoderm and ectoderm in the fetal body, an ability called “pluripotency.” A fundamental question in developmental biology is how an early embryonic cell makes its first decisions to become one of multiple specialized cell types. These cell fate decisions involve dynamic changes in the removal and addition of methyl groups at specific positions in DNA. Changes in DNA methylation regulate gene expression and phenotype without altering the DNA sequence, constituting an important part of “epigenetics” research. The TET DNA dioxygenases erase DNA methylation by reiterative oxidation of 5-methylcytosine and have major roles as epigenetic regulators in development and disease. Recent studies by Prof. Kian Koh, co-discoverer of the TET family, have revealed important functions of TET1 at critical cell fate transitions in reprogramming and embryonic lineage segregation. Through an interesting interplay of catalytic and non-catalytic activities, TET1 influences chromatin accessibility and developmental signals in distinct ways in different lineages to regulate gene expression and confer every cell its unique identity. Understanding the molecular underpinnings of these early life events may lead to new insights into the etiology of both congenital and middle-age metabolic syndromes. PROJECT Using transgenic mouse strains generated in the laboratory, projects are available to investigate distinct epigenetic mechanisms regulating chromatin accessibility, gene expression and DNA methylation in lineage-specific embryonic versus extra-embryonic development, neurulation and cell fate reprogramming. The candidate will complement in vivo work conducted in mice with in vitro studies using mouse and human pluripotent stem cell cultures. Ultimately, the studies will provide important information of how proper regulation of DNA methylation in early development can tip the balance between health and disease later in life, with a focus on aging-related neurological disorders, neurodegeneration and cancer. 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 in press (http://www.genesdev.org/cgi/doi/10.1101/gad.329474.119). • 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.
• You will be trained to conduct independent research using techniques including mouse embryo dissection, cell culture and differentiation, genome editing, immunoprecipitation, ChIP-seq/RNA-seq/ ATAC-seq and DNA methylation and single-cell data analysis.
• You will help to supervise PhD and Master students.
• You have good command of written and spoken English and are motivated to read and write manuscripts and research proposals.
• You have completed a PhD degree in molecular and cellular biology, biochemistry or a related biomedical field, within the past 3 years.
• You have a strong background in molecular/cell biology and in epigenetics and are motivated to learn and/or develop new techniques.
• Previous experience with bioinformatics data analysis will be an advantage.
• You desire international mobility and thrive in a multidisciplinary environment.
You will be paid salary and benefits based on KU Leuven employment guidelines. You will receive contracts with yearly renewal; longer-term contracts are available upon successful competition for European or Belgian national fellowships.
For more information contact Christina Vochten (email@example.com).
The application file must include:
-Cover letter containing statement of motivation
-CV (summarizing education, positions, academic work and scientific publications)
-Name and contact details of 3 referees.
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.
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