About the Project
Cell autonomous circadian clocks are responsible for generating 24 hour rhythms, governing cell division, differentiation, DNA damage repair and cell metabolism. Most somatic cell types contain functional clocks e.g. the Meng group has recently identified circadian clocks in chondrocytes that play essential roles in cartilage tissue homeostasis and integrity (1,2). However, in mouse embryonic stem (ES) cells a lack of circadian rhythms has been demonstrated (3). Remarkably, the clock function is instantly switched on with the differentiation of ES cells, and is switched off when differentiated cells are reprogrammed back to the induced pluripotent stem cell (iPSC) state. It is not known if a similar clock ‘switch on’ occurs in human ES cells (hESCs) or hiPSCs but our unpublished data shows that hESCs, like mouse ES cells, do not have a functional clock. This is in contrast to fully differentiated chondrocytes that do possess circadian clocks (1, 4). The circadian clock in somatic cells is severely dampened with age and this has been associated with ageing-dysfunction and disease. Therefore, understanding how the clock is switched off and on may lead to new strategies to alleviate age-related clock dysfunction. The Kimber group has generated 17 hESC and >7 iPSC lines (5) and has well-developed directed differentiation protocols (6). In this project we will use these lines and the iPSC reprogramming technology to understand how the circadian clock is first turned on (in hESCs during differentiation) and turned off (in somatic cells during reprogramming to iPSCs). The fact that we can switch the clock on in hESCs and iPSCs as they differentiate and switch the clock off as iPSCs are generated from blood gives us a unique model to understand the processes that turn the clock on and off and why the clock is down-regulated and dampened in aging and/or disrupted in disease. Elucidating the molecular regulation of the circadian clock mechanism will allow us to prevent age-related damping of circadian rhythms.
http://meng.lab.manchester.ac.uk/
http://www.manchester.ac.uk/nwescc
http://www.lab.ls.manchester.ac.uk/mtrscn/
http://www.manchester.ac.uk/msca
Funding Notes
This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form, full details on how to apply can be found on the BBSRC DTP website http://www.dtpstudentships.manchester.ac.uk/
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
References
1. Dudek M, Gossan N, Nan Yang N, Im H-J, Ruckshanthi JPD, Yoshitane H, Li X, Jin D, Wang P, Boudiffa M, Bellantuono I, Fukada Y, Boot-Handford RP & Meng QJ (2016). The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity. J Clin. Invest. 126 (1), 365-376.
2. Gossan N, Zeef L, Hensman J, Hughes A, Bateman JF, Rowley L, Little, CB, Piggins HD, Rattray M, Boot-Handford RP, Meng QJ (2013). The circadian clock in chondrocytes regulates genes controlling key aspects of cartilage homeostasis. Arthritis and Rheumatism. 65(9):2334-2345.
3. Janich P, Meng QJ, Benitah SA (2014). Circadian control of tissue homeostasis and adult stem cells. Curr Opin Cell Biol. 31:8-15.
4. Yagita K, Horie K, Koinuma S, Nakamura W, Yamanaka I, Urasaki A, Shigeyoshi Y, Kawakami K, Shimada S, Takeda J, Uchiyama Y. (2010). Development of the circadian oscillator during differentiation of mouse embryonic stem cells in vitro. PNAS. 107(8):3846.
5. Oldershaw RA, Baxter MA, Lowe ET, Bates N, Grady LN, Brison DR, Hardingham TE & Kimber SJ. 2010. The directed differentiation of human embryonic stem cells towards chondrocytes Nature Biotech 28, 1187-1193.
6. Cheng A, Kapacee Z, Peng J. Lucas R, Lu S, Lucas R, Hardingham TE & Kimber SJ (2014) Cartilage Repair Using Human Embryonic Stem Cell-derived Chondroprogenitors. Stem cell Translational Medicine 3, 1287-1294.
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