Role of circadian gene Clock during differentiation of mouse pluripotent stem cells

doi:10.1007/s13238-016-0319-9

Protein Cell

2016, Vol. 7

Issue (11) : 820-832 https://doi.org/10.1007/s13238-016-0319-9

RESEARCH ARTICLE

Role of circadian gene Clock during differentiation of mouse pluripotent stem cells

Chao Lu^1,²,Yang Yang¹,Ran Zhao¹,Bingxuan Hua⁴,Chen Xu¹,Zuoqin Yan⁴,Ning Sun^1,^2,³(

),Ruizhe Qian^1,²(

)

¹. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
². Research Center on Aging and Medicine, Fudan University, Shanghai 200032, China
³. State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China
⁴. Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai 200032, China

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Abstract

Biological rhythms controlled by the circadian clock are absent in embryonic stem cells (ESCs). However, they start to develop during the differentiation of pluripotent ESCs to downstream cells. Conversely, biological rhythms in adult somatic cells disappear when they are reprogrammed into induced pluripotent stem cells (iPSCs). These studies indicated that the development of biological rhythms in ESCs might be closely associated with the maintenance and differentiation of ESCs. The core circadian gene Clock is essential for regulation of biological rhythms. Its role in the development of biological rhythms of ESCs is totally unknown. Here, we used CRISPR/CAS9-mediated genetic editing techniques, to completely knock out the Clock expression in mouse ESCs. By AP, teratoma formation, quantitative real-time PCR and Immunofluorescent staining, we did not find any difference between Clock knockout mESCs and wild type mESCs in morphology and pluripotent capability under the pluripotent state. In brief, these data indicated Clock did not influence the maintaining of pluripotent state. However, they exhibited decreased proliferation and increased apoptosis. Furthermore, the biological rhythms failed to develop in Clock knockout mESCs after spontaneous differentiation, which indicated that there was no compensational factor in most peripheral tissues as described in mice models before (DeBruyne et al., 2007b). After spontaneous differentiation, loss of CLOCK protein due to Clock gene silencing induced spontaneous differentiation of mESCs, indicating an exit from the pluripotent state, or its differentiating ability. Our findings indicate that the core circadian gene Clock may be essential during normal mESCs differentiation by regulating mESCs proliferation, apoptosis and activity.

Keywords Circadian gene Clock mouse embryonic stem cells gene knockout pluripotency cell proliferation cell apoptosis cell differentiation

Corresponding Author(s): Ning Sun,Ruizhe Qian

Issue Date: 28 November 2016

Cite this article:

Chao Lu,Yang Yang,Ran Zhao, et al. Role of circadian gene Clock during differentiation of mouse pluripotent stem cells[J]. Protein Cell, 2016, 7(11): 820-832.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-016-0319-9
https://academic.hep.com.cn/pac/EN/Y2016/V7/I11/820

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