SIRT6 deficiency results in developmental retardation in cynomolgus monkeys

Weiqi Zhang, Haifeng Wan, Guihai Feng, Jing Qu, Jiaqiang Wang, Yaobin Jing, Ruotong Ren, Zunpeng Liu, Linlin Zhang, Zhiguo Chen, Shuyan Wang, Yong Zhao, Zhaoxia Wang, Yun Yuan, Qi Zhou, Wei Li (), Guang-Hui Liu () and Baoyang Hu ()
Additional contact information
Weiqi Zhang: CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Haifeng Wan: Institute of Zoology, Chinese Academy of Sciences
Guihai Feng: Institute of Zoology, Chinese Academy of Sciences
Jing Qu: Institute of Zoology, Chinese Academy of Sciences
Jiaqiang Wang: Institute of Zoology, Chinese Academy of Sciences
Yaobin Jing: CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Ruotong Ren: CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Zunpeng Liu: Institute of Zoology, Chinese Academy of Sciences
Linlin Zhang: Institute of Zoology, Chinese Academy of Sciences
Zhiguo Chen: Xuanwu Hospital Capital Medical University
Shuyan Wang: Xuanwu Hospital Capital Medical University
Yong Zhao: School of Life Sciences, Sun Yat-sen University
Zhaoxia Wang: Peking University First Hospital
Yun Yuan: Peking University First Hospital
Qi Zhou: Institute of Zoology, Chinese Academy of Sciences
Wei Li: Institute of Zoology, Chinese Academy of Sciences
Guang-Hui Liu: CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Baoyang Hu: Institute of Zoology, Chinese Academy of Sciences

Nature, 2018, vol. 560, issue 7720, 661-665

Abstract: Abstract SIRT6 acts as a longevity protein in rodents1,2. However, its biological function in primates remains largely unknown. Here we generate a SIRT6-null cynomolgus monkey (Macaca fascicularis) model using a CRISPR–Cas9-based approach. SIRT6-deficient monkeys die hours after birth and exhibit severe prenatal developmental retardation. SIRT6 loss delays neuronal differentiation by transcriptionally activating the long non-coding RNA H19 (a developmental repressor), and we were able to recapitulate this process in a human neural progenitor cell differentiation system. SIRT6 deficiency results in histone hyperacetylation at the imprinting control region of H19, CTCF recruitment and upregulation of H19. Our results suggest that SIRT6 is involved in regulating development in non-human primates, and may provide mechanistic insight into human perinatal lethality syndrome.

Date: 2018
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DOI: 10.1038/s41586-018-0437-z

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