SIRT6 deficiency results in developmental retardation in cynomolgus monkeys
| Autor: | Guang-Hui Liu, Yun Yuan, Wei Li, Qi Zhou, Haifeng Wan, Yong Zhao, Jiaqiang Wang, Shuyan Wang, Jing Qu, Zunpeng Liu, Zhiguo Chen, Guihai Feng, Baoyang Hu, Ruotong Ren, Weiqi Zhang, Yaobin Jing, Zhaoxia Wang, Linlin Zhang |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male CCCTC-Binding Factor Cellular differentiation Developmental Disabilities Neurogenesis Human Embryonic Stem Cells Repressor Biology Transcriptome Histones 03 medical and health sciences Genomic Imprinting Downregulation and upregulation Neural Stem Cells Animals Humans Sirtuins Progenitor cell Fetal Death Gene Editing Multidisciplinary Muscles Brain Acetylation Cell Differentiation Cell biology Macaca fascicularis 030104 developmental biology Animals Newborn CTCF Female RNA Long Noncoding Genomic imprinting Gene Deletion |
| Zdroj: | Nature. 560(7720) |
| ISSN: | 1476-4687 |
| Popis: | 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. A cynomolgus monkey model deficient in SIRT6 protein exhibits severe retardation in prenatal development, in which neuronal differentiation is delayed by activation of the H19 long non-coding RNA. |
| Databáze: | OpenAIRE |
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