SIRT6 deficiency results in developmental retardation in cynomolgus monkeys

Abstract

SIRT6 acts as a longevity protein in rodents. 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.

Local transgene expression and whole‐body transgenesis to model brain diseases in nonhuman primate

“…Notably, a smaller brain and thinner cortical layers in the cerebral and cerebellar hemispheres were described in the transgenic newborn monkeys, evoking neuronal maturation delay. It was consistent to the loss‐of‐function mutation of SIRT6 described in humans that causes late fetal loss with intrauterine growth restriction . So, the use of CRISPR/Cas9 appears to be a promising way to obtain new transgenic animal model.…”

Spatially resolved gene regulatory and disease vulnerability map of the adult Macaque cortex

“…The cynomolgus monkey (Macaca fascicularis) is one of the most studied non-human primates (NHP) in neuroscience and medicine (6,7). Recent advances in transgenesis and genome-editing technologies have led to successful development of 5 new cynomolgus monkey models to study genetic human neurological disorders (8)(9)(10), making this species an excellent experimental NHP model for brain researchers.…”

New Insights for Cellular and Molecular Mechanisms of Aging and Aging-Related Diseases: Herbal Medicine as Potential Therapeutic Approach

“…In the latest research by Zhang et al [99], they found that by performing a whole-body knockout of "longevity gene" SIRT6 in nonhuman primates, they could obtain the world's first cynomolgus monkey model of longevity gene knockout, thereby revealing the new role of the SIRT6 gene in regulating embryonic development of primates. They could also elucidate the differences in aging and longevity regulation pathways between primates and rodents, laying an important foundation for research on the mechanisms of human development and aging and the treatment of related diseases [99]. SIRT7 could result in antiaging and prolong life by regulating the repair of the nonhomologous DNA damage to maintain the stable heredity of cells [100].…”