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Linking SIRT6 Loss to Developmental Retardation in Non-Human Primates

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Review of “SIRT6 deficiency results in developmental retardation in cynomolgus monkeys” from Nature by Stuart P. Atkinson 

Studies have discovered that Sirt6, a stress-responsive protein deacetylase and mono-ADP ribosyltransferase enzyme, represents a longevity factor in mice. Sirt6 improves overall health and extends lifespan when overexpressed [1] and causes early mortality and signs of premature aging in its absence [2]. However, we know relatively little regarding the biological function in primates, although a recent report hinted at a key role for human SIRT6 in embryonic development [3].

To widen our knowledge base in the role of SIRT6, a research team from the University of Chinese Academy of Sciences (Beijing, China) recently applied CRISPR/Cas9 genome editing technology to generate and analyze a cynomolgus monkey SIRT6-null model [4]. In their new Nature article, Zhang et al. describe how SIRT6 loss leads to severe developmental defects, which, in combination with the findings of other related studies [5], may indicate a pro-longevity role for SIRT6 in humans.

The authors of this fascinating new report discovered that SIRT6-null cynomolgus monkeys displayed whole-body developmental delay upon birth, displaying similarities to wild-type fetal monkeys at a gestational age of 2-4 months, and died during gestation or a few hours after birth. Of note, previous studies in a mouse model failed to uncover severe brain defects following Sirt6 loss. While SIRT6 deficiency caused pan-tissue developmental retardation, the authors highlighted the fetus-like brain characteristics of full-term/near-full term SIRT6-null cynomolgus monkeys, suggesting that SIRT6 functions as a mediator of neural progenitor differentiation.

To understand the molecular mechanisms affected following SIRT6 loss, the authors compared transcriptomes from seven major organs between healthy and SIRT6-deficient monkeys. While many differentially expressed genes associated with previously reported alterations in glucose and energy metabolism, the authors highlighted the long non-coding RNA H19 as one of the most upregulated genes, especially in the brain. H19, a maternally-expressed imprinted gene that regulates fetal development, plays a known role in brain tissue development [6] and its overexpression is linked to a development retardation disorder in humans [7]. This study revealed that the lack of histone deacetylase activity caused by SIRT6 deficiency prompted H19 expression by hyperacetylation of the H19 control region and induced CTCF recruitment, thereby providing a delay in neuronal differentiation. 

Overall, these findings suggest that SIRT6 plays a crucial role in the developing non-human primate, and the authors hope that their CRISPR/Cas9-mediated monkey model of SIRT6 deficiency will also advance research into the pathogenesis of human perinatal lethality syndrome.

Now that we have begun to understand the effects of SIRT6 loss in non-human primates, will we soon see a study assessing the effects of SIRT6 overexpression? Stay tuned to the Stem Cells Portal to find out! 

References

  1. Kanfi Y, Naiman S, Amir G, et al., The sirtuin SIRT6 regulates lifespan in male mice. Nature 2012;483:218-21.
  2. Mostoslavsky R, Chua KF, Lombard DB, et al., Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 2006;124:315-29.
  3. Ferrer CM, Alders M, Postma AV, et al., An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality. Genes Dev 2018;32:373-388.
  4. Zhang W, Wan H, Feng G, et al., SIRT6 deficiency results in developmental retardation in cynomolgus monkeys. Nature 2018;560:661-665.
  5. Kaluski S, Portillo M, Besnard A, et al., Neuroprotective Functions for the Histone Deacetylase SIRT6. Cell Rep 2017;18:3052-3062.
  6. Gabory A, Jammes H, and Dandolo L, The H19 locus: role of an imprinted non-coding RNA in growth and development. Bioessays 2010;32:473-80.
  7. Wakeling EL, Brioude F, Lokulo-Sodipe O, et al., Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat Rev Endocrinol 2017;13:105-124.