ArticleGenes & development2018
An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality.
Article in Genes & development, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 60 citations in OpenAlex.
- Conserved Transcriptomic Signatures of Sirt6 Activity: A Cross-Species RNA-seq Meta-analysis.bioRxiv : the preprint server for biology · 2026Article
- Long-lived mammals contain more phosphorylation sites in the SIRT6 C-terminus that enhance PARP1 interaction and resistance to oxidative stress.GeroScience · 2026Article
- Targeting the SIRT6-TDO2/KYNA-mTOR axis rescues synaptic and cognitive deficits in fetal growth restriction offspring.Experimental & molecular medicine · 2026Article
- Long-lived mammals contain more phosphorylation sites in the SIRT6 C-terminus that enhance PARP1 interaction and resistance to oxidative stress.bioRxiv : the preprint server for biology · 2026Article
- Chromatin Remodeling, DNA Double-Strand Break Repair, and Human Disease: How a Breakup Changes You.Biomolecules · 2026Review
- Nationwide Study of Pediatric Drug-Resistant Epilepsy in Estonia: Lower Incidence and Insights into Etiology.Pediatric reports · 2026Article
- Therapeutic Perspectives of SIRT6 Regulation: Computational Analysis of Activation and Inhibition by Bioactive Molecules.Journal of molecular recognition : JMR · 2026Article
- Sirt6 prevents the age-related decline of HProceedings of the National Academy of Sciences of the United States of America · 2025Article
- The association of the SIRT6 rs117385980 variant with frailty and longevity: an exploratory study.Scientific reports · 2025Article
- Sirt6 loss activates Got1 and facilitates cleft palate through abnormal activating glycolysis.Cell death & disease · 2025Article
- Genes as Genome Stabilizers in Pluripotent Stem Cells.Advances in experimental medicine and biology · 2025Review
- Sirtuins and Their Implications in the Physiopathology of Gestational Diabetes Mellitus.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Human SIRT5 variants with reduced stability and activity do not cause neuropathology in mice.iScience · 2024Article
- Sirt6 regulates the proliferation of neural precursor cells and cortical neurogenesis in mice.iScience · 2024Article
- Review
- The many faces of SIRT6 in the retina and retinal pigment epithelium.Frontiers in cell and developmental biology · 2023Review
- NADOxidative medicine and cellular longevity · 2023Review
- A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A.The EMBO journal · 2022Article
- DNA repair as a shared hallmark in cancer and ageing.Molecular oncology · 2022Review
- Article
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Authors and funding
18 authors at 7 institutions in 2 countries.
Funding
Abstract
It has been well established that histone and DNA modifications are critical to maintaining the equilibrium between pluripotency and differentiation during early embryogenesis. Mutations in key regulators of DNA methylation have shown that the balance between gene regulation and function is critical during neural development in early years of life. However, there have been no identified cases linking epigenetic regulators to aberrant human development and fetal demise. Here, we demonstrate that a homozygous inactivating mutation in the histone deacetylase SIRT6 results in severe congenital anomalies and perinatal lethality in four affected fetuses. In vitro, the amino acid change at Asp63 to a histidine results in virtually complete loss of H3K9 deacetylase and demyristoylase functions. Functionally, SIRT6 D63H mouse embryonic stem cells (mESCs) fail to repress pluripotent gene expression, direct targets of SIRT6, and exhibit an even more severe phenotype than Sirt6-deficient ESCs when differentiated into embryoid bodies (EBs). When terminally differentiated toward cardiomyocyte lineage, D63H mutant mESCs maintain expression of pluripotent genes and fail to form functional cardiomyocyte foci. Last, human induced pluripotent stem cells (iPSCs) derived from D63H homozygous fetuses fail to differentiate into EBs, functional cardiomyocytes, and neural progenitor cells due to a failure to repress pluripotent genes. Altogether, our study described a germline mutation in SIRT6 as a cause for fetal demise, defining SIRT6 as a key factor in human development and identifying the first mutation in a chromatin factor behind a human syndrome of perinatal lethality.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.