Research output: Contribution to journal › Article › Academic › peer-review
An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality. / Ferrer, Christina M.; Alders, Marielle; Postma, Alex V. et al.
In: Genes & development, Vol. 32, No. 5-6, 2018, p. 373-388.Research output: Contribution to journal › Article › Academic › peer-review
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TY - JOUR
T1 - An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality
AU - Ferrer, Christina M.
AU - Alders, Marielle
AU - Postma, Alex V.
AU - Park, Seonmi
AU - Klein, Mark A.
AU - Cetinbas, Murat
AU - Pajkrt, Eva
AU - Glas, Astrid
AU - van Koningsbruggen, Silvana
AU - Christoffels, Vincent M.
AU - Mannens, Marcel M. A. M.
AU - Knegt, Lia
AU - Etchegaray, Jean-Pierre
AU - Sadreyev, Ruslan I.
AU - Denu, John M.
AU - Mostoslavsky, Gustavo
AU - van Maarle, Merel C.
AU - Mostoslavsky, Raul
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85044713586&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29555651
U2 - 10.1101/gad.307330.117
DO - 10.1101/gad.307330.117
M3 - Article
C2 - 29555651
VL - 32
SP - 373
EP - 388
JO - Genes & development
JF - Genes & development
SN - 0890-9369
IS - 5-6
ER -
ID: 5497224