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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

Harvard

Ferrer, CM, Alders, M, Postma, AV, Park, S, Klein, MA, Cetinbas, M, Pajkrt, E, Glas, A, van Koningsbruggen, S, Christoffels, VM, Mannens, MMAM, Knegt, L, Etchegaray, J-P, Sadreyev, RI, Denu, JM, Mostoslavsky, G, van Maarle, MC & Mostoslavsky, R 2018, 'An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality', Genes & development, vol. 32, no. 5-6, pp. 373-388. https://doi.org/10.1101/gad.307330.117

APA

Ferrer, C. M., Alders, M., Postma, A. V., Park, S., Klein, M. A., Cetinbas, M., Pajkrt, E., Glas, A., van Koningsbruggen, S., Christoffels, V. M., Mannens, M. M. A. M., Knegt, L., Etchegaray, J-P., Sadreyev, R. I., Denu, J. M., Mostoslavsky, G., van Maarle, M. C., & Mostoslavsky, R. (2018). An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality. Genes & development, 32(5-6), 373-388. https://doi.org/10.1101/gad.307330.117

Vancouver

Ferrer CM, Alders M, Postma AV, Park S, Klein MA, Cetinbas M et al. An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality. Genes & development. 2018;32(5-6):373-388. doi: 10.1101/gad.307330.117

Author

Ferrer, Christina M. ; Alders, Marielle ; Postma, Alex V. et al. / An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality. In: Genes & development. 2018 ; Vol. 32, No. 5-6. pp. 373-388.

BibTeX

@article{a6645a4fb4fa45fe952e757e2a363239,
title = "An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality",
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.",
author = "Ferrer, {Christina M.} and Marielle Alders and Postma, {Alex V.} and Seonmi Park and Klein, {Mark A.} and Murat Cetinbas and Eva Pajkrt and Astrid Glas and {van Koningsbruggen}, Silvana and Christoffels, {Vincent M.} and Mannens, {Marcel M. A. M.} and Lia Knegt and Jean-Pierre Etchegaray and Sadreyev, {Ruslan I.} and Denu, {John M.} and Gustavo Mostoslavsky and {van Maarle}, {Merel C.} and Raul Mostoslavsky",
year = "2018",
doi = "10.1101/gad.307330.117",
language = "English",
volume = "32",
pages = "373--388",
journal = "Genes & development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "5-6",

}

RIS

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