An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality [Research Papers]

Publication Date:
2018-03-29
Publisher:
Cold Spring Harbor Laboratory Press
Print ISSN:
0890-9369
Topics:
Biology
Published by:
http://www.cshlpress.com/
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autor 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.
beschreibung 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.
citation_standardnr 6220403
datenlieferant ipn_articles
feed_id 1644
feed_publisher Cold Spring Harbor Laboratory Press
feed_publisher_url http://www.cshlpress.com/
insertion_date 2018-03-29
journalissn 0890-9369
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher Cold Spring Harbor Laboratory Press
quelle Genes & Development
relation http://genesdev.cshlp.org/cgi/content/short/32/5-6/373?rss=1
search_space articles
shingle_author_1 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.
shingle_author_2 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.
shingle_author_3 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.
shingle_author_4 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.
shingle_catch_all_1 An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality [Research Papers]
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.
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.
Cold Spring Harbor Laboratory Press
0890-9369
08909369
shingle_catch_all_2 An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality [Research Papers]
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.
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.
Cold Spring Harbor Laboratory Press
0890-9369
08909369
shingle_catch_all_3 An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality [Research Papers]
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.
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.
Cold Spring Harbor Laboratory Press
0890-9369
08909369
shingle_catch_all_4 An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality [Research Papers]
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.
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.
Cold Spring Harbor Laboratory Press
0890-9369
08909369
shingle_title_1 An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality [Research Papers]
shingle_title_2 An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality [Research Papers]
shingle_title_3 An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality [Research Papers]
shingle_title_4 An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality [Research Papers]
timestamp 2025-06-30T23:33:54.721Z
titel An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality [Research Papers]
titel_suche An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality [Research Papers]
topic W
uid ipn_articles_6220403