An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality

Genes Dev. 2018 Mar 1;32(5-6):373-388. doi: 10.1101/gad.307330.117.

Christina M Ferrer ^# ¹ ², Marielle Alders ^# ³, Alex V Postma ^# ³ ⁴, Seonmi Park ⁵, Mark A Klein ⁶ ⁷, Murat Cetinbas ⁸ ⁹ ¹⁰, Eva Pajkrt ⁴, Astrid Glas ³, Silvana van Koningsbruggen ³, Vincent M Christoffels ⁴, Marcel M A M Mannens ³, Lia Knegt ³, Jean-Pierre Etchegaray ¹ ², Ruslan I Sadreyev ⁸ ⁹ ¹⁰, John M Denu ⁶, Gustavo Mostoslavsky ⁵, Merel C van Maarle ³, Raul Mostoslavsky ¹ ² ¹¹

Affiliations

1 The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
2 The Massachusetts General Hospital Center for Regenerative Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
3 Department of Clinical Genetics, Academic Medical Center, Amsterdam 1105 AZ, the Netherlands.
4 Department of Obstetrics and Gynecology, Academic Medical Center, Amsterdam NL-1105 AZ, the Netherlands.
5 The Center for Regenerative Medicine (CReM), Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
6 Department of Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin 53715, USA.
7 The Wisconsin Institute for Discovery, University of Wisconsin, Madison, Wisconsin 53715, USA.
8 Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
9 Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
10 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
11 The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
# Contributed equally.

PMID: 29555651 DOI: 10.1101/gad.307330.117

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.

Keywords

SIRT6; chromatin; embryonic development; epigenetics; human syndrome.

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