An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality.
An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality.
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DOI：
10.1101/gad.307330.117
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发表时间：
2018-03-01
影响因子：
10.5
通讯作者：
Mostoslavsky R
中科院分区：
文献类型：
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作者：
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 JP;Sadreyev RI;Denu JM;Mostoslavsky G;van Maarle MC;Mostoslavsky R
Ferrer等人证明，组蛋白去乙酰化酶SIRT6的纯合子失活突变导致了四个受影响胎儿的严重先天性异常和围产期死亡。来源于D63H纯合子胎儿的人诱导多能干细胞由于不能抑制多能基因而不能分化为胚胎样体、功能性心肌细胞和神经祖细胞。在早期胚胎发生过程中，组蛋白和DNA修饰对于维持多能性和分化之间的平衡至关重要。DNA甲基化关键调控因子的突变表明，基因调控和功能之间的平衡在生命早期的神经发育中至关重要。然而，目前还没有发现将表观遗传调控因子与人类异常发育和胎儿死亡联系起来的病例。在这里，我们证明了组蛋白去乙酰化酶SIRT6的纯合子失活突变导致了四个受影响胎儿的严重先天性异常和围产期死亡。在体外，Asp63的氨基酸转变为组氨酸导致H3K9去乙酰化酶和去淀粉酰化酶功能几乎完全丧失。在功能上，SIRT6 D63H小鼠胚胎干细胞（mESCs）不能抑制SIRT6的直接靶点多能基因表达，并且在分化为胚状体（EBs）时表现出比SIRT6缺陷的ESCs更严重的表型。当最终向心肌细胞谱系分化时，D63H突变mESCs保持多能基因的表达，不能形成功能性心肌细胞灶。最后，来自D63H纯合子胎儿的人诱导多能干细胞（iPSCs）由于未能抑制多能基因而无法分化为EBs、功能性心肌细胞和神经祖细胞。总之，我们的研究描述了SIRT6的种系突变是胎儿死亡的原因，将SIRT6定义为人类发育的关键因素，并确定了人类围产期死亡综合征背后的染色质因子的第一个突变。
Ferrer et al. demonstrate that a homozygous inactivating mutation in the histone deacetylase SIRT6 results in severe congenital anomalies and perinatal lethality in four affected fetuses. Human induced pluripotent stem cells derived from D63H homozygous fetuses fail to differentiate into embryoid bodies, functional cardiomyocytes, and neural progenitor cells due to a failure to repress pluripotent genes. 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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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.5
作者：
Kugel S;Sebastián C;Fitamant J;Ross KN;Saha SK;Jain E;Gladden A;Arora KS;Kato Y;Rivera MN;Ramaswamy S;Sadreyev RI;Goren A;Deshpande V;Bardeesy N;Mostoslavsky R
通讯作者：
Mostoslavsky R
FOXG1 综合征的核心表型包括出生后小头畸形、严重智力低下、语言缺失、运动障碍和胼胝体发育不全。
影响因子：
4
作者：
Kortüm F;Das S;Flindt M;Morris-Rosendahl DJ;Stefanova I;Goldstein A;Horn D;Klopocki E;Kluger G;Martin P;Rauch A;Roumer A;Saitta S;Walsh LE;Wieczorek D;Uyanik G;Kutsche K;Dobyns WB
通讯作者：
Dobyns WB
影响因子：
21.3
作者：
Etchegaray JP;Chavez L;Huang Y;Ross KN;Choi J;Martinez-Pastor B;Walsh RM;Sommer CA;Lienhard M;Gladden A;Kugel S;Silberman DM;Ramaswamy S;Mostoslavsky G;Hochedlinger K;Goren A;Rao A;Mostoslavsky R
通讯作者：
Mostoslavsky R
影响因子：
82.9
作者：
通讯作者：
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