Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling

Ming Hu, Xiao Jian Sun, Yuan Liang Zhang, Ying Kuang, Chao Quan Hu, Wei Li Wu, Shu Hong Shen, Ting Ting Du, Hong Li, Fei He, Hua Sheng Xiao, Zhu Gang Wang, Ting Xi Liu, He Lu, Qiu Hua Huang, Sai Juan Chen, Zhu Chen

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

HYPB is a human histone H3 lysine 36 (H3K36) - specific methyltransferase and acts as the ortholog of yeast Set2. This study explored the physiological function of mammalian HYPB using knockout mice. Homozygous disruption of Hypb impaired H3K36 trimethylation but not mono- or dimethylation, and resulted in embryonic lethality at E10.5-E11.5. Severe vascular defects were observed in the Hypb-/- embryo, yolk sac, and placenta. The abnormally dilated capillaries in mutant embryos and yolk sacs could not be remodeled into large blood vessels or intricate networks, and the aberrantly rounded mesodermal cells exhibited weakened interaction with endothelial cells. The embryonic vessels failed to invade the labyrinthine layer of placenta, which impaired the embryonic - maternal vascular connection. These defects could not be rescued by wildtype tetraploid blastocysts, excluding the possibility that they were caused by the extraembryonic tissues. Consistent with these phenotypes, gene expression profiling in wild-type and Hypb-/- yolk sacs revealed that the Hypb disruption altered the expression of some genes involved in vascular remodeling. At the cellular level, Hypb-/- embryonic stem cell - derived embryonic bodies, as well as in vitro - cultured human endothelial cells with siRNA-mediated suppression of HYPB, showed obvious defects in cell migration and invasion during vessel formation, suggesting an intrinsic role of Hypb in vascular development. Taken together, these results indicate that Hypb is required for embryonic vascular remodeling and provide a tool to study the function of H3K36 methylation in vasculogenesis/angiogenesis.

Original languageEnglish (US)
Pages (from-to)2956-2961
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number7
DOIs
StatePublished - Feb 16 2010
Externally publishedYes

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Methyltransferases
Histones
Yolk Sac
Lysine
Blood Vessels
Placenta
Embryonic Structures
Endothelial Cells
Tetraploidy
Gene Expression Profiling
Blastocyst
Embryonic Stem Cells
Knockout Mice
Methylation
Small Interfering RNA
Cell Movement
Yeasts
Mothers
Phenotype
Gene Expression

Keywords

  • Angiogenesis
  • Capillary tubule formation
  • Embryonic lethality
  • Knockout mice
  • Vasculogenesis

ASJC Scopus subject areas

  • General

Cite this

Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling. / Hu, Ming; Sun, Xiao Jian; Zhang, Yuan Liang; Kuang, Ying; Hu, Chao Quan; Wu, Wei Li; Shen, Shu Hong; Du, Ting Ting; Li, Hong; He, Fei; Xiao, Hua Sheng; Wang, Zhu Gang; Liu, Ting Xi; Lu, He; Huang, Qiu Hua; Chen, Sai Juan; Chen, Zhu.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 7, 16.02.2010, p. 2956-2961.

Research output: Contribution to journalArticle

Hu, M, Sun, XJ, Zhang, YL, Kuang, Y, Hu, CQ, Wu, WL, Shen, SH, Du, TT, Li, H, He, F, Xiao, HS, Wang, ZG, Liu, TX, Lu, H, Huang, QH, Chen, SJ & Chen, Z 2010, 'Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 7, pp. 2956-2961. https://doi.org/10.1073/pnas.0915033107
Hu, Ming ; Sun, Xiao Jian ; Zhang, Yuan Liang ; Kuang, Ying ; Hu, Chao Quan ; Wu, Wei Li ; Shen, Shu Hong ; Du, Ting Ting ; Li, Hong ; He, Fei ; Xiao, Hua Sheng ; Wang, Zhu Gang ; Liu, Ting Xi ; Lu, He ; Huang, Qiu Hua ; Chen, Sai Juan ; Chen, Zhu. / Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 7. pp. 2956-2961.
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abstract = "HYPB is a human histone H3 lysine 36 (H3K36) - specific methyltransferase and acts as the ortholog of yeast Set2. This study explored the physiological function of mammalian HYPB using knockout mice. Homozygous disruption of Hypb impaired H3K36 trimethylation but not mono- or dimethylation, and resulted in embryonic lethality at E10.5-E11.5. Severe vascular defects were observed in the Hypb-/- embryo, yolk sac, and placenta. The abnormally dilated capillaries in mutant embryos and yolk sacs could not be remodeled into large blood vessels or intricate networks, and the aberrantly rounded mesodermal cells exhibited weakened interaction with endothelial cells. The embryonic vessels failed to invade the labyrinthine layer of placenta, which impaired the embryonic - maternal vascular connection. These defects could not be rescued by wildtype tetraploid blastocysts, excluding the possibility that they were caused by the extraembryonic tissues. Consistent with these phenotypes, gene expression profiling in wild-type and Hypb-/- yolk sacs revealed that the Hypb disruption altered the expression of some genes involved in vascular remodeling. At the cellular level, Hypb-/- embryonic stem cell - derived embryonic bodies, as well as in vitro - cultured human endothelial cells with siRNA-mediated suppression of HYPB, showed obvious defects in cell migration and invasion during vessel formation, suggesting an intrinsic role of Hypb in vascular development. Taken together, these results indicate that Hypb is required for embryonic vascular remodeling and provide a tool to study the function of H3K36 methylation in vasculogenesis/angiogenesis.",
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AU - Hu, Ming

AU - Sun, Xiao Jian

AU - Zhang, Yuan Liang

AU - Kuang, Ying

AU - Hu, Chao Quan

AU - Wu, Wei Li

AU - Shen, Shu Hong

AU - Du, Ting Ting

AU - Li, Hong

AU - He, Fei

AU - Xiao, Hua Sheng

AU - Wang, Zhu Gang

AU - Liu, Ting Xi

AU - Lu, He

AU - Huang, Qiu Hua

AU - Chen, Sai Juan

AU - Chen, Zhu

PY - 2010/2/16

Y1 - 2010/2/16

N2 - HYPB is a human histone H3 lysine 36 (H3K36) - specific methyltransferase and acts as the ortholog of yeast Set2. This study explored the physiological function of mammalian HYPB using knockout mice. Homozygous disruption of Hypb impaired H3K36 trimethylation but not mono- or dimethylation, and resulted in embryonic lethality at E10.5-E11.5. Severe vascular defects were observed in the Hypb-/- embryo, yolk sac, and placenta. The abnormally dilated capillaries in mutant embryos and yolk sacs could not be remodeled into large blood vessels or intricate networks, and the aberrantly rounded mesodermal cells exhibited weakened interaction with endothelial cells. The embryonic vessels failed to invade the labyrinthine layer of placenta, which impaired the embryonic - maternal vascular connection. These defects could not be rescued by wildtype tetraploid blastocysts, excluding the possibility that they were caused by the extraembryonic tissues. Consistent with these phenotypes, gene expression profiling in wild-type and Hypb-/- yolk sacs revealed that the Hypb disruption altered the expression of some genes involved in vascular remodeling. At the cellular level, Hypb-/- embryonic stem cell - derived embryonic bodies, as well as in vitro - cultured human endothelial cells with siRNA-mediated suppression of HYPB, showed obvious defects in cell migration and invasion during vessel formation, suggesting an intrinsic role of Hypb in vascular development. Taken together, these results indicate that Hypb is required for embryonic vascular remodeling and provide a tool to study the function of H3K36 methylation in vasculogenesis/angiogenesis.

AB - HYPB is a human histone H3 lysine 36 (H3K36) - specific methyltransferase and acts as the ortholog of yeast Set2. This study explored the physiological function of mammalian HYPB using knockout mice. Homozygous disruption of Hypb impaired H3K36 trimethylation but not mono- or dimethylation, and resulted in embryonic lethality at E10.5-E11.5. Severe vascular defects were observed in the Hypb-/- embryo, yolk sac, and placenta. The abnormally dilated capillaries in mutant embryos and yolk sacs could not be remodeled into large blood vessels or intricate networks, and the aberrantly rounded mesodermal cells exhibited weakened interaction with endothelial cells. The embryonic vessels failed to invade the labyrinthine layer of placenta, which impaired the embryonic - maternal vascular connection. These defects could not be rescued by wildtype tetraploid blastocysts, excluding the possibility that they were caused by the extraembryonic tissues. Consistent with these phenotypes, gene expression profiling in wild-type and Hypb-/- yolk sacs revealed that the Hypb disruption altered the expression of some genes involved in vascular remodeling. At the cellular level, Hypb-/- embryonic stem cell - derived embryonic bodies, as well as in vitro - cultured human endothelial cells with siRNA-mediated suppression of HYPB, showed obvious defects in cell migration and invasion during vessel formation, suggesting an intrinsic role of Hypb in vascular development. Taken together, these results indicate that Hypb is required for embryonic vascular remodeling and provide a tool to study the function of H3K36 methylation in vasculogenesis/angiogenesis.

KW - Angiogenesis

KW - Capillary tubule formation

KW - Embryonic lethality

KW - Knockout mice

KW - Vasculogenesis

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JO - Proceedings of the National Academy of Sciences of the United States of America

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