Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Identification of a novel risk factor for intracranial aneurysms in ADPKD using iPSC models [Affymetrix]

ABSTRACT: Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca2+ entry and gene expression profiles compared with those from control-iPSCs. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in the iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed a statistically significant correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that the serum MMP1 levels may be a novel risk factor and become more beneficial when combined with other risk factors. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors. The gene expression profiles of vascular endothelia and smooth muscle cells derived from ADPKD-iPSCs were analyzed. Seven ADPKD-iPSC derived ECs, and seven ADPKD-iPSC derived SMCs were analyzed.

ORGANISM(S): Homo sapiens

SUBMITTER: Akira Watanabe

PROVIDER: E-GEOD-74452 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models.

Ameku Tomonaga T Taura Daisuke D Sone Masakatsu M Numata Tomohiro T Nakamura Masahiro M Shiota Fumihiko F Toyoda Taro T Matsui Satoshi S Araoka Toshikazu T Yasuno Tetsuhiko T Mae Shin-Ichi S Kobayashi Hatasu H Kondo Naoya N Kitaoka Fumiyo F Amano Naoki N Arai Sayaka S Ichisaka Tomoko T Matsuura Norio N Inoue Sumiko S Yamamoto Takuya T Takahashi Kazutoshi K Asaka Isao I Yamada Yasuhiro Y Ubara Yoshifumi Y Muso Eri E Fukatsu Atsushi A Watanabe Akira A Sato Yasunori Y Nakahata Tatsutoshi T Mori Yasuo Y Koizumi Akio A Nakao Kazuwa K Yamanaka Shinya S Osafune Kenji K

Scientific reports 20160715

Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca(2+) en ...[more]

PMID: 27418197

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Project description:DNA methylation changes dynamically during development and is essential for embryogenesis in mammals. However, how DNA methylation affects developmental gene expression and cell differentiation remains elusive. During embryogenesis, many key transcription factors are used repeatedly, triggering different outcomes depending on the cell type and developmental stage. Here, we report that DNA methylation modulates transcription-factor output in the context of cell differentiation. Using a drug-inducible Gata4 system and a mouse embryonic stem (ES) cell model of mesoderm differentiation, we examined the cellular response to Gata4 in ES and mesoderm cells. The activation of Gata4 in ES cells is known to drive their differentiation to endoderm. We show that the differentiation of wild-type ES cells into mesoderm blocks their Gata4-induced endoderm differentiation, while mesoderm cells derived from ES cells that are deficient in the DNA methyltransferases Dnmt3a and Dnmt3b can retain their response to Gata4, allowing lineage conversion from mesoderm cells to endoderm in part. Transcriptome analysis of the cells' response to Gata4 over time revealed groups of endoderm and mesoderm developmental genes whose expression was induced by Gata4 only when DNA methylation was lost, suggesting that DNA methylation restricts the ability of these genes to respond to Gata4, rather than controlling their transcription per se. Our data indicate that epigenetic regulation by DNA methylation functions as a heritable safeguard to prevent transcription factors from activating inappropriate downstream genes, thereby contributing to the restriction of the differentiation potential of somatic cells. To understand how mouse cells differentially respond to Gata4 in cell type- and DNA methylation-dependent manners and to examine what genes are differentially regulated, we analyzed temporal change of gene expression profile in response to Gata4 in ES or Flk1(+) mesoderm cells in WT and Dnmt3a-/-Dnmt3b-/- (DKO) background, in total 108 samples.

Dataset Information

Identification of a novel risk factor for intracranial aneurysms in ADPKD using iPSC models [Affymetrix]

Publications

Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models.

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