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ID 53140
フルテキストURL
著者
Kobayashi, Junko Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Cardiovasc Surg
Yoshida, Masashi Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Cardiovasc Med Kaken ID
Tarui, Suguru Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Cardiovasc Surg
Hirata, Masataka Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Cardiovasc Surg
Nagai, Yusuke Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Cardiovasc Physiol
Kasahara, Shingo Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Cardiovasc Surg Kaken ID publons
Naruse, Keiji Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Cardiovasc Physiol ORCID Kaken ID publons researchmap
Ito, Hiroshi Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Cardiovasc Med Kaken ID
Sano, Shunji Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Cardiovasc Surg Kaken ID publons researchmap
Oh, Hidemasa Okayama Univ Hosp, Dept Regenerat Med, Ctr Innovat Clin Med ORCID Kaken ID researchmap
抄録
The genetic basis of hypoplastic left heart syndrome (HLHS) remains unknown, and the lack of animal models to reconstitute the cardiac maldevelopment has hampered the study of this disease. This study investigated the altered control of transcriptional and epigenetic programs that may affect the development of HLHS by using disease-specific induced pluripotent stem (iPS) cells. Cardiac progenitor cells (CPCs) were isolated from patients with congenital heart diseases to generate patient-specific iPS cells. Comparative gene expression analysis of HLHS- and biventricle (BV) heart-derived iPS cells was performed to dissect the complex genetic circuits that may promote the disease phenotype. Both HLHS- and BV heart-derived CPCs were reprogrammed to generate disease-specific iPS cells, which showed characteristic human embryonic stem cell signatures, expressed pluripotency markers, and could give rise to cardiomyocytes. However, HLHS-iPS cells exhibited lower cardiomyogenic differentiation potential than BV-iPS cells. Quantitative gene expression analysis demonstrated that HLHS-derived iPS cells showed transcriptional repression of NKX2-5, reduced levels of TBX2 and NOTCH/HEY signaling, and inhibited HAND1/2 transcripts compared with control cells. Although both HLHS-derived CPCs and iPS cells showed reduced SRE and TNNT2 transcriptional activation compared with BV-derived cells, co-transfection of NKX2-5, HAND1, and NOTCH1 into HLHS-derived cells resulted in synergistic restoration of these promoters activation. Notably, gain- and loss-of-function studies revealed that NKX2-5 had a predominant impact on NPPA transcriptional activation. Moreover, differentiated HLHS-derived iPS cells showed reduced H3K4 dimethylation as well as histone H3 acetylation but increased H3K27 trimethylation to inhibit transcriptional activation on the NKX2-5 promoter. These findings suggest that patient-specific iPS cells may provide molecular insights into complex transcriptional and epigenetic mechanisms, at least in part, through combinatorial expression of NKX2-5, HAND1, and NOTCH1 that coordinately contribute to cardiac malformations in HLHS.
発行日
2014-07-22
出版物タイトル
PLoS ONE
9巻
7号
出版者
Public Library Science
ISSN
1932-6203
資料タイプ
学術雑誌論文
関連URL
http://ousar.lib.okayama-u.ac.jp/metadata/53131
言語
English
著作権者
© 2014 Kobayashi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
論文のバージョン
publisher
査読
有り
DOI
Web of Science KeyUT