| RRC ID |
45190
|
| 著者 |
Kobayashi J, Yoshida M, Tarui S, Hirata M, Nagai Y, Kasahara S, Naruse K, Ito H, Sano S, Oh H.
|
| タイトル |
Directed differentiation of patient-specific induced pluripotent stem cells identifies the transcriptional repression and epigenetic modification of NKX2-5, HAND1, and NOTCH1 in hypoplastic left heart syndrome.
|
| ジャーナル |
PLoS One
|
| Abstract |
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.
|
| 巻・号 |
9(7)
|
| ページ |
e102796
|
| 公開日 |
2014-1-1
|
| DOI |
10.1371/journal.pone.0102796
|
| PII |
PONE-D-13-20040
|
| PMID |
25050861
|
| PMC |
PMC4106834
|
| MeSH |
Animals
Basic Helix-Loop-Helix Transcription Factors / genetics*
Basic Helix-Loop-Helix Transcription Factors / metabolism
Cell Differentiation
Cells, Cultured
Epigenesis, Genetic*
Histones / metabolism
Homeobox Protein Nkx-2.5
Homeodomain Proteins / genetics*
Homeodomain Proteins / metabolism
Humans
Hypoplastic Left Heart Syndrome / genetics*
Hypoplastic Left Heart Syndrome / metabolism
Hypoplastic Left Heart Syndrome / pathology
Induced Pluripotent Stem Cells / physiology*
Mice, Inbred NOD
Mice, SCID
Myocytes, Cardiac / metabolism
Promoter Regions, Genetic
Protein Processing, Post-Translational
Receptor, Notch1 / genetics*
Receptor, Notch1 / metabolism
Transcription Factors / genetics*
Transcription Factors / metabolism
Transcription, Genetic
|
| IF |
2.74
|
| 引用数 |
23
|
|
WOS 分野
|
CARDIAC & CARDIOVASCULAR SYSTEMS
|
| リソース情報 |
| ヒト・動物細胞 |
201B7(HPS0063) |
