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| Status |
Public on May 30, 2018 |
| Title |
Downregulation of Endothelin Receptor B Contributes to Defective B Cell Lymphopoiesis in Trisomy 21 Pluripotent Cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Individuals with Trisomy 21 (T21) exhibit numerous hematological abnormalities, including reductions in numbers of circulating B and T lymphocytes. To elucidate molecular mechanisms underlying these phenotypes, we differentiated human isogenic disomic and trisomic pluripotent cells, and observed that trisomic cells showed defects in B cell, but not T, cell differentiation. Global gene expression of differentiated, trisomic B cells revealed reduced expression of genes encoding endothelin signaling components, namely the Endothelin Receptor B (Ednrb), and its ligand Endothelin1 (Edn1).. Depletion of Ednrb mRNA in cord blood CD34+ cells led to defective B cell differentiation, supporting an hypothesis that low expression of Ednrb in T21 contributes to intrinsic lymphoid defects. Further evidence for the role of the Ednrb pathway in B cell differentiation was obtained through CRISPR/Cas9 gene targeting in disomic and trisomic iPS cells. Knockout of Ednrb in both cell backgrounds reduced the capacity for B cell differentiation. Collectively, this work identifies downregulation of Ednrb as a causative factor for impaired B lymphocyte generation in trisomic cells, which may contribute to defects in immune function associated with T21. Furthermore, a novel role for endothelin signaling in regulation of B cell development has been identified.
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| Overall design |
Disomic and trisomic isogenic iPS cells were differentiated in parallel, and after co-culture with MS5 cells, CD45+ CD34- CD19+ cells were isolated by FACS. RNA was extracted using Trizol. Global gene expression analysis by microarray was performed on the Human HG U133 Plus 2.0 platform. Each group contains three biological replicates.
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| Contributor(s) |
MacLean GA, Huang J |
| Citation(s) |
29789608 |
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| Submission date |
Feb 02, 2018 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Jialiang Huang |
| E-mail(s) |
jhuang@xmu.edu.cn
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| Organization name |
Dana-Farber Cancer Institute
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| Street address |
450 Brookline Avenue
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02215 |
| Country |
USA |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA432705 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE110064_RAW.tar |
26.7 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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