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| Status |
Public on Sep 01, 2022 |
| Title |
A double negative thymocyte specific enhancer augments Notch1 signaling to direct early T cell progenitor expansion, lineage restriction and b-selection. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
T-cell differentiation requires Notch1 signaling. Here we show that an enhancer upstream of Notch1 active in double-negative (DN) thymocytes is responsible for raising Notch1 signaling intra-thymically. This enhancer is required to expand multipotent progenitors intra-thymically while delaying early differentiation until lineage restrictions are established. Early thymic progenitors lacking the enhancer show accelerated differentiation through the DN stages and increased frequency of B-, ILC-, and NK-cell differentiation. Transcription regulators for T-cell lineage restriction and commitment are expressed normally, but ILC- and NK-cell gene expression persists after T-lineage commitment and TCR V-DJ recombination, Cd3 expression and -selection are impaired. This Notch1 enhancer is inactive in double-positive (DP) thymocytes. Its aberrant reactivation at this stage in Ikaros mutants is required for leukemogenesis. Thus, the DN-specific Notch1 enhancer harnesses the regulatory architecture of DN and DP thymocytes to achieve carefully orchestrated changes in Notch1 signaling required for early lineage restrictions and normal T-cell differentiation.
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| Overall design |
34 bulk RNAseq, 4 single-cell RNAseq
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| Contributor(s) |
Kashiwagi M |
| Citation(s) |
36316479 |
| |
| Submission date |
Aug 11, 2022 |
| Last update date |
Dec 01, 2022 |
| Contact name |
Katia Georgopoulos |
| E-mail(s) |
katia.georgopoulos@cbrc2.mgh.harvard.edu
|
| Phone |
6177264445
|
| Organization name |
Harvard Medical School
|
| Department |
CBRC
|
| Lab |
Georgopoulos
|
| Street address |
13th street
|
| City |
Charlestown |
| State/province |
MA |
| ZIP/Postal code |
02129 |
| Country |
USA |
| |
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| Platforms (3) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
| GPL21626 |
NextSeq 550 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
|
| Samples (34)
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| Relations |
| BioProject |
PRJNA869100 |
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