 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Dec 01, 2011 |
| Title |
PU.1 restricts adult hematopoietic stem cell proliferation via cell specific autoregulation |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| Summary |
To guarantee blood supply throughout adult life hematopoietic stem cells (HSCs) need to carefully balance between self-renewing cell divisions and quiescence. Identification of genes controlling HSC self-renewal is of utmost importance given that HSCs are the only stem cells with broad clinical applications. Transcription factor PU.1 is one of the major regulators of myeloid and lymphoid development. Recent reports suggest that PU.1 mediates its functions via gradual expression level changes rather than binary on/off states. So far, this has not been considered in any study of HSCs and thus, PU.1’s role in HSC function has remained largely unclear. Here we demonstrate using hypomorphic mice with an engineered disruption of an autoregulatory feedback loop that decreased PU.1 levels resulted in loss of key HSC functions, all of which could be fully rescued by restoration of proper PU.1 levels via a human PU.1 transgene. Mechanistically, we found excessive HSC cell divisions and altered expression of cell cycle regulators whose promoter regions were bound by PU.1 in normal HSCs. Adequate PU.1 levels were maintained by a mechanism of direct autoregulation restricted to HSCs through a physical interaction of a -14kb enhancer with the proximal promoter. Our findings identify PU.1 as novel regulator controling the switch between cell division and quiescence in order to prevent exhaustion of HSCs. Given that even moderate level changes greatly impact stem cell function, our data suggest important therapeutic implications for leukemic patients with reduced PU.1 levels. Moreover, we provide first proof, that autoregulation of a transcription factor, PU.1, has a crucial function in vivo. We anticipate that our concept of how autoregulation forms an active chromosomal conformation will impact future research on transcription factor networks regulating stem cell fate.
|
| |
|
| Overall design |
HSCs of Pu.1 knock-in (PU.1ki/ki) mice were used for RNA extraction and hybridization on Affymetrix microarrays. We compared these microarray samples with the corresponding wild type.
|
| |
|
| Contributor(s) |
Staber PB, Zhang P, Ye M, Welner R, Nombela-Arrieta C, Ye M, Bach C, Kerenyi M, Bartholdy BA, Lee S, Yang H, Zhang J, Leddin M, Silberstein LE, Höfler G, Rosenbauer F, Huang G, Tenen DG |
| Citation(s) |
23395001 |
| |
| Submission date |
Oct 18, 2011 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Henry Yang |
| E-mail(s) |
[email protected]
|
| Organization name |
Cancer Science Institute of Singapore
|
| Street address |
28 Medical Drive
|
| City |
Singapore |
| ZIP/Postal code |
117456 |
| Country |
Singapore |
| |
|
| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
|
| Samples (6)
|
|
| Relations |
| BioProject |
PRJNA149539 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE33031_RAW.tar |
20.3 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
|
|
|
|
 |
Less...
More...