The MicroRNA-132 and MicroRNA-212 Cluster Regulates Hematopoietic Stem Cell Maintenance and Survival with Age by Buffering FOXO3 Expression
Abstract
MicroRNAs are critical post-transcriptional regulators of hematopoietic cell-fate decisions, though little remains known about their role in aging hematopoietic stem cells (HSCs). We found that the microRNA-212/132 cluster (Mirc19) is enriched in HSCs and is upregulated during aging. Both overexpression and deletion of microRNAs in this cluster leads to inappropriate hematopoiesis with age. Enforced expression of miR-132 in the bone marrow of mice led to rapid HSC cycling and depletion. A genetic deletion of Mirc19 in mice resulted in HSCs that had altered cycling, function, and survival in response to growth factor starvation. We found that miR-132 exerted its effect on aging HSCs by targeting the transcription factor FOXO3, a known aging associated gene. Our data demonstrate that Mirc19 plays a role in maintaining balanced hematopoietic output by buffering FOXO3 expression. We have thus identified it as a potential target that might play a role in age-related hematopoietic defects.
Additional Information
© 2015 Elsevier Inc. Received: December 28, 2014; Revised: February 28, 2015; Accepted: May 20, 2015; Published: June 16, 2015. We thank Diana Perez at the Caltech Flow Cytometry core facility, and Igor Antoshechkin and Vijaya Kumar at the Caltech Genetics and Genomics Laboratory for their assistance. We also thank Michael T. Bethune for helpful discussions throughout the preparation of this manuscript. This work was supported by an NIH RO1AI079243 (D.B.), National Research Service Award CA183220 (A.M.), HL110691 (J.L.Z.), the UCLA/Caltech Medical Scientist Training Program (A.M. and J.L.Z.), the Human Frontiers Science Foundation (M.M.), and the Broad Institute (M.S.K. and A.R.). Author Contributions: A.M., J.L.Z., and D.B. designed the study. A.M. conducted all the experimental work with assistance from N.S., M.M., M.S.K., R.P.G, and X.D. and with guidance from J.L.Z. G.K.M. and A.M. performed bioinformatics analysis. E.E. and K.C. contributed the Mirc19-/- mice. A.M. and D.B. wrote the manuscript with contributions from all authors.Attached Files
Accepted Version - nihms698173.pdf
Supplemental Material - mmc1.pdf
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Additional details
- PMCID
- PMC4471877
- Eprint ID
- 58395
- DOI
- 10.1016/j.immuni.2015.05.017
- Resolver ID
- CaltechAUTHORS:20150622-093830007
- RO1AI079243
- NIH
- CA183220
- NIH Predoctoral Fellowship
- HL110691
- NIH Predoctoral Fellowship
- UCLA/Caltech Medical Scientist Training Program
- Human Frontier Science Program
- Broad Institute
- Created
-
2015-06-22Created from EPrint's datestamp field
- Updated
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2022-06-01Created from EPrint's last_modified field