Genetic screen identifies microRNA cluster 99b/let-7e/125a as a regulator of primitive hematopoietic cells
| Autor: | Sandra Olthof, Alice Gerrits, Leonid Bystrykh, Martha Ritsema, Gerald de Haan, Ellen Weersing, Marta A. Walasek, Erik Zwart, Ronald van Os |
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| Přispěvatelé: | Faculteit Medische Wetenschappen/UMCG, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Stem Cell Aging Leukemia and Lymphoma (SALL) |
| Rok vydání: | 2011 |
| Předmět: |
EXPRESSION
Male Cell type Immunology Biology FREQUENCY Real-Time Polymerase Chain Reaction Biochemistry 03 medical and health sciences Mice 0302 clinical medicine Erythroid Cells Animals Myeloid Cells Progenitor cell Gene Cells Cultured 030304 developmental biology Oligonucleotide Array Sequence Analysis NUMBERS 0303 health sciences Gene Expression Profiling PROLIFERATION ALLOPHENIC MICE Cell Biology Hematology Hematopoietic Stem Cells Molecular biology Gene expression profiling Transplantation Mice Inbred C57BL Haematopoiesis MicroRNAs DIFFERENTIATION 030220 oncology & carcinogenesis Mice Inbred CBA POPULATIONS Female Stem cell STEM-CELLS LEUKEMIA GENOMICS Biomarkers Genetic screen |
| Zdroj: | Blood, 119(2), 377-387. AMER SOC HEMATOLOGY |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Hematopoietic stem/progenitor cell (HSPC) traits differ between genetically distinct mouse strains. For example, DBA/2 mice have a higher HSPC frequency compared with C57BL/6 mice. We performed a genetic screen for micro-RNAs that are differentially expressed between LSK, LS−K+, erythroid and myeloid cells isolated from C57BL/6 and DBA/2 mice. This analysis identified 131 micro-RNAs that were differentially expressed between cell types and 15 that were differentially expressed between mouse strains. Of special interest was an evolutionary conserved miR cluster located on chromosome 17 consisting of miR-99b, let-7e, and miR-125a. All cluster members were most highly expressed in LSKs and down-regulated upon differentiation. In addition, these microRNAs were higher expressed in DBA/2 cells compared with C57BL/6 cells, and thus correlated with HSPC frequency. To functionally characterize these microRNAs, we overexpressed the entire miR-cluster 99b/let-7e/125a and miR-125a alone in BM cells from C57BL/6 mice. Overexpression of the miR-cluster or miR-125a dramatically increased day-35 CAFC activity and caused severe hematopoietic phenotypes upon transplantation. We showed that a single member of the miR-cluster, namely miR-125a, is responsible for the majority of the observed miR-cluster overexpression effects. Finally, we performed genome-wide gene expression arrays and identified candidate target genes through which miR-125a may modulate HSPC fate. |
| Databáze: | OpenAIRE |
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