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In Vivo RNAi Screen Unveils PPAR? as a Regulator of Hematopoietic Stem Cell Homeostasis.


ABSTRACT: Hematopoietic stem cell (HSC) defects can cause repopulating impairment leading to hematologic diseases. To target HSC deficiency in a disease setting, we exploited the repopulating defect of Fanconi anemia (FA) HSCs to conduct an in vivo short hairpin RNA (shRNA) screen. We exposed Fancd2-/- HSCs to a lentiviral shRNA library targeting 947 genes. We found enrichment of shRNAs targeting genes involved in the PPAR? pathway that has not been linked to HSC homeostasis. PPAR? inhibition by shRNA or chemical compounds significantly improves the repopulating ability of Fancd2-/- HSCs. Conversely, activation of PPAR? in wild-type HSCs impaired hematopoietic repopulation. In mouse HSCs and patient-derived lymphoblasts, PPAR? activation is manifested in upregulating the p53 target p21. PPAR? and co-activators are upregulated in total bone marrow and stem/progenitor cells from FA patients. Collectively, this work illustrates the utility of RNAi technology coupled with HSC transplantation for the discovery of novel genes and pathways involved in stress hematopoiesis.

PROVIDER: S-EPMC5425620 | BioStudies |

REPOSITORIES: biostudies

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