TY - JOUR
T1 - The SCL/TAL1 transcription factor represses the stress protein DDiT4/REDD1 in human hematopoietic stem/progenitor cells
AU - Benyoucef, Aissa
AU - Calvo, Julien
AU - Renou, Laurent
AU - Arcangeli, Marie Laure
AU - Van Den Heuvel, Anita
AU - Amsellem, Sophie
AU - Mehrpour, Maryam
AU - Larghero, Jerome
AU - Soler, Eric
AU - Naguibneva, Irina
AU - Pflumio, Francoise
N1 - Publisher Copyright:
© 2015 AlphaMed Press.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - Hematopoietic stem/progenitor cells (HSPCs) are regulated through numerous molecular mechanisms that have not been interconnected. The transcription factor stem cell leukemia/T-cell acute leukemia 1 (TAL1) controls human HSPC but its mechanism of action is not clarified. In this study, we show that knockdown (KD) or short-term conditional over-expression (OE) of TAL1 in human HSPC ex vivo, respectively, blocks and maintains hematopoietic potentials, affecting proliferation of human HSPC. Comparative gene expression analyses of TAL1/KD and TAL1/OE human HSPC revealed modifications of cell cycle regulators as well as previously described TAL1 target genes. Interestingly an inverse correlation between TAL1 and DNA damage-induced transcript 4 (DDiT4/REDD1), an inhibitor of the mammalian target of rapamycin (mTOR) pathway, is uncovered. Low phosphorylation levels of mTOR target proteins in TAL1/KD HSPC confirmed an interplay between mTOR pathway and TAL1 in correlation with TAL1-mediated effects of HSPC proliferation. Finally chromatin immunoprecipitation experiments performed in human HSPC showed that DDiT4 is a direct TAL1 target gene. Functional analyses showed that TAL1 represses DDiT4 expression in HSPCs. These results pinpoint DDiT4/REDD1 as a novel target gene regulated by TAL1 in human HSPC and establish for the first time a link between TAL1 and the mTOR pathway in human early hematopoietic cells.
AB - Hematopoietic stem/progenitor cells (HSPCs) are regulated through numerous molecular mechanisms that have not been interconnected. The transcription factor stem cell leukemia/T-cell acute leukemia 1 (TAL1) controls human HSPC but its mechanism of action is not clarified. In this study, we show that knockdown (KD) or short-term conditional over-expression (OE) of TAL1 in human HSPC ex vivo, respectively, blocks and maintains hematopoietic potentials, affecting proliferation of human HSPC. Comparative gene expression analyses of TAL1/KD and TAL1/OE human HSPC revealed modifications of cell cycle regulators as well as previously described TAL1 target genes. Interestingly an inverse correlation between TAL1 and DNA damage-induced transcript 4 (DDiT4/REDD1), an inhibitor of the mammalian target of rapamycin (mTOR) pathway, is uncovered. Low phosphorylation levels of mTOR target proteins in TAL1/KD HSPC confirmed an interplay between mTOR pathway and TAL1 in correlation with TAL1-mediated effects of HSPC proliferation. Finally chromatin immunoprecipitation experiments performed in human HSPC showed that DDiT4 is a direct TAL1 target gene. Functional analyses showed that TAL1 represses DDiT4 expression in HSPCs. These results pinpoint DDiT4/REDD1 as a novel target gene regulated by TAL1 in human HSPC and establish for the first time a link between TAL1 and the mTOR pathway in human early hematopoietic cells.
KW - DDiT4
KW - Hematopoietic stem cells
KW - Maintenance/self-renewal
KW - SCL/TAL1
UR - http://www.scopus.com/inward/record.url?scp=84931572536&partnerID=8YFLogxK
U2 - 10.1002/stem.2028
DO - 10.1002/stem.2028
M3 - Article
C2 - 25858676
AN - SCOPUS:84931572536
SN - 1066-5099
VL - 33
SP - 2268
EP - 2279
JO - Stem Cells
JF - Stem Cells
IS - 7
ER -