The transcriptional mediator subunit MED1/TRAP220 in stromal cells is involved in hematopoietic stem/progenitor cell support through osteopontin expression.
MED1/TRAP220, a subunit of the transcriptional Mediator/TRAP complex, is crucial for various biological events through its interaction with distinct activators, such as nuclear receptors and GATA family activators. In hematopoiesis, MED1 plays a pivotal role in optimal nuclear receptor-mediated myelomonopoiesis and GATA-1-induced erythropoiesis. In this study, we present evidence that MED1 in stromal cells is involved in supporting hematopoietic stem and/or progenitor cells (HSPCs) through osteopontin (OPN) expression. We found that the proliferation of bone marrow (BM) cells cocultured with MED1 knockout (Med1(-/-)) mouse embryonic fibroblasts (MEFs) was significantly suppressed compared to the control. Furthermore, the number of long-term culture-initiating cells (LTC-ICs) was attenuated for BM cells cocultured with Med1(-/-) MEFs. The vitamin D receptor (VDR)- and Runx2-mediated expression of OPN, as well as Mediator recruitment to the Opn promoter, was specifically attenuated in the Med1(-/-) MEFs. Addition of OPN to these MEFs restored the growth of cocultured BM cells and the number of LTC-ICs, both of which were attenuated by the addition of the anti-OPN antibody to Med1(+/+) MEFs and to BM stromal cells. Consequently, MED1 in niche appears to play an important role in supporting HSPCs by upregulating VDR- and Runx2-mediated transcription on the Opn promoter.
Sumitomo
Akiko
A
Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan.
Ishino
Ruri
R
Urahama
Norinaga
N
Inoue
Kana
K
Yonezawa
Kenji
K
Hasegawa
Natsumi
N
Horie
Osamu
O
Matsuoka
Hiroshi
H
Kondo
Toru
T
Roeder
Robert G
RG
Ito
Mitsuhiro
M
D000818:Animals; D018920:Coculture Techniques; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D056913:Mediator Complex Subunit 1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053495:Osteopontin / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*; D014162:Transfection; D020798:Two-Hybrid System Techniques
D050659:Core Binding Factor Alpha 1 Subunit; C538855:MED1 protein, human; C538856:Med1 protein, mouse; D056913:Mediator Complex Subunit 1; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D011994:Recombinant Proteins; C493716:Runx2 protein, mouse; C506896:Spp1 protein, mouse; D053495:Osteopontin