T cell development requires constraint of the myeloid regulator C/EBP-α by the Notch target and transcriptional repressor Hes1.

T cell development requires constraint of the myeloid regulator C/EBP-α by the Notch target and transcriptional repressor Hes1.
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DOI:
10.1038/ni.2760
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发表时间:
2013-12
期刊:
影响因子:
30.5
通讯作者:
Bhandoola, Avinash
Bhandoola, Avinash
中科院分区:
医学1区
文献类型:
--
作者:
De Obaldia, Maria Elena;Bell, J. Jeremiah;Wang, Xinxin;Harly, Christelle;Yashiro-Ohtani, Yumi;DeLong, Jonathan H.;Zlotoff, Daniel A.;Sultana, Dil Afroz;Pear, Warren S.;Bhandoola, Avinash

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Notch signaling induces gene expression of the T cell lineage and discourages alternative fate outcomes. Hematopoietic deficiency in the Notch target Hes1 results in severe T cell lineage defects; however, the underlying mechanism is unknown. We found here that Hes1 constrained myeloid gene-expression programs in T cell progenitor cells, as deletion of the myeloid regulator C/EBPa restored the development of T cells from Hes1-deficient progenitor cells. Repression of Cebpa by Hes1 required its DNA-binding and Groucho-recruitment domains. Hes1-deficient multipotent progenitor cells showed a developmental bias toward myeloid and dendritic cells after Notch signaling, whereas Hes1-deficient lymphoid progenitor cells required additional cytokine signaling for diversion into the myeloid lineage. Our findings establish the importance of constraining developmental programs of the myeloid lineage early in T cell development.
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