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


ABSTRACT: 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/EBP-? 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 cells 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.

SUBMITTER: De Obaldia ME 

PROVIDER: S-EPMC4038953 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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

De Obaldia Maria Elena ME   Bell J Jeremiah JJ   Wang Xinxin X   Harly Christelle C   Yashiro-Ohtani Yumi Y   DeLong Jonathan H JH   Zlotoff Daniel A DA   Sultana Dil Afroz DA   Pear Warren S WS   Bhandoola Avinash A  

Nature immunology 20131103 12


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/EBP-α restored the development of T cells from Hes1-deficient progenitor cells. Repression of Cebpa by Hes1 required its  ...[more]

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