T cell development requires constraint of the myeloid regulator C/EBP-α 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/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.

Limited niche availability suppresses murine intrathymic dendritic-cell development from noncommitted progenitors

“…16 Absence of Notch1 is likely to lift Hes1-dependent repression of the key myeloid transcription factor gene, Cebpa. 17 These experiments support the notion that ETPs are basically equipped with DC potential, but do not adopt DC fate in a microenvironment rich in Notch ligands, such as the thymus. However, this hypothesis remains to be tested with ETPs that retain an intrinsic capacity to develop into T cells.…”

An Overview of the Intrathymic Intricacies of T Cell Development

“…HES1, a bHLH transcriptional repressor, is a major component of Notch1-induced signaling during T-lineage com- mitment (30) and is important for constraining myeloid cell fate outcomes (31,32 Cre-mediated deletion of Hes1 in BM cells results in a reduction in the DN and DP cell compartments in competitive situations, and intrathymic transfer of these cells gave rise to T cells; however, there was an increase in the DN1 compartment, which was composed of immature B cells. The investigators hypothesized that this was a consequence of HSCs receiving weak Notch signals, because Hes1-deleted HSCs receiving suboptimal Notch signals were unable to adopt the T cell lineage, indicating that Hes1 is essential to induce a Notch1-dependent genetic program for efficient T cell commitment (30).…”

The Notch driven long non-coding RNA repertoire in T-cell acute lymphoblastic leukemia

“…[6][7][8][9] The role of Notch signaling has been particularly well documented in T-cell development where Notch1/Dll4 interactions are crucial to induce T-lineage differentiation at the expense of other hematopoietic lineages. [10][11][12][13][14] Subsequently, Notch signaling is implemented in TCR-rearrangements, 15,16 modulation of TCR-αb versus -gd development, [17][18][19][20][21] and in the support of proliferation during b-selection. [22][23][24] Sustained activation of Notch1 signaling beyond this developmental checkpoint has been shown to cause T-cell acute lymphoblastic leukemia (T-ALL) and NOTCH1 activating mutations are amongst the most frequently observed genetic alterations in T-ALL.…”