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HES1 and HES4 have non-redundant roles downstream of Notch during early human T-cell development

(2021) HAEMATOLOGICA. 106(1). p.130-141
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Abstract
In both mouse and human, Notch1 activation is the main initial driver to induce T-cell development in hematopoietic progenitor cells. The initiation of this developmental process coincides with Notch1-dependent repression of differentiation towards other hematopoietic lineages. Although well described in mice, the role of the individual Notch1 target genes during these hematopoietic developmental choices is still unclear in human, particularly for HES4 since no orthologous gene is present in the mouse. Here, we investigated the functional capacity of the Notch1 target genes HES1 and HES4 to modulate human Notch1-dependent hematopoietic lineage decisions and their requirement during early T-cell development. We show that both genes are upregulated in a Notch-dependent manner during early T-cell development and that HES1 acts as a repressor of differentiation by maintaining a quiescent stem cell signature in CD34(+) hematopoietic progenitor cells. While HES4 can also inhibit natural killer and myeloid cell development like HES1, it acts differently on the T- versus B-cell lineage choice. Surprisingly, HES4 is incapable of repressing B-cell development, the most sensitive hematopoietic lineage with respect to Notch-mediated repression. In contrast to HES1, HES4 promotes initiation of early T-cell development, but ectopic expression of HES4, or HES1 and HES4 combined, is insufficient to induce T-lineage differentiation. Importantly, knockdown of HES1 or HES4 significantly reduces human T-cell development. Overall, we show that the Notch1 target genes HES1 and HES4 have non-redundant roles during early human T-cell development which may relate to differences in mediating Notch-dependent human hematopoietic lineage decisions.
Keywords
Hematology

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MLA
De Decker, Matthias, et al. “HES1 and HES4 Have Non-Redundant Roles Downstream of Notch during Early Human T-Cell Development.” HAEMATOLOGICA, vol. 106, no. 1, 2021, pp. 130–41, doi:10.3324/haematol.2019.226126.
APA
De Decker, M., Lavaert, M., Roels, J., Tilleman, L., Vandekerckhove, B., Leclercq, G., … Taghon, T. (2021). HES1 and HES4 have non-redundant roles downstream of Notch during early human T-cell development. HAEMATOLOGICA, 106(1), 130–141. https://doi.org/10.3324/haematol.2019.226126
Chicago author-date
De Decker, Matthias, Marieke Lavaert, Juliette Roels, Laurentijn Tilleman, Bart Vandekerckhove, Georges Leclercq, Filip Van Nieuwerburgh, Pieter Van Vlierberghe, and Tom Taghon. 2021. “HES1 and HES4 Have Non-Redundant Roles Downstream of Notch during Early Human T-Cell Development.” HAEMATOLOGICA 106 (1): 130–41. https://doi.org/10.3324/haematol.2019.226126.
Chicago author-date (all authors)
De Decker, Matthias, Marieke Lavaert, Juliette Roels, Laurentijn Tilleman, Bart Vandekerckhove, Georges Leclercq, Filip Van Nieuwerburgh, Pieter Van Vlierberghe, and Tom Taghon. 2021. “HES1 and HES4 Have Non-Redundant Roles Downstream of Notch during Early Human T-Cell Development.” HAEMATOLOGICA 106 (1): 130–141. doi:10.3324/haematol.2019.226126.
Vancouver
1.
De Decker M, Lavaert M, Roels J, Tilleman L, Vandekerckhove B, Leclercq G, et al. HES1 and HES4 have non-redundant roles downstream of Notch during early human T-cell development. HAEMATOLOGICA. 2021;106(1):130–41.
IEEE
[1]
M. De Decker et al., “HES1 and HES4 have non-redundant roles downstream of Notch during early human T-cell development,” HAEMATOLOGICA, vol. 106, no. 1, pp. 130–141, 2021.
@article{8663528,
  abstract     = {{In both mouse and human, Notch1 activation is the main initial driver to induce T-cell development in hematopoietic progenitor cells. The initiation of this developmental process coincides with Notch1-dependent repression of differentiation towards other hematopoietic lineages. Although well described in mice, the role of the individual Notch1 target genes during these hematopoietic developmental choices is still unclear in human, particularly for HES4 since no orthologous gene is present in the mouse. Here, we investigated the functional capacity of the Notch1 target genes HES1 and HES4 to modulate human Notch1-dependent hematopoietic lineage decisions and their requirement during early T-cell development. We show that both genes are upregulated in a Notch-dependent manner during early T-cell development and that HES1 acts as a repressor of differentiation by maintaining a quiescent stem cell signature in CD34(+) hematopoietic progenitor cells. While HES4 can also inhibit natural killer and myeloid cell development like HES1, it acts differently on the T- versus B-cell lineage choice. Surprisingly, HES4 is incapable of repressing B-cell development, the most sensitive hematopoietic lineage with respect to Notch-mediated repression. In contrast to HES1, HES4 promotes initiation of early T-cell development, but ectopic expression of HES4, or HES1 and HES4 combined, is insufficient to induce T-lineage differentiation. Importantly, knockdown of HES1 or HES4 significantly reduces human T-cell development. Overall, we show that the Notch1 target genes HES1 and HES4 have non-redundant roles during early human T-cell development which may relate to differences in mediating Notch-dependent human hematopoietic lineage decisions.}},
  author       = {{De Decker, Matthias and Lavaert, Marieke and Roels, Juliette and Tilleman, Laurentijn and Vandekerckhove, Bart and Leclercq, Georges and Van Nieuwerburgh, Filip and Van Vlierberghe, Pieter and Taghon, Tom}},
  issn         = {{0390-6078}},
  journal      = {{HAEMATOLOGICA}},
  keywords     = {{Hematology}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{130--141}},
  title        = {{HES1 and HES4 have non-redundant roles downstream of Notch during early human T-cell development}},
  url          = {{http://dx.doi.org/10.3324/haematol.2019.226126}},
  volume       = {{106}},
  year         = {{2021}},
}

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