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TNF-alpha and Notch signaling regulates the expression of HOXB4 and GATA3 during early T lymphopoiesis

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Abstract

During the early thymus colonization, Notch signaling activation on hematopoietic progenitor cells (HPCs) drives proliferation and T cell commitment. Although these processes are driven by transcription factors such as HOXB4 and GATA3, there is no evidence that Notch directly regulates their transcription. To evaluate the role of NOTCH and TNF signaling in this process, human CD34+ HPCs were cocultured with OP9-DL1 cells, in the presence or absence of TNF. The use of a Notch signaling inhibitor and a protein synthesis inhibitor allowed us to distinguish primary effects, mediated by direct signaling downstream Notch and TNF, from secondary effects, mediated by de novo synthesized proteins. A low and physiologically relevant concentration of TNF promoted T lymphopoiesis in OP9-DL1 cocultures. TNF positively modulated the expression of both transcripts in a Notch-dependent manner; however, GATA3 induction was mediated by a direct mechanism, while HOXB4 induction was indirect. Induction of both transcripts was repressed by a GSK3β inhibitor, indicating that activation of canonical Wnt signaling inhibits rather than induces their expression. Our study provides novel evidences of the mechanisms integrating Notch and TNF-alpha signaling in the transcriptional induction of GATA3 and HOXB4. This mechanism has direct implications in the control of self-renewal, proliferation, commitment, and T cell differentiation.

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Acknowledgments

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Financiadora de Estudos e Projetos (FINEP), Brazil. JLSS is responsible for the conception and design, provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, manuscript writing; LHBO for the provision of study material, manuscript writing; AGA, MDO, and PVBP for the collection and/or assembly of data; DTC and MAZ for the final approval of manuscript; and RAP for the conception and design, provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript. This study was approved by the institutional Research Ethics Committee of Medical School of of Ribeirão Preto (FMRR-USP). Human umbilical cord blood (UCB) samples (approximately 90 mL/sample) were obtained after informed consent, at MATER Hospital (Ribeirão Preto, Brazil).

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Authors and Affiliations

  1. Department of Genetics, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

    Josiane Lilian dos Santos Schiavinato & Rodrigo Alexandre Panepucci

  2. National Institute of Science and Technology in Stem Cell and for Cell Therapy (INCTC) Center for Cell Therapy (CTC) and Regional Blood Center, Ribeirão Preto, SP, Brazil

    Josiane Lilian dos Santos Schiavinato, Lucila Habib Bourguignon Oliveira, Maristela Delgado Orellana, Patrícia Viana Bonini de Palma, Dimas Tadeu Covas, Marco Antonio Zago & Rodrigo Alexandre Panepucci

  3. Medical School of Ribeirão Preto, University of São Paulo , Ribeirão Preto, São Paulo, Brazil

    Josiane Lilian dos Santos Schiavinato, Lucila Habib Bourguignon Oliveira, Amélia Goes Araujo, Maristela Delgado Orellana, Dimas Tadeu Covas & Marco Antonio Zago

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  1. Josiane Lilian dos Santos Schiavinato
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Figure S1

The action of the different drugs and signals in the context of the OP9-DL1 coculture system. The OP9-DL1 mouse stromal line expresses high levels of the Notch ligand DL-1. Upon binding of DL-1 to the Notch receptor expressed in cocultured human UCB CD34+ HSCs, the intracellular domain of Notch (NICD) is released (through the enzymatic action of the gamma-secretase complex) and translocates to the nucleus where it binds to its DNA binding partner CSL, recruiting additional transcriptional coactivators (such as the histone acetyltransferase p300) to specific gene regulatory regions, activating the transcription of targets genes. Soluble TNF-alpha binds to TNFR1 and, through adaptor proteins such as TRADD, TRAF2, and RIP1, induces multiple downstream signaling cascades, including IKK, JNK, ERK, and p38 MAPKs, leading to the activation of NF-kB and other transcription factors such as AP-1 (c-Jun and c-Fos), ATF2, and Elk1. Cycloheximide (CHX) blocks protein synthesis, allowing the distinction between primary effects (i.e., direct signaling downstream Notch and TNF, mediated by existing proteins) and secondary effects (i.e., mediated by de novo synthesized proteins). The gamma-secretase inhibitor DAPT blocks NICD formation, allowing the specific assessment of Notch signaling. HSC (hematopoietic stem cells), UCB (umbilical cord blood), DL-1 (Delta-like 1), TNF-α (tumor necrosis factor alpha), NICD (notch intra cellular domain), CHX (cycloheximide), DAPT (Notch gamma-secretase inhibitor), JNK (c-Jun N-terminal kinase), ERK (extracellular signal-regulated kinase), p38 MAPKs (p38 mitogen-activated protein kinases), CSL (CBF1/Su(H)/Lag-1), NF-kB (nuclear factor-kappaB), TRADD (TNFR1 associated death domain protein), TRAF2 (TNFR-associated factor 2), RIP (receptor interacting protein), TAK1 (TGF-β–activated kinase 1), IKK (IkB kinase complex). (GIF 127 kb)

High Resolution Image (TIF 335 kb)

Figure S2

Temporal evaluation of HOXB4. The HOXB4 transcriptional level analysis from human CD34+ HSC cocultured on OP9-GFP (control) or OP9-DL1cells for 36 h. Expression levels (relative to control OP9-GFP cocultures) were determined by quantitative real-time PCR analysis, using GAPDH as an endogenous control. These data are representative of two independent experiments. (GIF 20 kb)

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dos Santos Schiavinato, J.L., Oliveira, L.H.B., Araujo, A.G. et al. TNF-alpha and Notch signaling regulates the expression of HOXB4 and GATA3 during early T lymphopoiesis. In Vitro Cell.Dev.Biol.-Animal 52, 920–934 (2016). https://doi.org/10.1007/s11626-016-0055-8

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