WNT signaling pathway regulates several processes involved in the homeostasis of normal cells. Its dysregulation is associated with pathological outcomes like cancer. We previously demonstrated that downregulation of WNT7A correlates with higher proliferation rates in acute lymphoblastic leukemia. However, the regulation of this gene in pathological and normal conditions remains unexplored. In this work, we aimed to analyze the transcriptional regulation of WNT7A in leukemic cells and in normal T lymphocytes after a proliferative stimulus. WNT7A expression was measured in blood cells and in T lymphocytes after phytohemagglutinin-L (PHA-L) treatment or T-cell receptor (TCR) activation by qPCR and Western blot. Promoter methylation was assessed using methylation-sensitive restriction enzymes, and histone modifications were determined by chromatin immunoprecipitation and qPCR. In T-cell acute lymphoblastic leukemia (T-ALL), WNT7A expression is silenced through DNA methylation of CpG island in the promoter region. In normal peripheral blood cells, WNT7A is mainly expressed by monocytes and T lymphocytes. TCR activation induces the downregulation of WNT7A in normal T lymphocytes by changes in histone methylation marks (H3K4me2/3) and histone deacetylases. A proliferative stimulus mediated by IL-2 keeps WNT7A expression at low levels but in the absence of IL-2, the expression of this gene tends to be restored. Furthermore, after TCR activation and WNT7A downregulation, target genes associated with the WNT canonical pathway were upregulated indicating an independent activity of WNT7A from the WNT canonical pathway. WNT7A expression is silenced by long-term DNA methylation in T-ALL-derived cells and downregulated by histone modifications after TCR activation in normal T lymphocytes.
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This work was supported by the Fondo de Investigación en Salud – IMSS, grant number FIS/IMSS/PROT/G13/1243 and FIS/IMSS/PROT/G14/1316 both to Luis Felipe Jave-Suárez. Christian Barreto-Vargas and Monserrat Alvarez-Zavala are grateful for their scholarship obtained from Consejo Nacional de Ciencia y Tecnología (CONACyT), Mexico. We are grateful to Cristina Artaza Irigaray for proofreading of the manuscript.
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Barreto-Vargas, C., Alvarez-Zavala, M., Garcia-Chagollan, M. et al. WNT7A Expression is Downregulated in T Lymphocytes after T-Cell Receptor Activation Due to Histone Modifications and in T-ALL by DNA Methylation. Arch. Immunol. Ther. Exp. 68, 18 (2020). https://doi.org/10.1007/s00005-020-00583-5
- WNT signaling
- Transcription regulation
- T lymphocytes
- DNA methylation
- Histone modification