Although the scientific evidence linking low nephron number to progressive renal disease is well established, the basic mechanisms which determine nephron endowment are not completely understood. Six2+ cells in the cap mesenchyme are the nephron """"""""stem-like"""""""" cells. Self-renewal and lineage-specific differentiation are essential properties of these multipotent progenitor cells. Failure of either of these processes disrupts nephrogenesis and thus predisposes to chronic kidney disease and hypertension. This grant application examines how epigenetic chromatin-based mechanisms control nephron progenitor cell maintenance and differentiation. Transcriptionally silent genes can be marked by histone modifications and regulatory proteins that indicate the genes'potential to be activated. Such bivalent marks have been identified in pluripotent cells, but it is unknown how such marks occur in descendant cells that have restricted cell fate choices. Furthermore, it is not known whether enzymes that establish chromatin states can control embryonic fate choices. Genome-wide chromatin maps included in the proposal strongly suggest that nephron progenitor cells are epigenetically"""""""" poised"""""""". Indeed, targeted deletion ofthe histone lysine 27 methyltransferase, Ezh2, from the cap mesenchyme disrupts self-renewal of progenitors and drives precocious differentiation. Inactivation of histone deacetylases, HDAC1&2, which act as partners in the Ezh2/PRC2 complex, also disrupts nephron progenitors homeostasis. The overall hypothesis to be tested in this proposal is that the histone methylation and acetylation machineries are essential for nephron progenitor, cell renewal and fate. In this proposal we will determine that chromatin bivalency, which is partly mediated by Ezh2, is a requisite to maintain silent differentiation genes in a poised state. We will also investigate the functional cross-talk between histone deacetylases and methyltransferases in nephron progenitor cell maintenance and differentiation. Finally, our studies will delineate the transcriptional regulatory networks downstream of Ezh2 and HDAC1/2 which control nephron progenitor cell multipotency.
Approximately 40% of chronic kidney disease cases in children are caused by congenital anomalies ofthe kidney and urinary tract. This project will provide insight into the regulation of kidney progenitor cell differentiation. This will have significant impact on diseases that affect progenitor cell maintenance such as renal hypoplasia and Wilms tumor, as well as on therapies that depend on stem cell regeneration.
| Liu, Hongbing; Chen, Shaowei; Yao, Xiao et al. (2018) Histone deacetylases 1 and 2 regulate the transcriptional programs of nephron progenitors and renal vesicles. Development 145: |
| Neubauer, Bjoern; Schrankl, Julia; Steppan, Dominik et al. (2018) Angiotensin II Short-Loop Feedback: Is There a Role of Ang II for the Regulation of the Renin System In Vivo? Hypertension 71:1075-1082 |
| Gomez, R Ariel; Sequeira-Lopez, Maria Luisa S (2018) Renin cells in homeostasis, regeneration and immune defence mechanisms. Nat Rev Nephrol 14:231-245 |
| Sequeira-Lopez, Maria Luisa S; Gomez, R Ariel (2018) Preserving kidney health during intensive blood pressure control. Nat Rev Nephrol 14:537-538 |
| Chevalier, Robert L (2018) Evolution, kidney development, and chronic kidney disease. Semin Cell Dev Biol : |
| Mohamed, Tahagod; Sequeira-Lopez, Maria Luisa S (2018) Development of the renal vasculature. Semin Cell Dev Biol : |
| Gomez, R Ariel; Lopez, Maria Luisa S Sequeira (2017) Plasticity of Renin Cells in the Kidney Vasculature. Curr Hypertens Rep 19:14 |
| Oka, Masafumi; Medrano, Silvia; Sequeira-L?pez, Maria Luisa S et al. (2017) Chronic Stimulation of Renin Cells Leads to Vascular Pathology. Hypertension 70:119-128 |
| Song, Renfang; Lopez, Maria Luisa S Sequeira; Yosypiv, Ihor V (2017) Foxd1 is an upstream regulator of the renin-angiotensin system during metanephric kidney development. Pediatr Res 82:855-862 |
| Chevalier, Robert L (2017) Evolutionary Nephrology. Kidney Int Rep 2:302-317 |
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