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Super-enhancers maintain renin-expressing cell identity and memory to preserve multi-system homeostasis
Maria Florencia Martinez, … , Maria Luisa S. Sequeira-Lopez, R. Ariel Gomez
Maria Florencia Martinez, … , Maria Luisa S. Sequeira-Lopez, R. Ariel Gomez
Published August 21, 2018
Citation Information: J Clin Invest. 2018;128(11):4787-4803. https://doi.org/10.1172/JCI121361.
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Research Article Endocrinology Nephrology

Super-enhancers maintain renin-expressing cell identity and memory to preserve multi-system homeostasis

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Abstract

Renin cells are crucial for survival — they control fluid-electrolyte and blood pressure homeostasis, vascular development, regeneration, and oxygen delivery to tissues. During embryonic development, renin cells are progenitors for multiple cell types that retain the memory of the renin phenotype. When there is a threat to survival, those descendants are transformed and reenact the renin phenotype to restore homeostasis. We tested the hypothesis that the molecular memory of the renin phenotype resides in unique regions and states of these cells’ chromatin. Using renin cells at various stages of stimulation, we identified regions in the genome where the chromatin is open for transcription, mapped histone modifications characteristic of active enhancers such as H3K27ac, and tracked deposition of transcriptional activators such as Med1, whose deletion results in ablation of renin expression and low blood pressure. Using the rank ordering of super-enhancers, epigenetic rewriting, and enhancer deletion analysis, we found that renin cells harbor a unique set of super-enhancers that determine their identity. The most prominent renin super-enhancer may act as a chromatin sensor of signals that convey the physiologic status of the organism, and is responsible for the transformation of renin cell descendants to the renin phenotype, a fundamental process to ensure homeostasis.

Authors

Maria Florencia Martinez, Silvia Medrano, Robin Isadora Brown, Turan Tufan, Stephen Shang, Nadia Bertoncello, Omar Guessoum, Mazhar Adli, Brian C. Belyea, Maria Luisa S. Sequeira-Lopez, R. Ariel Gomez

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Figure 1

Identity of the renin cells and transformation of renin cell descendants to the renin phenotype when homeostasis is threatened.

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Identity of the renin cells and transformation of renin cell descendants...
The 3 renin cell models used in the present study. (A) Schematic showing juxtaglomerular (JG) cells, the classical renin-expressing cells, located at the entrance to the glomerulus (yellow) in the adult unstressed animal and along the afferent arteriole in response to a threat to survival. These cells secrete the hormone RENIN, a key enzyme of the renin angiotensin system that culminates in the generation of angiotensin II, a powerful vasoconstrictor that regulates blood pressure and fluid electrolyte homeostasis. (B) Kidney section from a Ren1c-YFP WT mouse. In this mouse YFP expression is driven by the renin promoter thus marking the JG renin-expressing cells. The YFP signal is restricted to the afferent arterioles at the entrance to the glomerulus. Scale bar: 100 μM. (C) In renin-deficient mice, SMCs that descended from renin precursors are chronically stimulated to adopt the renin phenotype. Kidney section from a Ren1c–/– Ren1c-YFP mouse. YFP+ cells reporting the activity of the renin promoter are distributed along the afferent arterioles (aa), interlobular arteries (IA), larger intrarenal arteries (A), at the entrance to the glomerulus (JG), and in the mesangium. Scale bar: 100 μM. (D) As4.1 cells, mouse kidney tumoral cells that constitutively produce renin. Numerous renin granules detected with the vital marker neutral red are present in the cytoplasm of these cells. Scale bar: 10 μM. (E) Schematic depicting our working hypotheses and the methods used to test the renin cells using as an example the chromatin at the renin locus. Briefly, we hypothesize that renin cells possess unique sets of renin cell–specific genomic elements such as super-enhancers that determine renin cell identity and the molecular memory of the renin phenotype, allowing renin cell descendants to switch on the renin program when homeostasis is threatened.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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