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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 November 1, 2018; First published August 21, 2018
Citation Information: J Clin Invest. 2018;128(11):4787-4803. https://doi.org/10.1172/JCI121361.
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Categories: 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, Evan A. 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 5

The molecular memory of the renin phenotype resides within the renin super-enhancer.

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The molecular memory of the renin phenotype resides within the renin sup...
(A) In vitro model to study the molecular memory of the renin cell phenotype. The immortalized SMCCFP/YFP cell line derived from the mouse kidney constitutively expresses the renin lineage marker CFP and can be induced to express renin (and YFP) upon stimulation. The nuclease-null dCas9 protein is fused to the catalytic core of p300 and catalyzes the acetylation of H3K27. The renin locus showing the renin super-enhancer region in renin cells (indicated by the grey bar on top) previously characterized H3K27ac signal in renin cells. The schematic shows the locations of the sgRNAs used to target the SE region of renin. (B) Bright field images (left panels) of corresponding fluorescent images (right panels). Top, no YFP+ cells were observed in the controls where cells were transfected with a plasmid containing dCas9 bearing mutated p300. Middle, SMCCFP/YFP expressing YFP 72 hours after transfection with a plasmid containing the sequence for the dCas9p300 core and 5 sgRNAs targeted to the renin super-enhancer. Bottom, YFP expression in SMCCFP/YFP treated with 1 mM dB-cAMP and 0.1 mM IBMX for 72 hours to stimulate renin expression. Scale bars: 10 μm. (C) Relative mRNA expression of Ren1, determined by qRT-PCR. The levels of renin expression increased 4.37 to 477 times in response to dCas9p300 + sgRNAs (n = 6) or to exogenous cAMP (n = 6), respectively, versus control samples (dCas9p300-mutated and untreated cells, n = 3 and n = 6, respectively). Data are mean ± SD. **P < 0.01; ***P < 0. 001, by unpaired, 2-sided Student’s t test.
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