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

• Published in: The Journal of clinical investigation 2018-11, Vol.128 (11), p.4787-4803
• Main Authors: Martinez, Maria Florencia, Medrano, Silvia, Brown, Robin Isadora, Tufan, Turan, Shang, Stephen, Bertoncello, Nadia, Guessoum, Omar, Adli, Mazhar, Belyea, Brian C, Sequeira-Lopez, Maria Luisa S, Gomez, R Ariel
• Format: Article
• Language: English
• Subjects: Animals; Binding sites; Biomedical research; Blood pressure; Chromatin; Clonal deletion; CRISPR; Electrolytes; Embryogenesis; Enhancers; Epigenesis, Genetic; Epigenetics; Gene expression; Genetic transformation; Genomes; Genotype & phenotype; Histone Code; Histones - genetics; Histones - metabolism; Homeostasis; Kidneys; Mediator Complex Subunit 1 - genetics; Mediator Complex Subunit 1 - metabolism; Mice; Mice, Transgenic; Phenotypes; Proteins; Renin; Renin - biosynthesis; Renin - genetics; Rodents; Smooth muscle; Stem cells; Stem Cells - cytology; Stem Cells - metabolism; Transcription factors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI121361

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.