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

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.

Sox6: A new modulator of renin expression during physiological conditions

“…Gene centric arrays and genome wide association studies have shown a strong association of Sox6 with hypertension (7,8,16,21). Sox6 is expressed and has biding site in the renin promoter within the super-enhancer region (22). In vitro, we found that Sox6 is necessary for the c-AMP-mediated induction of renin expression in renal tissue specific stem-progenitor or mesenchymal stromal cells.…”

“…Moreover, transcription factors such as CRAB/CREM, HOX/PBX, and LXRα bind to the renin promoter where they exert positive and negative control over renin expression in vitro (4,14). Also, a recently published study show that super-enhancers are involved to maintain renin-expressing cell identity and memory to preserve multi-system homeostasis (22).…”

A primitive type of renin-expressing lymphocyte protects the organism against infections

“…Renin mRNA was not present in cells from renin null mice (16). To further document these findings, we obtained peritoneal cells from Ren1 c-YFP mice (17), where YFP is under the control of the renin super-enhancer (3,18) and reports the transcriptional activity of the renin gene. Figure 2c shows YFP+ cells from the peritoneal cavity, indicating that these cells actively transcribe renin and YFP.…”

“…Renin-expressing cells emerged in nature over 400 million years ago (1,2). Throughout evolution, they have acquired numerous defensive functions that rendered them as perfect machines to ensure our survival in response to a variety of homeostatic threats (3). They control blood pressure, fluid-electrolyte balance, vascular development, glomerular regeneration and may participate in the regulation of oxygen delivery to tissues (1,3).…”

“…Throughout evolution, they have acquired numerous defensive functions that rendered them as perfect machines to ensure our survival in response to a variety of homeostatic threats (3). They control blood pressure, fluid-electrolyte balance, vascular development, glomerular regeneration and may participate in the regulation of oxygen delivery to tissues (1,3). Although renin cells were first discovered in the juxtaglomerular areas of the adult kidney arterioles, from where they release renin to the circulation to regulate blood pressure and fluid-electrolyte homeostasis, their appearance in this organ is a late event in their developmental history (1).…”