دورية أكاديمية
Inhibition of Renin Expression Is Regulated by an Epigenetic Switch From an Active to a Poised State.
العنوان: | Inhibition of Renin Expression Is Regulated by an Epigenetic Switch From an Active to a Poised State. |
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المؤلفون: | Smith JP; Department of Pediatrics, Child Health Research Center (J.P.S., R.P., S.M., M.L.S.S.-L., R.A.G.), University of Virginia, Charlottesville, VA., Paxton R; Department of Pediatrics, Child Health Research Center (J.P.S., R.P., S.M., M.L.S.S.-L., R.A.G.), University of Virginia, Charlottesville, VA.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (R.P.)., Medrano S; Department of Pediatrics, Child Health Research Center (J.P.S., R.P., S.M., M.L.S.S.-L., R.A.G.), University of Virginia, Charlottesville, VA., Sheffield NC; Center for Public Health Genomics (N.C.S.), University of Virginia, Charlottesville, VA.; Department of Public Health Sciences (N.C.S.), University of Virginia, Charlottesville, VA.; Department of Biomedical Engineering (N.C.S.), University of Virginia, Charlottesville, VA.; Department of Biochemistry and Molecular Genetics (N.C.S.), University of Virginia, Charlottesville, VA., Sequeira-Lopez MLS; Department of Pediatrics, Child Health Research Center (J.P.S., R.P., S.M., M.L.S.S.-L., R.A.G.), University of Virginia, Charlottesville, VA., Gomez RA; Department of Pediatrics, Child Health Research Center (J.P.S., R.P., S.M., M.L.S.S.-L., R.A.G.), University of Virginia, Charlottesville, VA. |
المصدر: | Hypertension (Dallas, Tex. : 1979) [Hypertension] 2024 Sep; Vol. 81 (9), pp. 1869-1882. Date of Electronic Publication: 2024 Jul 11. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Lippincott, Williams & Wilkins Country of Publication: United States NLM ID: 7906255 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4563 (Electronic) Linking ISSN: 0194911X NLM ISO Abbreviation: Hypertension Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Original Publication: [Dallas, Tex.] : [American Heart Association], [©1979]- |
مواضيع طبية MeSH: | Epigenesis, Genetic* , Renin*/metabolism , Renin*/genetics , Transcription Factors*/genetics , Transcription Factors*/metabolism, Animals ; Mice ; Gene Expression Regulation ; Juxtaglomerular Apparatus/metabolism ; p300-CBP Transcription Factors/metabolism ; p300-CBP Transcription Factors/genetics ; Bromodomain Containing Proteins ; Nuclear Proteins |
مستخلص: | Background: Renin-expressing cells are myoendocrine cells crucial for the maintenance of homeostasis. Renin is regulated by cAMP, p300 (histone acetyltransferase p300)/CBP (CREB-binding protein), and Brd4 (bromodomain-containing protein 4) proteins and associated pathways. However, the specific regulatory changes that occur following inhibition of these pathways are not clear. Methods: We treated As4.1 cells (tumoral cells derived from mouse juxtaglomerular cells that constitutively express renin) with 3 inhibitors that target different factors required for renin transcription: H-89-dihydrochloride, PKA (protein kinase A) inhibitor; JQ1, Brd4 bromodomain inhibitor; and A-485, p300/CBP inhibitor. We performed assay for transposase-accessible chromatin with sequencing (ATAC-seq), single-cell RNA sequencing, cleavage under targets and tagmentation (CUT&Tag), and chromatin immunoprecipitation sequencing for H3K27ac (acetylation of lysine 27 of the histone H3 protein) and p300 binding on biological replicates of treated and control As4.1 cells. Results: In response to each inhibitor, Ren1 expression was significantly reduced and reversible upon washout. Chromatin accessibility at the Ren1 locus did not markedly change but was globally reduced at distal elements. Inhibition of PKA led to significant reductions in H3K27ac and p300 binding specifically within the Ren1 super-enhancer region. Further, we identified enriched TF (transcription factor) motifs shared across each inhibitory treatment. Finally, we identified a set of 9 genes with putative roles across each of the 3 renin regulatory pathways and observed that each displayed differentially accessible chromatin, gene expression, H3K27ac, and p300 binding at their respective loci. Conclusions: Inhibition of renin expression in cells that constitutively synthesize and release renin is regulated by an epigenetic switch from an active to poised state associated with decreased cell-cell communication and an epithelial-mesenchymal transition. This work highlights and helps define the factors necessary for renin cells to alternate between myoendocrine and contractile phenotypes. Competing Interests: None. |
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معلومات مُعتمدة: | P50 DK096373 United States DK NIDDK NIH HHS; R01 DK116196 United States DK NIDDK NIH HHS; R01 DK116718 United States DK NIDDK NIH HHS; R01 HL148044 United States HL NHLBI NIH HHS |
فهرسة مساهمة: | Keywords: chromatin; data analysis; multiomics; nuclear proteins; renin |
المشرفين على المادة: | EC 3.4.23.15 (Renin) 0 (Transcription Factors) EC 2.3.1.48 (p300-CBP Transcription Factors) 0 (Brd4 protein, mouse) 0 (Bromodomain Containing Proteins) 0 (Nuclear Proteins) |
تواريخ الأحداث: | Date Created: 20240711 Date Completed: 20240814 Latest Revision: 20240823 |
رمز التحديث: | 20240823 |
مُعرف محوري في PubMed: | PMC11337216 |
DOI: | 10.1161/HYPERTENSIONAHA.124.22886 |
PMID: | 38989586 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1524-4563 |
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DOI: | 10.1161/HYPERTENSIONAHA.124.22886 |