The transcriptional regulation of the human angiotensinogen gene after high-fat diet is haplotype-dependent: Novel insights into the gene-regulatory networks and implications for human hypertension

• Published in: PloS one Vol. 12; no. 5; p. e0176373
• Main Authors: Rana, Anita, Jain, Sudhir, Puri, Nitin, Kaw, Meenakshi, Sirianni, Natalie, Eren, Deniz, Mopidevi, Brahma Raju, Kumar, Ashok
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.05.2017; Public Library of Science (PLoS)
• Subjects: Adipose tissue; Aldosterone; Angiotensin; Angiotensinogen; Angiotensinogen - genetics; Animal tissues; Binding; Biology and life sciences; Blood; Blood pressure; Care and treatment; Chromatin; Cytokines; Development and progression; Diet; Diet, High-Fat; Gene expression; Gene Expression Regulation; Gene regulation; Gene Regulatory Networks; Genetic aspects; Genetic regulation; Haplotypes; Health aspects; High fat diet; Humans; Hypertension; Hypertension - genetics; Identification and classification; Kinases; Liver; Medicine and Health Sciences; Mice; Obesity; Pharmacology; Physiology; Plasma levels; Proteins; Renin; Rodents; Signal transduction; Single-nucleotide polymorphism; Stat3 protein; Transcription factors; Transcription, Genetic; Transgenic mice; New York; United States > US; Ohio
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0176373

Single nucleotide polymorphisms (SNPs) in the human angiotensinogen (hAGT) gene may modulate its transcription and affect the regulation of blood pressure via activation of the renin-angiotensin aldosterone system (RAAS). In this regard, we have identified polymorphisms in the 2.5 Kb promoter of the hAGT gene that form two haplotype (Hap) blocks: -6A/G (-1670A/G, -1562C/T, -1561T/C) and -217A/G (-532T/C, -793A/G, -1074T/C & -1178G/A). hAGT gene with Hap -6A/-217A (Hap I) is associated with increased blood pressure whereas, Hap -6G/-217G (Hap II) is associated with normal blood pressure in human subjects. Since RAAS over activity contributes to hypertension in obesity, we have made transgenic mice (TG) containing either Hap I or Hap II of the hAGT gene to understand the role of obesity on its transcriptional regulation. Although, a high-fat diet (60% Kcal from fat, 12 weeks) elevates hAGT and mAGT regardless of haplotype, this effect is significantly (p<0.05) accentuated in Hap I mice, in both adipose and liver tissues. Chromatin Immuno- precipitation (ChIP) assay shows an increased binding of transcription factors including, GR, CEBPβ and STAT3 to the chromatin of the Hap I TG mice after high-fat diet as compared to Hap II TG mice (p<0.05). Differential plasma levels of hAGT in Hap II and I mice, after high-fat diet, further corroborate the variable transcriptional regulation of the hAGT, governed by gene-haplotypes. Taken together, our results show that SNPs in the Hap-I of the hAGT gene promote high-fat diet-induced binding of transcription factors GR, CEBP-β and STAT3, which lead to elevated expression of the hAGT gene in hepatic and adipose tissues.