NDLI: Conserved regulatory motifs at phenylethanolamine N-methyltransferase (PNMT) are disrupted by common functional genetic variation: an integrated computational/experimental approach

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Conserved regulatory motifs at phenylethanolamine N-methyltransferase (PNMT) are disrupted by common functional genetic variation: an integrated computational/experimental approach

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Mammalian Genome : Volume 21, Issue 1-2, February 2010

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Conserved regulatory motifs at phenylethanolamine N-methyltransferase (PNMT) are disrupted by common functional genetic variation: an integrated computational/experimental approach

Content Provider	Springer Nature Link
Author	Rodríguez Flores, Juan L. Zhang, Kuixing Kang, Sun Woo Wen, Gen Ghosh, Sajalendu Friese, Ryan S. Mahata, Sushil K. Subramaniam, Shankar Hamilton, Bruce A. O’Conr, Daniel T.
Copyright Year	2010
Abstract	The adrenomedullary hormone epinephrine transduces environmental stressors into cardiovascular events (tachycardia and hypertension). Although the epinephrine biosynthetic enzyme PNMT genetic locus displays both linkage and association to such traits, genetic variation underlying these quantitative phenotypes is not established. Using an integrated suite of computational and experimental approaches, we elucidate a functional mechanism for common (minor allele frequencies > 30%) genetic variants at PNMT. Transcription factor binding motif prediction on mammalian PNMT promoter alignments identified two variant regulatory motifs, SP1 and EGR1, disrupted by G-367A (rs3764351), and SOX17 motif created by G-161A (rs876493). Electrophoretic mobility shifts of approximately 30-bp oligonucleotides containing ancestral versus variant alleles validated the computational hypothesis. Queried against chromaffin cell nuclear protein extracts, only the G-367 and -161A alleles shifted. Specific antibodies applied in electrophoretic gel shift experiments confirmed binding of SP1 and EGR1 to G-367 and SOX17 to -161A. The in vitro allele-specific binding was verified in cella through promoter reporter assays: lower activity for -367A haplotypes cotransfected by SP1 (p = 0.002) and EGR1 (p = 0.034); and enhanced inhibition of -161A haplotypes (p = 0.0003) cotransfected with SP1 + SOX17. Finally, we probed cis/trans regulation with endogenous factors by chromatin immunoprecipitation using SP1/EGR1/SOX17 antibodies. We describe the systematic application of complementary computational and experimental techniques to detect and document functional genetic variation in a trait-associated regulatory region. The results provide insight into cis and trans transcriptional mechanisms whereby common variation at PNMT can give rise to quantitative changes in human physiological and disease traits. Thus, PNMT variants in cis may interact with nuclear factors in trans to govern adrenergic activity.
Starting Page	195
Ending Page	204
Page Count	10
File Format	PDF
ISSN	09388990
Journal	Mammalian Genome
Volume Number	21
Issue Number	3-4
e-ISSN	14321777
Language	English
Publisher	Springer-Verlag
Publisher Date	2010-03-05
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Zoology Anatomy Cell Biology
Content Type	Text
Resource Type	Article
Subject	Genetics

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Conserved regulatory motifs at phenylethanolamine N-methyltransferase (PNMT) are disrupted by common functional genetic variation: an integrated computational/experimental approach

Conserved regulatory motifs at phenylethanolamine N-methyltransferase (PNMT) are disrupted by common functional genetic variation: an integrated computational/experimental approach

Phenylethanolamine N-Methyltransferase Gene Expression SP1 AND MAZ POTENTIAL FOR TISSUE-SPECIFIC EXPRESSION

Effects of ACTH and corticosteroids on phenylethanoIamine‐N‐methyltransferase (PNMT) expression as determined by immunocytochemical localization in the adrenal gland of the lizard Podarcis sicula

Effects of dexamethasone on phenylethanolamine N-methyl-transferase (PNMT) and adrenaline (A) in the brains of adult and neonatal rats.

Neural regulation of phenylethanolamine N-methyltransferase (PNMT) gene expression in bovine chromaffin cells differs from other catecholamine enzyme genes

V1R promoters are well conserved and exhibit common putative regulatory motifs

Rabbit Lung Indolethylamine N-Methyltransferase cDNA AND GENE CLONING AND CHARACTERIZATION

The Reaction Mechanism of Phenylethanolamine N-Methyltransferase: A Density Functional Theory Study

Conserved regulatory motifs at phenylethanolamine N-methyltransferase (PNMT) are disrupted by common functional genetic variation: an integrated computational/experimental approach

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Conserved regulatory motifs at phenylethanolamine N-methyltransferase (PNMT) are disrupted by common functional genetic variation: an integrated computational/experimental approach

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Effects of ACTH and corticosteroids on phenylethanoIamine‐N‐methyltransferase (PNMT) expression as determined by immunocytochemical localization in the adrenal gland of the lizard Podarcis sicula

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Conserved regulatory motifs at phenylethanolamine N-methyltransferase (PNMT) are disrupted by common functional genetic variation: an integrated computational/experimental approach