NET silencing by let-7i in postural tachycardia syndrome
Abdul Waheed Khan, Mark Ziemann, Susan J. Corcoran, Harikrishnan K.N, Jun Okabe, Haloom Rafehi, Scott S. Maxwell, Murray D. Esler, Assam El-Osta
Abdul Waheed Khan, Mark Ziemann, Susan J. Corcoran, Harikrishnan K.N, Jun Okabe, Haloom Rafehi, Scott S. Maxwell, Murray D. Esler, Assam El-Osta
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Research Article Cardiology

NET silencing by let-7i in postural tachycardia syndrome

Abstract

While strongly implicated in postural tachycardia syndrome (POTS), considerable controversy exists regarding norepinephrine transporter (NET) loss of function. POTS is characterized by the clinical symptoms of orthostatic intolerance, lightheadedness, tachycardia, and syncope or near syncope with upright posture. Abnormal sympathetic nervous system activity is typical, of a type which suggests dysfunction of the NET, with evidence that the gene responsible is under tight epigenetic control. Using RNA of isolated chromatin combined with massive parallel sequencing (RICh-seq) we show that let-7i miRNA suppresses NET by methyl-CpG-binding protein 2 (MeCP2). Vorinostat restores epigenetic control and NET expression in leukocytes derived from POTS participants.

Authors

Abdul Waheed Khan, Mark Ziemann, Susan J. Corcoran, Harikrishnan K.N, Jun Okabe, Haloom Rafehi, Scott S. Maxwell, Murray D. Esler, Assam El-Osta

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Figure 3

Chromatinization of NET involves MeCP2 and let-7i interactions in POTS leukocytes.

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Chromatinization of NET involves MeCP2 and let-7i interactions in POTS l...
(A) Expression of norepinephrine transporter (NET) promoter–bound RNAs SCARNA4, SNORA46, SNORD94, TUFM, and let-7i in leukocytes isolated from postural tachycardia syndrome (POTS) and healthy participants assessed by quantitative reverse transcription PCR (qRT-PCR) (n = 9). Relative expression was measured against U6-2 using qRT-PCR. (B) Let-7i interacts with NET chromatin. RNA of isolated chromatin (RICh) assay was performed in leukocytes derived from healthy (n = 5) and POTS (n = 4) participants and shows let-7i binding at the NET promoter using qRT-PCR. (C) Methyl-CpG-binding protein 2 (MeCP2) interacts with let-7i. RNA immunopurification (RIP) assay using anti-MeCP2 antibody followed by the detection of let-7i using qRT-PCR (n = 3). Data are the mean ± SEM. *P ≤ 0.05, **P ≤ 0.01 by Student’s t test.