MicroRNA-17-92, a Direct Ap-2α Transcriptional Target, Modulates T-Box Factor Activity in Orofacial Clefting

Wang, Jun; Bai, Yan; Li, Hong; Greene, Stephanie; Klysik, Elzbieta; Yu, Wei; Schwartz, Robert J.; Williams, Trevor; Martin, James F.

doi:10.1371/journal.pgen.1003785

Cited by 68 publications

(71 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To determine the miR-17-92 expression pattern in heart, we generated an miR-17-92 bacterial artificial chromosome transgenic LacZ reporter line (20) and compared it with a Pitx2 LacZ knock-in allele (16). In E12.5 hearts, LacZ staining indicated that miR-17-92 is expressed in the outflow tract (OFT), left atrium (LA), coronary sinus, and atrioventricular canal (Fig.…”

Section: Resultsmentioning

confidence: 99%

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Wang¹,

Bai

Li³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

109

View full text Add to dashboard Cite

The molecular mechanisms underlying atrial fibrillation, the most common sustained cardiac arrhythmia, remain poorly understood. Genome-wide association studies uncovered a major atrial fibrillation susceptibility locus on human chromosome 4q25 in close proximity to the paired-like homeodomain transcription factor 2 (Pitx2) homeobox gene. Pitx2, a target of the left-sided Nodal signaling pathway that initiates early in development, represses the sinoatrial node program and pacemaker activity on the left side. To address the mechanisms underlying this repressive activity, we hypothesized that Pitx2 regulates microRNAs (miRs) to repress the sinoatrial node genetic program. MiRs are small noncoding RNAs that regulate gene expression posttranscriptionally. Using an integrated genomic approach, we discovered that Pitx2 positively regulates miR-17-92 and miR-106b-25. Intracardiac electrical stimulation revealed that both miR-17-92 and miR-106b-25 deficient mice exhibit pacing-induced atrial fibrillation. Furthermore electrocardiogram telemetry revealed that mice with miR-17-92 cardiac-specific inactivation develop prolonged PR intervals whereas mice with miR-17-92 cardiac-specific inactivation and miR-106b-25 heterozygosity develop sinoatrial node dysfunction. Both arrhythmias are risk factors for atrial fibrillation in humans. Importantly, miR-17-92 and miR-106b-25 directly repress genes, such as Shox2 and Tbx3, that are required for sinoatrial node development. Together, to our knowledge, these findings provide the first genetic evidence for an miR loss-of-function that increases atrial fibrillation susceptibility. irregular heart rate | single nucleotide variant | mouse genetics A trial fibrillation (AF), the most common arrhythmia in adult patients, increases in prevalence with age to almost 5% of the population over 65. Patients with AF have an increased risk of stroke, dementia, and heart failure (1). Electrical impulses that are critical for a coordinated, physiologic heartbeat originate in the sinoatrial node (SAN). In AF, abnormal fibrillatory atrial impulses override normal SAN function, with resultant irregular conduction to the ventricles. Many cases of ectopic electrical activity originate in the pulmonary vein (2). Other sites of ectopy include the left atrial posterior wall, superior vena cava, interatrial septum, crista terminalis, and coronary sinus myocardium (3, 4).Multiple approaches have been used to uncover genes that may contribute to the AF phenotype in adult patients. A seminal genome-wide association study (GWAS), subsequently replicated by multiple studies, uncovered a single nucleotide variant (SNV) on human 4q25 that was strongly associated with familial AF (5). Patients with the 4q25 variant exhibited early onset AF that was independent from other risk factors such as hypertension and diabetes, suggesting a novel biologic mechanism involving genes located on chromosome 4q25. The presence of the 4q25 SNV also had prognostic value because patients with the SNV are prone to cardioembolic str...

show abstract

Section: Resultsmentioning

confidence: 99%

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Wang¹,

Bai

Li³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

109

View full text Add to dashboard Cite

show abstract

“…Several reports have given an illustration of the differential expression of tissue miRNAs in murine upper lip [8], specific role of miRNAs in mouse embryos craniofacial morphogenesis [7,23]. Additionally, SNPs in the miRNA-binding sites were reported to be associated with non-syndromic orofacial clefts susceptibility [24].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, several studies revealed that tissue miRNAs could be functionally important in regulating vertebrate and mammalian orofacial clefting [6][7][8]. However, there is little information available on the roles of specific miRNAs in human cleft lip.…”

Section: Introductionmentioning

confidence: 99%

Expression profile of plasma microRNAs in nonsyndromic cleft lip and their clinical significance as biomarkers

Zou

et al. 2016

Biomedicine & Pharmacotherapy

View full text Add to dashboard Cite

“…Embryonic orofacial tissues from wild-type mice at stages E10.5-E11.5 were dissected for Yap ChIP analysis, as previously described (Wang et al, 2013;Morikawa et al, 2015). Normal mouse IgG was used as a replacement control for the anti-Yap ChIP assay to show nonspecific immunoprecipitation of the chromatin.…”

Section: Chromatin Immunoprecipitationmentioning

confidence: 99%

Yap and Taz play a crucial role in neural crest-derived craniofacial development

et al. 2015

Self Cite

View full text Add to dashboard Cite

The role of the Hippo signaling pathway in cranial neural crest (CNC) development is poorly understood. We used the Wnt1Cre and Wnt1Cre2SOR drivers to conditionally ablate both Yap and Taz in the CNC of mice. When using either Cre driver, Yap and Taz deficiency in the CNC resulted in enlarged, hemorrhaging branchial arch blood vessels and hydrocephalus. However, Wnt1Cre2SOR embryos had an open cranial neural tube phenotype that was not evident in Wnt1Cre embryos. In O9-1 CNC cells, the loss of Yap and Taz impaired smooth muscle cell differentiation. RNA-sequencing data indicated that Yap and Taz regulate genes encoding Fox transcription factors, specifically Foxc1. Proliferation was reduced in the branchial arch mesenchyme of Yap and Taz CNC conditional knockout (CKO) embryos. Moreover, Yap and Taz CKO embryos had cerebellar aplasia similar to Dandy Walker spectrum malformations observed in human patients and mouse embryos with mutations in Foxc1. In embryos and O9-1 cells deficient for Yap and Taz, Foxc1 expression was significantly reduced. Analysis of Foxc1 regulatory regions revealed a conserved recognition element for the Yap and Taz DNA binding co-factor Tead. ChIP-pcr experiments further supported the conclusion that Foxc1 is directly regulated by the Yap/Tead complex. Our findings uncover important roles for Yap and Taz in CNC diversification and development.

show abstract

MicroRNA-17-92, a Direct Ap-2α Transcriptional Target, Modulates T-Box Factor Activity in Orofacial Clefting

Cited by 68 publications

References 42 publications

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Expression profile of plasma microRNAs in nonsyndromic cleft lip and their clinical significance as biomarkers

Yap and Taz play a crucial role in neural crest-derived craniofacial development

Contact Info

Product

Resources

About