Large-scale discovery of enhancers from human heart tissue

May, Dalit; Blow, Matthew J.; Kaplan, Tommy; McCulley, David J.; Jensen, Brian C.; Akiyama, Jennifer A.; Holt, Amy; Plajzer-Frick, Ingrid; Shoukry, Malak; Wright, Crystal; Afzal, Veena; Simpson, Paul C.; Rubin, Edward M.; Black, Brian L.; Bristow, James; Pennacchio, Len A.; Visel, Axel

doi:10.1038/ng.1006

Cited by 246 publications

(229 citation statements)

References 41 publications

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“…The Pitx2-occupied chromatin also are DNase I hypersensitive sites (ENCODE, 8-wk heart) and are occupied by p300 (ChIPSeq data from GEO accession no. GSE32587) (19), suggesting Pitx2 actively regulates miR-17-92 and miR-106b-25. The Pitx2 binding regions were further confirmed by real-time PCR using E13.5 Pitx2-Flag mouse heart ChIP chromatin, indicating that Pitx2 directly binds miR-17-92 and miR-106b-25 chromatin during embryogenesis (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Taken together, our findings (18) for Pitx2-bound loci at upstream of miR-17-92 and miR-106b-25. The peaks from different datasets including Pitx2 ChIPSeq, input track, P2 mouse heart p300 ChIP-Seq (GSE32587) (19), and 8-wk-old heart DNase I Hypersensitive Site (HS) Seq (ENCODE), as well as mammal conservation (cons) track, are aligned for comparison. Locations of real-time PCR validation of ChIP enrichment are indicated under datasets.…”

Section: Resultsmentioning

confidence: 99%

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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.

107

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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...

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Section: Resultsmentioning

confidence: 99%

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.

107

View full text Add to dashboard Cite

show abstract

“…Concerning the latter strategy, many investigations in recent years have used genome-wide chromatin immunoprecipitation to map epigenetic marks that are typical for enhancers and, in some cases, to test the elements in transgenic mouse analysis (reviewed in [24,25]). Such studies have detected a large proportion of enhancers that are conserved among several mammals but also a significant fraction of enhancers without apparent evolutionary constraint [22,26,27]. It remains to be tested, however, the relative importance of conserved versus weakly-or non-conserved enhancers in the regulation of the genes they control.…”

Section: (A) Enhancer Evolution In Vertebratesmentioning

confidence: 99%

Enhancer turnover and conserved regulatory function in vertebrate evolution

Domené

Bumaschny

Souza

et al. 2013

Phil. Trans. R. Soc. B

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Mutations in regulatory regions including enhancers are an important source of variation and innovation during evolution. Enhancers can evolve by changes in the sequence, arrangement and repertoire of transcription factor binding sites, but whole enhancers can also be lost or gained in certain lineages in a process of turnover. The proopiomelanocortin gene ( Pomc ), which encodes a prohormone, is expressed in the pituitary and hypothalamus of all jawed vertebrates. We have previously described that hypothalamic Pomc expression in mammals is controlled by two enhancers—nPE1 and nPE2—that are derived from transposable elements and that presumably replaced the ancestral neuronal Pomc regulatory regions. Here, we show that nPE1 and nPE2, even though they are mammalian novelties with no homologous counterpart in other vertebrates, nevertheless can drive gene expression specifically to POMC neurons in the hypothalamus of larval and adult transgenic zebrafish. This indicates that when neuronal Pomc enhancers originated de novo during early mammalian evolution, the newly created cis- and trans- codes were similar to the ancestral ones. We also identify the neuronal regulatory region of zebrafish pomca and confirm that it is not homologous to the mammalian enhancers. Our work sheds light on the process of gene regulatory evolution by showing how a locus can undergo enhancer turnover and nevertheless maintain the ancestral transcriptional output.

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“…Phylogenetic conservation has been used as an indicator for functional conservation of enhancers throughout evolution (16,(27)(28)(29)(30)(31)(32); however, varying degrees of sequence conservation between cell types in different species have been observed. In some human tissues, such as forebrain, enhancers are subject to stringent evolutionary constraint, whereas in others, such as heart, they are under weak evolutionary constraint (12,16,(33)(34)(35)(36)(37)(38). In some cell and tissue types, structural and functional conservation of enhancer elements is significantly lacking, even between species as close as mice and humans (34).…”

mentioning

confidence: 99%

“…In some human tissues, such as forebrain, enhancers are subject to stringent evolutionary constraint, whereas in others, such as heart, they are under weak evolutionary constraint (12,16,(33)(34)(35)(36)(37)(38). In some cell and tissue types, structural and functional conservation of enhancer elements is significantly lacking, even between species as close as mice and humans (34).…”

mentioning

confidence: 99%

Identification of Biologically Relevant Enhancers in Human Erythroid Cells

Steiner

Bogardus

et al. 2013

Journal of Biological Chemistry

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Background: Programs of cellular development and differentiation are controlled by enhancers. Results: Human erythroid cell type-specific enhancers are marked by p300 and groups of transcription factors. Conclusion: Enhancers are important regulators of species-specific erythroid cell structure and function. Significance: Deciphering how nonpromoter regulatory elements control gene expression in erythroid cells is important for understanding inherited and acquired hematologic disease.

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Large-scale discovery of enhancers from human heart tissue

Cited by 246 publications

References 41 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

Enhancer turnover and conserved regulatory function in vertebrate evolution

Identification of Biologically Relevant Enhancers in Human Erythroid Cells

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