NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network

Anderson, David J.; Kaplan, D.; Bell, Katrina M.; Koutsis, Katerina; Haynes, John M.; Mills, Richard J.; Phelan, Dean; Qian, Elizabeth; Leitoguinho, Ana Rita; Arasaratnam, Deevina; Labonne, Tanya; Ng, Elizabeth; Davis, Richard P.; Casini, Simona; Passier, Robert; Hudson, James E.; Porrello, Enzo R.; Costa, Mauro W.; Rafii, Arash; Curl, Claire L.; Delbridge, Lea M; Harvey, Richard P.; Oshlack, Alicia; Cheung, Michael; Mummery, Christine L.; Petrou, Stephen; Elefanty, Andrew G.; Elliott, David A.

doi:10.1038/s41467-018-03714-x

Cited by 88 publications

(80 citation statements)

References 70 publications

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“…Epigenetic analysis of early zebrafish cardiogenesis identified an enhancer, we have termed epicon21, situated 24 kb upstream of hey2 that is conserved from zebrafish to humans, and that overlaps with a recently identified enhancer bound by NKX2.5 in human pluripotent stem cells ( Fig. S2A; Anderson et al, 2018;Yuan et al, 2018). Following WISH analysis of Tg(epicon21:EGFP) and myl7 expression at 16.5, 20 and 24 hpf, it was evident that the transgenic closely matched the endogenous hey2 gene expression pattern (Fig.…”

Section: Myocardial Accretion Is Extended With Loss Of Hey2mentioning

confidence: 98%

“…Of note, Hey2 has been suggested to regulate growth of the heart via restraining cardiomyocyte (CM) proliferation (Jia et al, 2007), as well as functioning downstream of Nkx2.5 to prevent ectopic atrial identity within ventricular myocardium (Xin et al, 2007;Targoff et al, 2013). More recent work in human pluripotent stem cells has suggested a key function for HEY2 as an effector of NKX2.5 during cardiomyocyte differentiation (Anderson et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Hey2 regulates the size of the cardiac progenitor pool during vertebrate heart development

et al. 2018

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A key event in heart development is the timely addition of cardiac progenitor cells, defects in which can lead to congenital heart defects. However, how the balance and proportion of progenitor proliferation versus addition to the heart is regulated remains poorly understood. Here, we demonstrate that Hey2 functions to regulate the dynamics of cardiac progenitor addition to the zebrafish heart. We found that the previously noted increase in myocardial cell number found in the absence of Hey2 function was due to a pronounced expansion in the size of the cardiac progenitor pool. Expression analysis and lineage tracing of hey2-expressing cells showed that hey2 is active in cardiac progenitors. Hey2 acted to limit proliferation of cardiac progenitors, prior to heart tube formation. Use of a transplantation approach demonstrated a likely cell-autonomous (in cardiac progenitors) function for Hey2. Taken together, our data suggest a previously unappreciated role for Hey2 in controlling the proliferative capacity of cardiac progenitors, affecting the subsequent contribution of latedifferentiating cardiac progenitors to the developing vertebrate heart.

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Section: Myocardial Accretion Is Extended With Loss Of Hey2mentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Hey2 regulates the size of the cardiac progenitor pool during vertebrate heart development

et al. 2018

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“…The role as activator is consistent with other studies. [36,39] However, the TF can also function as a transcriptional repressor of genes like ISL1. [36,45] We were able to detect strong e ects of the NKX2-5 transcript on various target transcript and protein levels.…”

Section: Discussionmentioning

confidence: 99%

“…[36,39] However, the TF can also function as a transcriptional repressor of genes like ISL1. [36,45] We were able to detect strong e ects of the NKX2-5 transcript on various target transcript and protein levels. Most of the identified target genes are involved in contractile function or metabolism, two mechanisms highly linked to processes involved in AF.…”

Section: Discussionmentioning

confidence: 99%

“…In order to get more detailed information about complex molecular mechanisms underlying AF, we further analyzed the TF network of NKX2-5 (see Figure 5 A) since the TF has already been described in the context of cardiac development, [36] AF, [37,38,39] and congenital heart diseases. [40] To evaluate the downstream e ects of the SNP rs9481842 via the TF NKX2-5 in AF we analyzed the influence of NKX2-5 transcript levels on target genes by estimating NKX2-5 TF activity.…”

Section: Nkx2-5 Transcription Factor Networkmentioning

confidence: 99%

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Tissue-specific multiOMICs analysis of atrial fibrillation

Assum

Krause

Scheinhardt³

et al. 2020

Preprint

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RATIONALE:Genome-wide association studies (GWAS) for atrial fibrillation (AF) have uncovered numerous disease-associated variants. The molecular mechanisms of genotype-phenotype relationships, especially consequences of sequence variants for mRNA and protein expression remain largely elusive. Novel multiOMICs approaches are needed for deciphering the underlying molecular networks. Recently, an omnigenic model postulated the existence of core genes, that accumulate trans regulatory e ects and are directly linked to disease phenotypes. However, the existence and identity of AF-relevant core genes remain unknown. OBJECTIVE:The aim was to systematically assess regulatory genetic variants and their downstream consequences on transcriptome, proteome and the disease phenotype AF on a genome-wide scale. METHODS AND RESULTS:We integrated genomics, transcriptomics, and proteomics of human atrial tissue. We identified widespread e ects of genetic variants on transcript (cis eQTL) and protein (cis pQTL) abundance of nearby genes with an overrepresentation of GWAS variants for AF. To investigate more complex genetic mechanisms we established a novel approach to identify candidates for AF core genes, as postulated by the omnigenic model. Our approach combined a polygenic risk score for AF with pathway enrichment analysis to uncover biological processes related to the genetic susceptibility of AF. Within these biological processes, we identified two trans eQTLs and six trans pQTLs for AF GWAS hits involved in cardiac contractile function or metabolism. Furthermore, we elucidated the role of the transcription factor NKX2-5 as a link between the GWAS SNP rs9481842 and thirteen putative AF core genes with a consistent downregulation in AF on proteomics level. CONCLUSIONS:We established an integrative multiOMICs approach for the identification of AF core gene candidates and applied this technique to uncover trans-acting genetic networks in AF. We provide a valuable resource to investigate atrial tissue-specific regulatory variants for transcript and protein levels in the context of cardiovascular disease.Tissue-specific multiOMICs analysis of atrial fibrillation April 6, 2020 heart coronary bypass surgery. For the current analyses, N=118 patients with multiOMICs data were available. Cardiovascular risk factor information was collected by questionnaire and from medical records. Baseline blood samples were aliquoted and stored prior to surgery. Atrial appendage tissue remnants were collected when the extracorporeal circulation was started and shock frozen immediately. Follow-up for AF and other cardiovascular disease outcomes was by questionnaire and medical chart review. The observational cohort study was approved by Ethikkommission Ärztekammer Hamburg (PV3982). The study was performed in compliance with the Declaration of Helsinki. The study enrollment and follow-up procedures were in accordance with institutional guidelines. All participants provided written informed consent. Sex stratification of the results was not possible due ...

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Homeobox Genes and Homeodomain Proteins: New Insights into Cardiac Development, Degeneration and Regeneration

Mikšiūnas

Mobasheri

Bironaitė

2019

Advances in Experimental Medicine and Biology

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NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network

Cited by 88 publications

References 70 publications

Hey2 regulates the size of the cardiac progenitor pool during vertebrate heart development

Hey2 regulates the size of the cardiac progenitor pool during vertebrate heart development

Tissue-specific multiOMICs analysis of atrial fibrillation

Homeobox Genes and Homeodomain Proteins: New Insights into Cardiac Development, Degeneration and Regeneration

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