Expression of MEF2 Genes during Human Cardiac Development.

Iida, Kazuki; Hidaka, Kumi; Takeuchi, Makoto; Nakayama, Masahiro; Yutani, Chikao; Mukai, Tsunehiro; Morisaki, Takayuki

doi:10.1620/tjem.187.15

Cited by 26 publications

(8 citation statements)

References 14 publications

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“…2B). These motifs resemble the binding specificity of TFs in the families of LMO2, MEF2, ETS, and SP1-transcription factors known to play roles in heart development (Iida et al 1999;Flesch 2001;Zhu et al 2005;Pham et al 2007;Gratzinger et al 2009). The fact that these novel motifs were chosen in addition to the database motifs can be explained by one of the three scenarios: (1) specificities of the TFs binding the database motifs may not have been characterized precisely; (2) these motifs could be recognized by novel TFs, the specificities of which have not been characterized so far; or (3) the database TFs, specificities of which are characterized using in vitro methods, may have slightly different specificities in the heart due to various cofactors in vivo.…”

Section: Selected Features Have Been Previously Implicated In Heart Dmentioning

confidence: 90%

Genome-wide discovery of human heart enhancers

Narlikar¹,

Sakabe²,

Blanski³

et al. 2010

Genome Res.

112

135

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The various organogenic programs deployed during embryonic development rely on the precise expression of a multitude of genes in time and space. Identifying the cis-regulatory elements responsible for this tightly orchestrated regulation of gene expression is an essential step in understanding the genetic pathways involved in development. We describe a strategy to systematically identify tissue-specific cis-regulatory elements that share combinations of sequence motifs. Using heart development as an experimental framework, we employed a combination of Gibbs sampling and linear regression to build a classifier that identifies heart enhancers based on the presence and/or absence of various sequence features, including known and putative transcription factor (TF) binding specificities. In distinguishing heart enhancers from a large pool of random noncoding sequences, the performance of our classifier is vastly superior to four commonly used methods, with an accuracy reaching 92% in cross-validation. Furthermore, most of the binding specificities learned by our method resemble the specificities of TFs widely recognized as key players in heart development and differentiation, such as SRF, MEF2, ETS1, SMAD, and GATA. Using our classifier as a predictor, a genome-wide scan identified over 40,000 novel human heart enhancers. Although the classifier used no gene expression information, these novel enhancers are strongly associated with genes expressed in the heart. Finally, in vivo tests of our predictions in mouse and zebrafish achieved a validation rate of 62%, significantly higher than what is expected by chance. These results support the existence of underlying cis-regulatory codes dictating tissue-specific transcription in mammalian genomes and validate our enhancer classifier strategy as a method to uncover these regulatory codes.

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Section: Selected Features Have Been Previously Implicated In Heart Dmentioning

confidence: 90%

Genome-wide discovery of human heart enhancers

Narlikar¹,

Sakabe²,

Blanski³

et al. 2010

Genome Res.

112

135

View full text Add to dashboard Cite

show abstract

“…The full dynamics of MEF2 isoform expression is outside the scope of this review and may be found elsewhere (Desjardins & Naya, 2016). Nevertheless, we summarize by noting that expression of individual isoforms of MEF2 initiates between e7.5 and e8.5 in mice; postnatally, MEF2A, MEF2C and MEF2D are expressed (Iida et al 1999). In the perinatal period, these MEF2 isoforms may have non-overlapping and even potentially antagonistic function (Desjardins & Naya, 2017).…”

Section: Mef2 Familymentioning

confidence: 99%

Regulation of cardiomyocyte maturation during critical perinatal window

Kannan

Kwon

2019

The Journal of Physiology

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A primary limitation in the use of pluripotent stem cell-derived cardiomyocytes (PSC-CMs) for both patient health and scientific investigation is the failure of these cells to achieve full functional maturity. In vivo, cardiomyocytes undergo numerous adaptive structural, functional and metabolic changes during maturation. By contrast, PSC-CMs fail to fully undergo these developmental processes, instead remaining arrested at an embryonic stage of maturation. There is thus a significant need to understand the biological processes underlying proper CM maturation in vivo. Here, we discuss what is known regarding the initiation and coordination of CM maturation. We postulate that there is a critical perinatal window, ranging from embryonic day 18.5 to postnatal day 14 in mice, in which the maturation process is exquisitely sensitive to perturbation. While the initiation mechanisms of this process are unknown, it is increasingly clear that maturation proceeds through interconnected regulatory circuits that feed into one another to coordinate concomitant structural, functional and metabolic CM maturation. We highlight PGC1α, SRF and the MEF2 family as transcription factors that may potentially mediate this cross-talk. We lastly discuss several emerging technologies that will facilitate future studies into the mechanisms of CM maturation. Further study will not only produce a better understanding of its key processes, but provide practical insights into developing a robust strategy to produce mature PSC-CMs. Abstract figure legendHere, we postulate that there is a critical window, ranging from embryonic day 18.5 to postnatal day 14 in mice, in which interconnected regulatory circuits enable coordinated, concomitant structural, functional and metabolic cardiomyocyte maturation.

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“…Furthermore, in mice ablation of Mef2c in the anterior second heart field causes outflow tract defects, such as overriding aorta, double outlet right ventricle and transposition of the great arteries 92 . In humans, all four MEF2 transcript variants (MEF2A, MEF2B, MEF2C and MEF2D) are expressed in all developmental stages of the heart 99 . More importantly, Kodo and colleagues made a sequence analysis of the MEF2C gene in 256 non-syndromic, non-familial patients with cardiac outflow tract defects, and identified a novel sequence variant (p.A103V) in a female patient with pulmonary atresia and VSD 100 .…”

Section: Discussionmentioning

confidence: 99%

MEF2C loss-of-function mutation contributes to congenital heart defects

Qiao¹,

Wang

Zhang

et al. 2017

Int. J. Med. Sci.

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Congenital heart disease (CHD) is the most common type of developmental abnormality in humans, and is a leading cause for substantially increased morbidity and mortality in affected individuals. Increasing studies demonstrates a pivotal role of genetic defects in the pathogenesis of CHD, and presently mutations in more than 60 genes have been associated with CHD. Nevertheless, CHD is of pronounced genetic heterogeneity, and the genetic basis underpinning CHD in a large proportion of patients remains unclear. In the present study, the whole coding exons and splicing donors/acceptors of the MEF2C gene, which codes for a transcription factor essential for normal cardiovascular development, were sequenced in 200 unrelated patients affected with CHD, and a novel heterozygous missense mutation, p.L38P, was identified in an index patient with patent ductus arteriosus (PDA) and ventricular septal defect (VSD). Genetic scan of the mutation carrier's family members available showed that the mutation was present in all affected family members but absent in unaffected family members. Analysis of the proband's pedigree revealed that the mutation co-segregated with PDA, which was transmitted as an autosomal dominant trait with complete penetrance. The mutation changed the amino acid that was completely conserved evolutionarily, and did not exist in 300 unrelated, ethnically-matched healthy individuals used as controls. Functional deciphers by using a dual-luciferase reporter assay system unveiled that the mutant MEF2C protein had a significantly reduced transcriptional activity. Furthermore, the mutation significantly diminished the synergistic activation between MEF2C and GATA4, another cardiac core transcription factor that has been causally linked to CHD. In conclusion, this is the first report on the association of a MEF2C loss-of-function mutation with an increased vulnerability to CHD in humans, which provides novel insight into the molecular mechanisms underlying CHD, implying potential implications for early diagnosis and timely prophylaxis of CHD.

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Expression of MEF2 Genes during Human Cardiac Development.

Cited by 26 publications

References 14 publications

Genome-wide discovery of human heart enhancers

Genome-wide discovery of human heart enhancers

Regulation of cardiomyocyte maturation during critical perinatal window

MEF2C loss-of-function mutation contributes to congenital heart defects

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