The Drosophila Transcription Factors Tinman and Pannier Activate and Collaborate with Myocyte Enhancer Factor-2 to Promote Heart Cell Fate

Lovato, TyAnna L.; Sensibaugh, Cheryl A.; Swingle, Kirstie L.; Martinez, Melody M.; Cripps, Richard M.

doi:10.1371/journal.pone.0132965

Cited by 13 publications

(13 citation statements)

References 55 publications

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“…The presence in the network of a hub around pnr , which encodes a transcription factor involved in cardiogenesis [ 85 ], is of interest because it suggests an undocumented contribution of Gro to the regulation of cardiac development. This connection is consistent with our finding that Gro binding sites are enriched for Tin binding motifs, since Tin works together with Pnr to regulate cardiac gene expression [ 86 – 88 ]. Finally, the network captures multiple Dorsal repression targets such as dpp [ 64 ], tolloid ( tld ) [ 89 ] and short gastrulation ( sog ) [ 90 , 91 ], consistent with the fact that Dorsal represses via Gro [ 47 ].…”

Section: Discussionsupporting

confidence: 92%

Mechanisms of Groucho-mediated repression revealed by genome-wide analysis of Groucho binding and activity

et al. 2017

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BackgroundThe transcriptional corepressor Groucho (Gro) is required for the function of many developmentally regulated DNA binding repressors, thus helping to define the gene expression profile of each cell during development. The ability of Gro to repress transcription at a distance together with its ability to oligomerize and bind to histones has led to the suggestion that Gro may spread along chromatin. However, much is unknown about the mechanism of Gro-mediated repression and about the dynamics of Gro targeting.ResultsOur chromatin immunoprecipitation sequencing analysis of temporally staged Drosophila embryos shows that Gro binds in a highly dynamic manner primarily to clusters of discrete (<1 kb) segments. Consistent with the idea that Gro may facilitate communication between silencers and promoters, Gro binding is enriched at both cis-regulatory modules, as well as within the promotors of potential target genes. While this Gro-recruitment is required for repression, our data show that it is not sufficient for repression. Integration of Gro binding data with transcriptomic analysis suggests that, contrary to what has been observed for another Gro family member, Drosophila Gro is probably a dedicated repressor. This analysis also allows us to define a set of high confidence Gro repression targets. Using publically available data regarding the physical and genetic interactions between these targets, we are able to place them in the regulatory network controlling development. Through analysis of chromatin associated pre-mRNA levels at these targets, we find that genes regulated by Gro in the embryo are enriched for characteristics of promoter proximal paused RNA polymerase II.ConclusionsOur findings are inconsistent with a one-dimensional spreading model for long-range repression and suggest that Gro-mediated repression must be regulated at a post-recruitment step. They also show that Gro is likely a dedicated repressor that sits at a prominent highly interconnected regulatory hub in the developmental network. Furthermore, our findings suggest a role for RNA polymerase II pausing in Gro-mediated repression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3589-6) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Mechanisms of Groucho-mediated repression revealed by genome-wide analysis of Groucho binding and activity

et al. 2017

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“…Recent studies have now implicated D-Mef2 in the regulation of cardiac cell fate. D-Mef2 was shown to collaborate with the cardiac transcription factors Tinman (Nkx2.5) and Pannier (GATA4) to expand the cardiogenic pool of cells from mesoderm [ 14 ].…”

Section: Cardiac Development and Differentiation—model Organismsmentioning

confidence: 99%

The Function of the MEF2 Family of Transcription Factors in Cardiac Development, Cardiogenomics, and Direct Reprogramming

Desjardins

Naya

2016

JCDD

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Proper formation of the mammalian heart requires precise spatiotemporal transcriptional regulation of gene programs in cardiomyocytes. Sophisticated regulatory networks have evolved to not only integrate the activities of distinct transcription factors to control tissue-specific gene programs but also, in many instances, to incorporate multiple members within these transcription factor families to ensure accuracy and specificity in the system. Unsurprisingly, perturbations in this elaborate transcriptional circuitry can lead to severe cardiac abnormalities. Myocyte enhancer factor–2 (MEF2) transcription factor belongs to the evolutionarily conserved cardiac gene regulatory network. Given its central role in muscle gene regulation and its evolutionary conservation, MEF2 is considered one of only a few core cardiac transcription factors. In addition to its firmly established role as a differentiation factor, MEF2 regulates wide variety of, sometimes antagonistic, cellular processes such as cell survival and death. Vertebrate genomes encode multiple MEF2 family members thereby expanding the transcriptional potential of this core transcription factor in the heart. This review highlights the requirement of the MEF2 family and their orthologs in cardiac development in diverse animal model systems. Furthermore, we describe the recently characterized role of MEF2 in direct reprogramming and genome-wide cardiomyocyte gene regulation. A thorough understanding of the regulatory functions of the MEF2 family in cardiac development and cardiogenomics is required in order to develop effective therapeutic strategies to repair the diseased heart.

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“…This enhancer contains three E-box binding sites for Twist in addition to an Even-skipped homeodomain binding sequence ( Figure 1A). This enhancer is responsive to Twist early in development but is not responsive to Twist after stage 10 (Yin et al 1997;Jin et al 2013;Lovato et al 2015) ( Figure 1A).…”

Section: A Double Interaction Screen Identifies Several Context-depenmentioning

confidence: 95%

A screen for Twist-interacting proteins identifies Twinstar as a regulator of muscle development during embryogenesis

Balakrishnan

Howard

et al. 2021

Preprint

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Myogenesis in Drosophila relies on the activity of the transcription factor Twist during several key events of mesoderm differentiation. To identify the mechanism(s) by which Twist establishes a unique gene expression profile in specific spatial and temporal locales, we employed a yeast-based double interaction screen to discover new Twist-interacting proteins (TIPs) at the myocyte enhancer factor 2 (mef2) and tinman (tinB) myogenic enhancers. We identified a number of proteins that interacted with Twist at one or both enhancers, and whose interactions with Twist and roles in muscle development were previously unknown. Through genetic interaction studies, we find that Twinstar (Tsr), and its regulators are required for muscle formation. Loss of function and null mutations in tsr and its regulators result in missing and/or misattached muscles. Our data suggest that the yeast double interaction screen is a worthy approach to investigate spatial-temporal mechanisms of transcriptional regulation in muscle and in other tissues.

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The Drosophila Transcription Factors Tinman and Pannier Activate and Collaborate with Myocyte Enhancer Factor-2 to Promote Heart Cell Fate

Cited by 13 publications

References 55 publications

Mechanisms of Groucho-mediated repression revealed by genome-wide analysis of Groucho binding and activity

Mechanisms of Groucho-mediated repression revealed by genome-wide analysis of Groucho binding and activity

The Function of the MEF2 Family of Transcription Factors in Cardiac Development, Cardiogenomics, and Direct Reprogramming

A screen for Twist-interacting proteins identifies Twinstar as a regulator of muscle development during embryogenesis

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