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Analysis of a gene regulatory cascade mediating circadian rhythm in zebrafish.

Li Y, Li G, Wang H, Du J, Yan J - PLoS Comput. Biol. (2013)

Bottom Line: Our computational analysis of the circadian gene regulatory network revealed several transcription factors (TFs) involved in diverse aspects of circadian physiology through transcriptional cascade.Of these, microphthalmia-associated transcription factor a (mitfa), a dark-induced TF, mediates a circadian rhythm of melanin synthesis, which may be involved in zebrafish's adaptation to daily light cycling.Our study describes a systematic method to discover previously unidentified TFs involved in circadian physiology in complex organisms.

View Article: PubMed Central - PubMed

Affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT
In the study of circadian rhythms, it has been a puzzle how a limited number of circadian clock genes can control diverse aspects of physiology. Here we investigate circadian gene expression genome-wide using larval zebrafish as a model system. We made use of a spatial gene expression atlas to investigate the expression of circadian genes in various tissues and cell types. Comparison of genome-wide circadian gene expression data between zebrafish and mouse revealed a nearly anti-phase relationship and allowed us to detect novel evolutionarily conserved circadian genes in vertebrates. We identified three groups of zebrafish genes with distinct responses to light entrainment: fast light-induced genes, slow light-induced genes, and dark-induced genes. Our computational analysis of the circadian gene regulatory network revealed several transcription factors (TFs) involved in diverse aspects of circadian physiology through transcriptional cascade. Of these, microphthalmia-associated transcription factor a (mitfa), a dark-induced TF, mediates a circadian rhythm of melanin synthesis, which may be involved in zebrafish's adaptation to daily light cycling. Our study describes a systematic method to discover previously unidentified TFs involved in circadian physiology in complex organisms.

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Related in: MedlinePlus

Gene regulatory network of circadian oscillating TFs and their motifs.Predicted regulatory events between all circadian oscillating TFs are connected by TF-motif and motif-target relationships. Circles represent circadian oscillating TFs and boxes represent cis-regulatory elements characterized by TF DNA-binding motifs. Arrowed edges represent motif-target relationships and circle-capped edges represent TF-motif relationships. The shaded areas represent the tissues or cell types where specific motifs are enriched.
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pcbi-1002940-g004: Gene regulatory network of circadian oscillating TFs and their motifs.Predicted regulatory events between all circadian oscillating TFs are connected by TF-motif and motif-target relationships. Circles represent circadian oscillating TFs and boxes represent cis-regulatory elements characterized by TF DNA-binding motifs. Arrowed edges represent motif-target relationships and circle-capped edges represent TF-motif relationships. The shaded areas represent the tissues or cell types where specific motifs are enriched.

Mentions: From this data we constructed a gene regulatory network of circadian TFs to depict how they regulate each other and how circadian oscillating genes in specific tissues are regulated (Figure 4). In this network, circadian-oscillating TFs were grouped by TF-motif and motif-target relationships, where TF-motif relationships were obtained from the TRANSFAC database, while motif-target relationships were predicted through promoter analysis in our comparative genomics pipeline (see Materials and Methods). This approach successfully recapitulated the known core transcriptional feedback loop in circadian clock regulation: E-BOX binding TFs arntl/clock regulate nr1d1 and rorab, which in turn regulate arntl through RRE. Most circadian TFs are directly regulated by the circadian clock via known circadian cis-elements. For example, mef2a, hsf2, tef, bhlhe40/41 (dec1/2), tfcp2l1, foxo3b, and ahr1a via E-BOX, myog, nfil3, atf4b1 via RRE and yy1a and smad3a via D-BOX. The remaining TFs are indirect targets of core circadian TFs via further transcriptional cascades. For example, maf and mitfa are regulated via cAMP responsive element (CRE), hnf1a and creb3l3 via the cis-element of the PPAR family TFs and pax6a and nr3c1 via the cis-element of foxo3b.


Analysis of a gene regulatory cascade mediating circadian rhythm in zebrafish.

Li Y, Li G, Wang H, Du J, Yan J - PLoS Comput. Biol. (2013)

Gene regulatory network of circadian oscillating TFs and their motifs.Predicted regulatory events between all circadian oscillating TFs are connected by TF-motif and motif-target relationships. Circles represent circadian oscillating TFs and boxes represent cis-regulatory elements characterized by TF DNA-binding motifs. Arrowed edges represent motif-target relationships and circle-capped edges represent TF-motif relationships. The shaded areas represent the tissues or cell types where specific motifs are enriched.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585402&req=5

pcbi-1002940-g004: Gene regulatory network of circadian oscillating TFs and their motifs.Predicted regulatory events between all circadian oscillating TFs are connected by TF-motif and motif-target relationships. Circles represent circadian oscillating TFs and boxes represent cis-regulatory elements characterized by TF DNA-binding motifs. Arrowed edges represent motif-target relationships and circle-capped edges represent TF-motif relationships. The shaded areas represent the tissues or cell types where specific motifs are enriched.
Mentions: From this data we constructed a gene regulatory network of circadian TFs to depict how they regulate each other and how circadian oscillating genes in specific tissues are regulated (Figure 4). In this network, circadian-oscillating TFs were grouped by TF-motif and motif-target relationships, where TF-motif relationships were obtained from the TRANSFAC database, while motif-target relationships were predicted through promoter analysis in our comparative genomics pipeline (see Materials and Methods). This approach successfully recapitulated the known core transcriptional feedback loop in circadian clock regulation: E-BOX binding TFs arntl/clock regulate nr1d1 and rorab, which in turn regulate arntl through RRE. Most circadian TFs are directly regulated by the circadian clock via known circadian cis-elements. For example, mef2a, hsf2, tef, bhlhe40/41 (dec1/2), tfcp2l1, foxo3b, and ahr1a via E-BOX, myog, nfil3, atf4b1 via RRE and yy1a and smad3a via D-BOX. The remaining TFs are indirect targets of core circadian TFs via further transcriptional cascades. For example, maf and mitfa are regulated via cAMP responsive element (CRE), hnf1a and creb3l3 via the cis-element of the PPAR family TFs and pax6a and nr3c1 via the cis-element of foxo3b.

Bottom Line: Our computational analysis of the circadian gene regulatory network revealed several transcription factors (TFs) involved in diverse aspects of circadian physiology through transcriptional cascade.Of these, microphthalmia-associated transcription factor a (mitfa), a dark-induced TF, mediates a circadian rhythm of melanin synthesis, which may be involved in zebrafish's adaptation to daily light cycling.Our study describes a systematic method to discover previously unidentified TFs involved in circadian physiology in complex organisms.

View Article: PubMed Central - PubMed

Affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT
In the study of circadian rhythms, it has been a puzzle how a limited number of circadian clock genes can control diverse aspects of physiology. Here we investigate circadian gene expression genome-wide using larval zebrafish as a model system. We made use of a spatial gene expression atlas to investigate the expression of circadian genes in various tissues and cell types. Comparison of genome-wide circadian gene expression data between zebrafish and mouse revealed a nearly anti-phase relationship and allowed us to detect novel evolutionarily conserved circadian genes in vertebrates. We identified three groups of zebrafish genes with distinct responses to light entrainment: fast light-induced genes, slow light-induced genes, and dark-induced genes. Our computational analysis of the circadian gene regulatory network revealed several transcription factors (TFs) involved in diverse aspects of circadian physiology through transcriptional cascade. Of these, microphthalmia-associated transcription factor a (mitfa), a dark-induced TF, mediates a circadian rhythm of melanin synthesis, which may be involved in zebrafish's adaptation to daily light cycling. Our study describes a systematic method to discover previously unidentified TFs involved in circadian physiology in complex organisms.

Show MeSH
Related in: MedlinePlus