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The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an AT Motif-Driven Axis.

Parsons MJ, Brancaccio M, Sethi S, Maywood ES, Satija R, Edwards JK, Jagannath A, Couch Y, Finelli MJ, Smyllie NJ, Esapa C, Butler R, Barnard AR, Chesham JE, Saito S, Joynson G, Wells S, Foster RG, Oliver PL, Simon MM, Mallon AM, Hastings MH, Nolan PM - Cell (2015)

Bottom Line: Using RNA sequencing, we found minimal effects on core clock genes in Zfhx3(Sci/+) SCN, whereas the expression of neuropeptides critical for SCN intercellular signaling was significantly disturbed.Lentiviral transduction of SCN slices showed that the ZFHX3-mediated activation of AT motifs is circadian, with decreased amplitude and robustness of these oscillations in Zfhx3(Sci/+) SCN slices.In conclusion, by cloning Zfhx3(Sci), we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms.

View Article: PubMed Central - PubMed

Affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.

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Functional Modules Determined for Zfhx3Sci/+ SCN Expression(A) The consensus AT motif derived from published AT sequences of genes regulated by Zfhx3 (see Experimental Procedures).(B) A protein-protein interaction network representing the differentially expressed transcripts in Zfhx3Sci/+ SCN for all modules. Clustering analysis compartmentalized the network into modules of densely connected nodes. Positive identification of the consensus AT motif within the promoter regions of these transcripts is denoted by yellow shading. Node shape denotes the significance at different time points. Module 1 contains the greatest number of downregulated genes, AT motifs, and connectivity compared to other modules.(C) The top nine overrepresented GO terms for genes in module 1. The number downregulated (gray) and number upregulated (blue) are listed for each term. Neuropeptide and signaling activities are among the top functional roles of the genes in this module.See also Tables S3 and S4.
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fig3: Functional Modules Determined for Zfhx3Sci/+ SCN Expression(A) The consensus AT motif derived from published AT sequences of genes regulated by Zfhx3 (see Experimental Procedures).(B) A protein-protein interaction network representing the differentially expressed transcripts in Zfhx3Sci/+ SCN for all modules. Clustering analysis compartmentalized the network into modules of densely connected nodes. Positive identification of the consensus AT motif within the promoter regions of these transcripts is denoted by yellow shading. Node shape denotes the significance at different time points. Module 1 contains the greatest number of downregulated genes, AT motifs, and connectivity compared to other modules.(C) The top nine overrepresented GO terms for genes in module 1. The number downregulated (gray) and number upregulated (blue) are listed for each term. Neuropeptide and signaling activities are among the top functional roles of the genes in this module.See also Tables S3 and S4.

Mentions: The limited work investigating this transcription factor to date has revealed a number of its gene targets (Berry et al., 2001; Mori et al., 2007; Qi et al., 2008; Yasuda et al., 1994). Using a phylogenetic shadowing-based approach (Bailey and Elkan, 1994), we constructed a motif-binding model for ZFHX3 based on the characterized binding motifs in these promoters (see Supplemental Experimental Procedures for more details) (Figure 3A). We then investigated whether this consensus AT motif, as well as the canonical circadian E-box, D-box, and RRE, were present in sequences upstream of the genes differentially regulated by ZFHX3 (Pscan score > 0.88). We found that the AT motif was present in promoter sequences from 39% of the differentially expressed genes, while the circadian motifs E-box, D-box, and RRE were absent (Figure 3B).


The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an AT Motif-Driven Axis.

Parsons MJ, Brancaccio M, Sethi S, Maywood ES, Satija R, Edwards JK, Jagannath A, Couch Y, Finelli MJ, Smyllie NJ, Esapa C, Butler R, Barnard AR, Chesham JE, Saito S, Joynson G, Wells S, Foster RG, Oliver PL, Simon MM, Mallon AM, Hastings MH, Nolan PM - Cell (2015)

Functional Modules Determined for Zfhx3Sci/+ SCN Expression(A) The consensus AT motif derived from published AT sequences of genes regulated by Zfhx3 (see Experimental Procedures).(B) A protein-protein interaction network representing the differentially expressed transcripts in Zfhx3Sci/+ SCN for all modules. Clustering analysis compartmentalized the network into modules of densely connected nodes. Positive identification of the consensus AT motif within the promoter regions of these transcripts is denoted by yellow shading. Node shape denotes the significance at different time points. Module 1 contains the greatest number of downregulated genes, AT motifs, and connectivity compared to other modules.(C) The top nine overrepresented GO terms for genes in module 1. The number downregulated (gray) and number upregulated (blue) are listed for each term. Neuropeptide and signaling activities are among the top functional roles of the genes in this module.See also Tables S3 and S4.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4537516&req=5

fig3: Functional Modules Determined for Zfhx3Sci/+ SCN Expression(A) The consensus AT motif derived from published AT sequences of genes regulated by Zfhx3 (see Experimental Procedures).(B) A protein-protein interaction network representing the differentially expressed transcripts in Zfhx3Sci/+ SCN for all modules. Clustering analysis compartmentalized the network into modules of densely connected nodes. Positive identification of the consensus AT motif within the promoter regions of these transcripts is denoted by yellow shading. Node shape denotes the significance at different time points. Module 1 contains the greatest number of downregulated genes, AT motifs, and connectivity compared to other modules.(C) The top nine overrepresented GO terms for genes in module 1. The number downregulated (gray) and number upregulated (blue) are listed for each term. Neuropeptide and signaling activities are among the top functional roles of the genes in this module.See also Tables S3 and S4.
Mentions: The limited work investigating this transcription factor to date has revealed a number of its gene targets (Berry et al., 2001; Mori et al., 2007; Qi et al., 2008; Yasuda et al., 1994). Using a phylogenetic shadowing-based approach (Bailey and Elkan, 1994), we constructed a motif-binding model for ZFHX3 based on the characterized binding motifs in these promoters (see Supplemental Experimental Procedures for more details) (Figure 3A). We then investigated whether this consensus AT motif, as well as the canonical circadian E-box, D-box, and RRE, were present in sequences upstream of the genes differentially regulated by ZFHX3 (Pscan score > 0.88). We found that the AT motif was present in promoter sequences from 39% of the differentially expressed genes, while the circadian motifs E-box, D-box, and RRE were absent (Figure 3B).

Bottom Line: Using RNA sequencing, we found minimal effects on core clock genes in Zfhx3(Sci/+) SCN, whereas the expression of neuropeptides critical for SCN intercellular signaling was significantly disturbed.Lentiviral transduction of SCN slices showed that the ZFHX3-mediated activation of AT motifs is circadian, with decreased amplitude and robustness of these oscillations in Zfhx3(Sci/+) SCN slices.In conclusion, by cloning Zfhx3(Sci), we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms.

View Article: PubMed Central - PubMed

Affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.

Show MeSH