Regulation of Notch Signalling

Analysis of aligned/conserved TFBS in the first 1000bp of the Notch1 promoter using rvista 2.0.

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Downstream targets of Notch signalling

There are 3 Growth arrest and DNA damage inducible 45 (Gadd45) genes, alpha (a), beta (b), gamma (g). From microarray studies Gadd45b is induced by both hypoxia and Notch signalling, Gadd45g is repressed by notch signalling and there is no change of Gadd45a in either condition. I have compared the promoter sequences of each to find conserved HIF-1alpha and/or CSL transcription factor binding sites to determine a mechanism for this altered regulation.

I have taken 10kb of promoter sequence from each gene for both mouse and human from UCSC

These sequences were then aligned using rvista 2.0 and further analysed for aligned/conserved HIF-1 alpha and CSL transcription factor binding sites.

The Gadd45a promoter did not contain any conserved HIF-1alpha or CSL binding sites - consistent with no regulation by either....

The Gadd45b promoter contained 2 conserved CSL binding sites and one conserved HIF-1alpha binding site - consitent with regulation by both notch and hypoxia....

The Gadd45g promoter contained 1 conserved HIF-1alpha binding site though no CSL binding site - seemingly no hypoxic regulation?? mechanism of Notch negative regulation??

However, unlike Gadd45b which has no conserved HIF-1alpha or CSL downstream, Gadd45g contains sites thus this CSL binding site may be involved in the negative regulation??

Conclusion - differences in distribution of HIF and CSL biding sites in promoter sequences may explain differentiatial regulation of target genes, further investigation required.