Journal
MOLECULAR SYSTEMS BIOLOGY
Volume 18, Issue 2, Pages -Publisher
WILEY
DOI: 10.15252/msb.20209816
Keywords
gene expression; modeling; motif search; mutational analysis; promoter
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Funding
- German Federal Ministry of Education and Research (BMBF: ebio-Innovationswettbewerb Systembiologie)
- German Research Foundation (DFG:large equipment grant for automated system Project) [213249687, SFB 1064]
- Center for Integrated Protein Science (CIPSM)
- Graduate School for Quantitative Biosciences Munich (QBM)
- Humboldt-Foundation (Alexander von Humboldt-Professorship)
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Through a comprehensive structure-function analysis, it was found that the activity of the core promoter is influenced by different types of mutations, including knockout of individual sequence motifs and motif combinations, variations of motif strength, nucleosome positioning, and flanking sequences. A linear combination of the individual motif features largely explains the combinatorial effects on core promoter activity.
The core promoter plays a central role in setting metazoan gene expression levels, but how exactly it computes expression remains poorly understood. To dissect its function, we carried out a comprehensive structure-function analysis in Drosophila. First, we performed a genome-wide bioinformatic analysis, providing an improved picture of the sequence motifs architecture. We then measured synthetic promoters' activities of similar to 3,000 mutational variants with and without an external stimulus (hormonal activation), at large scale and with high accuracy using robotics and a dual luciferase reporter assay. We observed a strong impact on activity of the different types of mutations, including knockout of individual sequence motifs and motif combinations, variations of motif strength, nucleosome positioning, and flanking sequences. A linear combination of the individual motif features largely accounts for the combinatorial effects on core promoter activity. These findings shed new light on the quantitative assessment of gene expression in metazoans.
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