PhD Student The University of Hong Kong, Hong Kong
Abstract:
Background: Most human protein-coding genes are regulated by multiple promoters, highlighting the importance of promoter selection in gene expression. However, the role of alternative promoters during embryonic development across species remains largely unexplored.
Methods: To investigate alternative promoter usage during development, we analyzed promoter activity in various organs across seven species using the ProActiv tool. We identified promoters that exhibited significant changes in activity at different developmental time points, despite overall gene expression levels remaining unchanged. We further explored the transcription factors (TFs) driving these changes using UniBind and ChIP-seq data.
Results: We detected alternative promoters in multiple organs and species, with the number of genes exhibiting promoter activity changes increasing over developmental time in mouse liver. For example, the gene Lsp1 showed minor changes in overall expression but significant alterations in isoform expression due to alternative promoter usage. We identified key TFs, including NR1D1, ESR1, FOXA2, and RXRA, associated with upregulated promoters in mouse liver at 9 weeks post-birth (9wpb). The canonical motifs for FOXA2 and HNF4A were significantly enriched in upregulated promoters compared to background promoters (p-values ranging from 0.01 to < 0.001). ChIP-seq data showed higher overlap of FOXA2 peaks with upregulated promoters. In contrast, downregulated promoters lacked overlap with these TF peaks. Additionally, promoter activity assessments in wild-type and HNF4A-knockout liver samples revealed that while overall promoter activity increased in the knockout samples, the activity of specific upregulated promoters decreased.
Conclusion: Our study provides insights into the dynamic regulation of alternative promoters during mammalian organ development, highlighting the critical role of specific TFs in driving promoter activity changes. Future work should focus on further elucidating the mechanisms underlying these observations and exploring their functional implications in development and disease.
