Understanding promoter diversity across vertebrates

Gene regulatory processes are integral to ensuring the right genes are expressed in the right place at the right time. However, despite their clear role in human health, regulatory elements, which often fall outside of protein-coding regions, have historically been relatively understudied, and consequently identifying disease-causing variation in them remains a challenge PMID:40229884.

Promoters are sequences of DNA that are fundamental to transcription initiation. Broadly split into two groups by content (CpG island and TATA box promoters) they house elements key to recruitment of the basal transcriptional machinery and modulate the way genes are transcribed. We recently showed that a new epigenetic mark - acetylation of histone H3 at lysine 115, contributes to nucleosome destabilization and represents a potential biomarker for important regulatory elements. This mark is only found at CpG island, and not TATA box promoters. PMID: 41778583.

It is puzzling therefore that the promoter type (CpG vs TATA) associated with homologs of the same genes can differ significantly between species. This raises questions about the evolutionary histories of promoters, their constituent elements, and the existence of alternative mechanisms that allow these genes to buffer against transcriptional noise.

This project will use large, multi-species data to map promoter diversity in human homologs across vertebrates. You will develop novel bioinformatic strategies and use state of the art comparative genomics methods to explore promoter evolution, identify key elements involved in their diversity, and provide important insights into their contributions to gene regulation.

In doing so this will enable us to pinpoint critical promoter elements within, and between species, and identify genes that are more, or less tolerant to changes in promoter composition. This will provide foundational knowledge to improve our ability to detect disease-causing variants in these important non-coding elements and inform the discourse around promoters as novel therapeutic targets.