Exploring the roles of conserved context-dependent cis-regulatory elements (cdCREs) in multicellularity, human health and disease.

Human development and health depend on the precise expression of relevant genes in specific cells, at precise times and in response to appropriate stimuli. This is known as context-dependent gene regulation and relies on the activities of a diverse 'zoo' of DNA elements within the genome that are collectively called context-dependent cis-regulatory elements (cdCREs). cdCREs may comprise as much as 10% of the genome and include better-known sequences such as enhancers, silencers and promoters that form the basis of complex multicellularity. Diverse vertebrate body plans not only share considerable phenotypic similarities but also cell types, the genes they express and, in a growing number of cases, in the function and nucleotide sequence of cdCREs. The current review will critically evaluate current methodologies to identify cdCREs and re-evaluate a place for comparative genomics amongst them. We will also explore the function of cdCREs and discuss methods of analysing their function in disease-associated physiologies and behaviours using in vivo models such as CRISPR-generated GA mouse lines. Finally, we will study the effects of epigenetic mechanisms such as DNA methylation on cdCRE activity and examine how genetics and epigenetics can interact to alter disease susceptibility. Given that genome-wide association studies (GWAS) suggest that 95% of disease-associated genomic variation reside in the 98% of the less understood noncoding genome, the need to understand the role of conserved vertebrate cdCREs in development and health in vivo has never been more pressing.