Studying novel histone acylations in the regulation of gene expression – CHROMACYL

In the nucleus of eukaryotes, DNA wraps around octamers of histone proteins to form a structure called chromatin. Dynamic post-translational modifications (PTMs) of histones are essential to regulate gene expression, in particular during development and cell differentiation. Acetylation of histone lysines was discovered more than 50 years ago; this PTM and its impact on chromatin accessibility and gene transcription have been thoroughly characterized. Over the past decade, however, a wealth of other lysine acylations resembling acetylation but varying in length and hydrophobicity has been described; yet, their probable specific functions compared to acetylation remain largely unexplored. One particular residue, lysine 27 of histone H3 (H3K27) has a central role in the control of gene expression: it either activates or represses transcription when modified by acetylation (ac) or trimethylation, respectively. Importantly, abnormal regulation of this histone mark can lead to developmental defects and cancers. H3K27ac is known to mark active transcription when localized at gene promoter regions or when present at distant genomic regions, called distal enhancers, that regulate gene expression via long-range interactions. We and others have identified other acylated forms of H3K27 which can be of similar abundance to the acetylated form, yet the roles of which remain poorly characterized.
The present proposal aims to thoroughly study these novel histone marks to improve our understanding of their involvement in the regulation of gene expression and to compare them to acetylation-dependent mechanisms.
Our objectives are to determine their dynamics and genomic distributions during cell differentiation, their link with gene expression both locally (at gene promoters) and distantly (at enhancers), and their specific protein binders. To address these questions, three academic research groups will combine their complementary expertise in proteomics, genomics and bioinformatics to perform cutting-edge quantitative omics analyses, protein complex purification and functional assays. Part of the proposal is based on data they previously acquired and published together, which demonstrated their ability to integrate proteomics and genomics data to compare the respective effects of lysine acylation and acetylation, including possible synergistic effects, on gene expression. The chosen biological context is the differentiation of mouse male germ cells, i.e. spermatogenesis, since many recently discovered histone lysine acylations have been identified and found to be abundant during this process, and because we have an expert knowledge of the collection of male germ cells at different stages. Spermatogenesis is also particularly relevant since it is one of the most dynamic differentiation processes in terms of gene expression and chromatin remodeling.
The data we will generate will be of direct interest to the fields of “proteomics” and “genomics/chromatin” as well as “reproductive biology”. It is worth noting that the abundance of acyl modifications depends on the available acyl-CoA metabolites. A growing body of evidence indicates that the environment, such as diet, exposure to chemicals, toxins, etc., which can influence metabolite availability, can affect male fertility and progeny’s health. Our work could therefore have clinical relevance in the long term.
Beside this context, a better characterization and comprehension of the mechanisms regulating gene expression may be relevant to other diseases which are caused by (epi)genetic deregulations and are often treated with epigenetic drugs, such as cancers.