Periodic Reporting for period 4 - SCORA (A systematic characterization of human regulatory architectures and their determinants of regulatory activity)
Reporting period: 2019-11-01 to 2021-01-31
The major challenges in the field and our main objectives are: 1) how to identify regulatory elements in the genome; 2) how to accurately determine the activity of a regulatory element; 3) to gain a better understanding of the functions of individual regulatory elements; and 4) to better understand function, interplay and regulatory output of multiple regulatory elements connected in larger regulatory architectures.
A better understanding of spatio-temporally restricted activities by enhancers and the interplay of regulatory elements in regulatory architectures will most likely lead to a better understanding of why and when dysregulation of transcription leads to disease.
Transcriptional regulation is tightly coupled with chromosomal positioning and three-dimensional chromatin architecture. However, it has been unclear what proportion of transcriptional activity is reflecting such organisation, how much can be informed by RNA expression alone, and how this organisation impacts disease. To this end, we have developed a transcriptional decomposition approach to separate the proportion of expression associated with genome organisation from independent effects not directly related to genomic positioning. We have shown that positionally attributable expression accounts for a considerable proportion of total levels and is highly informative of topological associating domain activities and organisation, revealing boundaries and chromatin compartments. Furthermore, using expression data alone we can accurately predict individual enhancer-promoter interactions, drawing features from expression strength, stabilities, insulation and distance. We have further characterised commonalities and differences across predictions in 76 human cell types, which allowed us to observe extensive sharing of domains, yet highly cell-type specific enhancer-promoter interactions and strong enrichments in relevant trait-associated variants. We have further applied this approach to investigate individual variation in regulatory activities and their associated chromatin architectures across a panel of genotyped human individuals. Our work demonstrates a close relationship between transcription and chromatin architecture, presenting a novel strategy and an unprecedented resource for investigating regulatory organisations and interpretations of disease associated genetic variants across cell types.
We have further investigated the role of regulatory elements in DNA replication and cell fates and answered an outstanding question in the field: how maintenance of chromatin epigenetic marks (histone modifications) are maintained during replication. Our work reveals regulatory elements as sites prone to sister chromatid histone modification asymmetry.
Our transcriptional decomposition approach is a completely novel strategy beyond state of the art, which has allowed us to generate an unprecedented resource for investigating regulatory organisations and interpretations of disease associated genetic variants across cell types. We expect that this approach will allow us to further investigate the architectures transcriptional regulatory elements and their regulatory landscapes, and to interpret chromatin architectures associated with disease. We have utilised this strategy to investigate healthy human individual variation to better assess the impact of genetic variants on individual regulatory elements and their function in larger chromatin architectures and make predictions on when and why genetic variants lead to disease.