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ERC

SCORA Report Summary

Project ID: 638273
Funded under: H2020-EU.1.1.

Periodic Reporting for period 1 - SCORA (A systematic characterization of human regulatory architectures and their determinants of regulatory activity)

Reporting period: 2015-05-01 to 2016-10-31

Summary of the context and overall objectives of the project

Gene transcription is tightly controlled in time and space by events at regulatory elements partly at gene promoters and at distal regulatory elements called enhancers. Regulatory activity at enhancers is the main determinant of cell type specific gene expression and context-dependent cellular activities.

Our main objectives and major challenges in the field 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 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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Genome-wide profiling of regulatory elements is often guided by the known properties of active regulatory elements. Enhancers and promoters need to be in open chromatin and carry the correct DNA sequences to be accessible by and able to bind transcription factor proteins. These proteins must also exist in sufficient amounts in the cell. State-of-the-art methods also rely on differential post-translational modifications (PTMs) of histone proteins that have been suggested to discern enhancers from gene promoters. Search for certain histone modifications in the genome distal to gene promoters is therefore often performed to predict enhancer loci and their activities across assayed cell types.

In our work, we have carefully profiled transcription initiation events at regulatory elements and the biogenesis and fate of produced RNAs. Our work shows that not only gene promoters but also enhancers initiate transcription, indicating promoter activity of enhancers. In addition, several studies have shown enhancer activities of bona fide gene promoters blurring their distinction. We have found that both enhancers and promoters initiate bidirectional transcription in a divergent manner and that the abundance and fate of produced RNAs rely not on the core regulatory regions themselves but on the flanking DNA surrounding each regulatory element. In addition, the abundances of produced RNAs reflect their proximal histone modifications. Based on these observations we conclude that histone modifications therefore should not guide the interpretation of function for a regulatory element. Rather, our results suggest that enhancers and gene promoters have many properties in common. We suggest regulatory elements to be considered to have a unified architecture and that the function of each regulatory element (enhancer or promoter activity) may be context specific.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

A unified architecture of regulatory elements has major impacts on the way we perceive and study transcriptional regulation and transcriptional dysregulation in disease. By considering enhancer activity of gene promoters and promoter activities of gene-distal enhancers as an indication of enhancer activity the community will likely gain a better understanding of the activities that dictates cell-specific functions.
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