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Summarizing internal dynamics boosts differential analysis and functional interpretation of super enhancers
Authors:Xiang Liu  Bo Zhao  Timothy I Shaw  Brooke L Fridley  Derek R Duckett  Aik Choon Tan  Mingxiang Teng
Institution:Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA;Division of Infectious Disease, Department of Medicine, Brigham and Women''s Hospital and Harvard Medical School, Boston, MA 02115, USA;Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Abstract:Super enhancers (SEs) are broad enhancer domains usually containing multiple constituent enhancers that hold elevated activities in gene regulation. Disruption in one or more constituent enhancers causes aberrant SE activities that lead to gene dysregulation in diseases. To quantify SE aberrations, differential analysis is performed to compare SE activities between cell conditions. The state-of-art strategy in estimating differential SEs relies on overall activities and neglect the changes in length and structure of SEs. Here, we propose a novel computational method to identify differential SEs by weighting the combinatorial effects of constituent-enhancer activities and locations (i.e. internal dynamics). In addition to overall activity changes, our method identified four novel classes of differential SEs with distinct enhancer structural alterations. We demonstrate that these structure alterations hold distinct regulatory impact, such as regulating different number of genes and modulating gene expression with different strengths, highlighting the differentiated regulatory roles of these unexplored SE features. When compared to the existing method, our method showed improved identification of differential SEs that were linked to better discernment of cell-type-specific SE activity and functional interpretation.
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