Henriette Miko1,2, Yunjiang Qiu3,4, Bjoern Gaertner5,6, Maike Sander5,6, Uwe Ohler7,8,9. 1. Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, 13125, Berlin, Germany. 2. Department of Computer Science, Humboldt-Universität zu Berlin, 10117, Berlin, Germany. 3. Ludwig Institute for Cancer Research, La Jolla, CA, 92093, USA. 4. Bioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, 92093, USA. 5. Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA. 6. Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, 92093, USA. 7. Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, 13125, Berlin, Germany. uwe.ohler@mdc-berlin.de. 8. Department of Computer Science, Humboldt-Universität zu Berlin, 10117, Berlin, Germany. uwe.ohler@mdc-berlin.de. 9. Department of Biology, Humboldt-Universität zu Berlin, 10117, Berlin, Germany. uwe.ohler@mdc-berlin.de.
Abstract
BACKGROUND: Co-localized combinations of histone modifications ("chromatin states") have been shown to correlate with promoter and enhancer activity. Changes in chromatin states over multiple time points ("chromatin state trajectories") have previously been analyzed at promoter and enhancers separately. With the advent of time series Hi-C data it is now possible to connect promoters and enhancers and to analyze chromatin state trajectories at promoter-enhancer pairs. RESULTS: We present TimelessFlex, a framework for investigating chromatin state trajectories at promoters and enhancers and at promoter-enhancer pairs based on Hi-C information. TimelessFlex extends our previous approach Timeless, a Bayesian network for clustering multiple histone modification data sets at promoter and enhancer feature regions. We utilize time series ATAC-seq data measuring open chromatin to define promoters and enhancer candidates. We developed an expectation-maximization algorithm to assign promoters and enhancers to each other based on Hi-C interactions and jointly cluster their feature regions into paired chromatin state trajectories. We find jointly clustered promoter-enhancer pairs showing the same activation patterns on both sides but with a stronger trend at the enhancer side. While the promoter side remains accessible across the time series, the enhancer side becomes dynamically more open towards the gene activation time point. Promoter cluster patterns show strong correlations with gene expression signals, whereas Hi-C signals get only slightly stronger towards activation. The code of the framework is available at https://github.com/henriettemiko/TimelessFlex . CONCLUSIONS: TimelessFlex clusters time series histone modifications at promoter-enhancer pairs based on Hi-C and it can identify distinct chromatin states at promoter and enhancer feature regions and their changes over time.
BACKGROUND: Co-localized combinations of histone modifications ("chromatin states") have been shown to correlate with promoter and enhancer activity. Changes in chromatin states over multiple time points ("chromatin state trajectories") have previously been analyzed at promoter and enhancers separately. With the advent of time series Hi-C data it is now possible to connect promoters and enhancers and to analyze chromatin state trajectories at promoter-enhancer pairs. RESULTS: We present TimelessFlex, a framework for investigating chromatin state trajectories at promoters and enhancers and at promoter-enhancer pairs based on Hi-C information. TimelessFlex extends our previous approach Timeless, a Bayesian network for clustering multiple histone modification data sets at promoter and enhancer feature regions. We utilize time series ATAC-seq data measuring open chromatin to define promoters and enhancer candidates. We developed an expectation-maximization algorithm to assign promoters and enhancers to each other based on Hi-C interactions and jointly cluster their feature regions into paired chromatin state trajectories. We find jointly clustered promoter-enhancer pairs showing the same activation patterns on both sides but with a stronger trend at the enhancer side. While the promoter side remains accessible across the time series, the enhancer side becomes dynamically more open towards the gene activation time point. Promoter cluster patterns show strong correlations with gene expression signals, whereas Hi-C signals get only slightly stronger towards activation. The code of the framework is available at https://github.com/henriettemiko/TimelessFlex . CONCLUSIONS: TimelessFlex clusters time series histone modifications at promoter-enhancer pairs based on Hi-C and it can identify distinct chromatin states at promoter and enhancer feature regions and their changes over time.
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