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Quantification of Differential Transcription Factor Activity and Multiomics-Based Classification into Activators and Repressors: DiffTF

96 Pages Posted: 6 Feb 2019 Publication Status: Under Review

See all articles by Ivan Berest

Ivan Berest

European Molecular Biology Laboratory (EMBL)- Germany - Structural and Computational Biology Unit

Christian Arnold

European Molecular Biology Laboratory (EMBL)- Germany - Structural and Computational Biology Unit

Armando Reyes-Palomares

European Molecular Biology Laboratory (EMBL)- Germany - Structural and Computational Biology Unit

Giovanni Palla

European Molecular Biology Laboratory (EMBL)- Germany - Structural and Computational Biology Unit

Kasper Dindler Rasmussen

Novo Nordisk Foundation Center for Stem Cell Biology

Kristian Helin

Novo Nordisk Foundation Center for Stem Cell Biology

Judith Zaugg

European Molecular Biology Laboratory (EMBL)- Germany - Structural and Computational Biology Unit

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Abstract

Transcription factor (TF) activity is an important read-out of cellular signalling pathways and thus to assess regulatory differences across conditions. However, current technologies lack the ability to simultaneously assess activity changes for multiple TFs and in particular to determine whether a specific TF acts globally as transcriptional repressor or activator. To this end, we introduce a widely applicable genome-wide method diffTF to assess differential TF activity and to classify TFs as activator or repressor (available at https://git.embl.de/grp-zaugg/diffTF). This is done by integrating any type of genome-wide chromatin accessibility data with RNA-Seq data and in-silico predicted TF binding sites. We corroborated the classification of TFs into repressors and activators by three independent analyses based on enrichments of active/repressive chromatin states, correlation of TF activity with gene expression, and activator- and repressor-specific chromatin footprints. To show the power of diffTF, we present two case studies: First, we applied diffTF in to a large ATAC-Seq/RNA-Seq dataset comparing mutated and unmutated chronic lymphocytic leukemia samples, where we identified dozens of known (40%) and potentially novel (60%) TFs that are differentially active. We were also able to classify almost half of them as either repressor and activator. Second, we applied diffTF to a small ATAC-Seq/RNA-Seq data set comparing two cell types along the hematopoietic differentiation trajectory (multipotent progenitors – MPP – versus granulocyte-macrophage progenitors – GMP). Here we identified the known drivers of differentiation and found that the majority of the differentially active TFs are transcriptional activators. Overall, diffTF was able to recover the known TFs in both case studies, additionally identified TFs that have been less well characterized in the given condition, and provides a classification of the TFs into transcriptional activators and repressors.

Suggested Citation

Berest, Ivan and Arnold, Christian and Reyes-Palomares, Armando and Palla, Giovanni and Rasmussen, Kasper Dindler and Helin, Kristian and Zaugg, Judith, Quantification of Differential Transcription Factor Activity and Multiomics-Based Classification into Activators and Repressors: DiffTF (February 6, 2019). Available at SSRN: https://ssrn.com/abstract=3329887 or http://dx.doi.org/10.2139/ssrn.3329887
This version of the paper has not been formally peer reviewed.

Ivan Berest

European Molecular Biology Laboratory (EMBL)- Germany - Structural and Computational Biology Unit

Heidelberg, 69117
Germany

Christian Arnold

European Molecular Biology Laboratory (EMBL)- Germany - Structural and Computational Biology Unit

Heidelberg, 69117
Germany

Armando Reyes-Palomares

European Molecular Biology Laboratory (EMBL)- Germany - Structural and Computational Biology Unit

Heidelberg, 69117
Germany

Giovanni Palla

European Molecular Biology Laboratory (EMBL)- Germany - Structural and Computational Biology Unit

Heidelberg, 69117
Germany

Kasper Dindler Rasmussen

Novo Nordisk Foundation Center for Stem Cell Biology

Blegdamsvej 3b
2200 Copenhagen N
Denmark

Kristian Helin

Novo Nordisk Foundation Center for Stem Cell Biology

Blegdamsvej 3b
2200 Copenhagen N
Denmark

Judith Zaugg (Contact Author)

European Molecular Biology Laboratory (EMBL)- Germany - Structural and Computational Biology Unit ( email )

Heidelberg, 69117
Germany

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