Retroelement-Linked Transcription Factor Binding Patterns Point to Quickly Developing Molecular Pathways in Human Evolution.

Daniil Nikitin,Nurshat Gaifullin,Maxim Sorokin,Dmitry Penzar,Andrew Garazha,Alexander Poltorak,Anton Buzdin,Pieter Borger,Alexander Markov,Victor Tkachev

doi:10.3390/cells8020130

Abstract

Background: Retroelements (REs) are transposable elements occupying ~40% of the human genome that can regulate genes by providing transcription factor binding sites (TFBS). RE-linked TFBS profile can serve as a marker of gene transcriptional regulation evolution. This approach allows for interrogating the regulatory evolution of organisms with RE-rich genomes. We aimed to characterize the evolution of transcriptional regulation for human genes and molecular pathways using RE-linked TFBS accumulation as a metric. Methods: We characterized human genes and molecular pathways either enriched or deficient in RE-linked TFBS regulation. We used ENCODE database with mapped TFBS for 563 transcription factors in 13 human cell lines. For 24,389 genes and 3124 molecular pathways, we calculated the score of RE-linked TFBS regulation reflecting the regulatory evolution rate at the level of individual genes and molecular pathways. Results: The major groups enriched by RE regulation deal with gene regulation by microRNAs, olfaction, color vision, fertilization, cellular immune response, and amino acids and fatty acids metabolism and detoxication. The deficient groups were involved in translation, RNA transcription and processing, chromatin organization, and molecular signaling. Conclusion: We identified genes and molecular processes that have characteristics of especially high or low evolutionary rates at the level of RE-linked TFBS regulation in human lineage.

Highlights

Retroelements (REs) are transposable elements occupying ~40% of the human genome that can regulate genes by providing transcription factor binding sites (TFBS)
To distinguish cell type-specific and general evolutionary features, in this study we investigated into the distributions of RE-linked hits for all 13 human cell lines TFBS-profiled for 563 DNA-binding proteins during ENCODE project [40] and representing eight different tissues/organs from the different individuals (Supplementary file 2, Figure 2A)
From the ENCODE project repository, we extracted experimental TFBS data based on the sequencing of immunoprecipitated DNA for 563 transcription factor proteins [6,58,59]

Summary

Introduction

Retroelements (REs) are transposable elements occupying ~40% of the human genome that can regulate genes by providing transcription factor binding sites (TFBS). We aimed to characterize the evolution of transcriptional regulation for human genes and molecular pathways using RE-linked TFBS accumulation as a metric. ~40% of thetranscription human genomefactor [1,2] and and regulate the expression of transposable human genes by providing functional binding regulate the expression of human genes by providing functional transcription factor binding sites sites (TFBS) [3,4,5,6], being one of the major forces of regulatory innovation [3,4,5]. RE-linked transcriptional regulation of human genes, can indicate quickly transforming gene regulatory modules [7,8,9] (Figure 1). At the level of individual genes, it can be investigated by analyzing structural and functional properties

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Conclusion