Predicting the three-dimensional folding of cis-regulatory regions in mammalian genomes using bioinformatic data and polymer models.

Chris A Brackley,Jill M Brown,Jim R Hughes,James Davies,Christian Babbs,Davide Marenduzzo,Veronica J Buckle,Dominic Waithe

doi:10.1186/s13059-016-0909-0

Abstract

The three-dimensional (3D) organization of chromosomes can be probed using methods like Capture-C. However, it is unclear how such population-level data relate to the organization within a single cell, and the mechanisms leading to the observed interactions are still largely obscure. We present a polymer modeling scheme based on the assumption that chromosome architecture is maintained by protein bridges, which form chromatin loops. To test the model, we perform FISH experiments and compare with Capture-C data. Starting merely from the locations of protein binding sites, our model accurately predicts the experimentally observed chromatin interactions, revealing a population of 3D conformations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-0909-0) contains supplementary material, which is available to authorized users.

Highlights

The three-dimensional (3D) spatial organization of mammalian chromosomes in vivo is a topic of fundamental importance in cell biology [1,2,3,4,5]
In this work, we have shown that a minimal polymer model informed by large bioinformatic data sets on protein binding can successfully reproduce the pattern of Capture-C contacts observed in the well-studied α and β globin loci within mouse erythroblasts, and within the less understood Slc25a37 (Mitoferrin1) locus
Our model is built on the hypothesis that there exist architectural protein bridges, which we assume are either CCCTC-binding factor (CTCF) or generic bridges made up by complexes of transcription factor (TF) and other DNAbinding proteins

Summary

Introduction

The three-dimensional (3D) spatial organization of mammalian chromosomes in vivo is a topic of fundamental importance in cell biology [1,2,3,4,5]. Understanding how chromatin conformation becomes modified on a local scale to up-regulate transcription from genes during differentiation or development is critical to decipher a fundamental biological process, and to delineate the role this process may play in human disease and potential therapies. While the TAD boundaries are thought to be largely conserved across cell types, the arrangement of the chromatin within a TAD is not [16] This internal organization depends on the activity of the genes within a domain, and is likely related to the action of cis-regulatory elements [DNA regions where the binding of a transcription factor (TF) can regulate the expression of a gene that is tens or hundreds of kilobase pairs (kbp) away] [17, 18]

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Conclusion