CTCF-mediated chromatin loops enclose inducible gene regulatory domains.

Martin Oti,Jonas Falck,Huiqing Zhou,Martijn A Huynen

doi:10.1186/s12864-016-2516-6

Abstract

BackgroundThe CCTC-binding factor (CTCF) protein is involved in genome organization, including mediating three-dimensional chromatin interactions. Human patient lymphocytes with mutations in a single copy of the CTCF gene have reduced expression of enhancer-associated genes involved in response to stimuli. We hypothesize that CTCF interactions stabilize enhancer-promoter chromatin interaction domains, facilitating increased expression of genes in response to stimuli. Here we systematically investigate this model using computational analyses.ResultsWe use CTCF ChIA-PET data from the ENCODE project to show that CTCF-associated chromatin loops have a tendency to enclose regions of enhancer-regulated stimulus responsive genes, insulating them from neighboring regions of constitutively expressed housekeeping genes. To facilitate cell type-specific CTCF loop identification, we develop an algorithm to predict CTCF loops from ChIP-seq data alone by exploiting the CTCF motif directionality in loop anchors. We apply this algorithm to a hundred ENCODE cell line datasets, confirming the universality of our observations as well as identifying a general distinction between primary and immortal cells in loop-enclosed gene content. Finally, we combine the existing evidence to propose a model for the formation of CTCF loops in which partner sites are brought together by chromatin template reeling through stationary RNA polymerases, consistent with the transcription factory hypothesis.ConclusionsWe provide computational evidence that CTCF-mediated chromatin interactions enclose domains of stimulus responsive enhancer-regulated genes, insulating them from nearby housekeeping genes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2516-6) contains supplementary material, which is available to authorized users.

Highlights

The CCTC-binding factor (CTCF) protein is involved in genome organization, including mediating three-dimensional chromatin interactions
CTCF loops insulate enhancer-regulated stimulus response genes from housekeeping genes To investigate whether CTCF loops are enriched for enhancers relative to surrounding regions, we investigated the enhancer-associated H3K4me1 as well as other chromatin marks within and around experimentally determined CTCF loops determined using the ChIA-PET technique in K562 myeloid leukemia and MCF-7 breast cancer cell lines
The ChIA-PET CTCF interaction data have been corroborated by the independent Hi-C technique, which does not focus on specific proteins [26]

Summary

Introduction

The CCTC-binding factor (CTCF) protein is involved in genome organization, including mediating three-dimensional chromatin interactions. The CCTC-binding factor (CTCF) protein [1] is involved in eukaryotic genome organization, including mediating chromatin interactions [2] It has functions affecting gene regulation such as enhancer blocking [3] and chromatin domain boundary demarcation [4] where the spread of repressive chromatin is blocked, the distinction between these two roles has been called into question [5]. It is involved in several more specialized genomic processes including imprinting [6], immune-related genomic recombination and gene expression regulation [7, 8], mammalian X-chromosome inactivation [9], alternative splicing [10] and alternative promoter choice [11]. They identified an enrichment of the enhancer-associated [15] H3K4me (histone 3 lysine 4 monomethylation) chromatin mark within CTCF loops that are

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