CTCF-mediated transcriptional regulation through cell type-specific chromosome organization in the {\beta}-globin locus

TL;DR

This study models how CTCF-mediated chromatin interactions organize the 3D structure of the eta-globin locus, revealing cell type-specific folding patterns that influence gene regulation.

Contribution

It introduces a polymer model integrating CTCF interaction data to elucidate chromatin folding and gene regulation mechanisms in different cell types.

Findings

In erythroid cells, the eta-globin locus forms a globule with active genes and LCR on the periphery.

In non-erythroid cells, the locus is less compact with fewer CTCF interactions.

CTCF contacts significantly alter spatial distances, affecting gene regulation.

Abstract

The principles underlying the architectural landscape of chromatin beyond the nucleosome level in living cells remains largely unknown despite its potential to play a role in mammalian gene regulation. We investigated the 3-dimensional folding of a 1 Mbp region of human chromosome 11 containing the {\beta}-globin genes by integrating looping interactions of the insulator protein CTCF determined comprehensively by chromosome conformation capture (3C) into a polymer model of chromatin. We find that CTCF-mediated cell type specific interactions in erythroid cells are organized to favor contacts known to occur in vivo between the {\beta}-globin locus control region (LCR) and genes. In these cells, the modeled {\beta}-globin domain folds into a globule with the LCR and the active globin genes on the periphery. By contrast, in non-erythroid cells, the globule is less compact with few but dominant CTCF interactions driving the genes away from the LCR. This leads to a decrease in contact frequencies that can exceed 1000-fold depending on the stiffness of the chromatin and the exact positioning of the genes. Our findings show that an ensemble of CTCF contacts functionally affects spatial distances between control elements and target genes contributing to chromosomal organization required for transcription.