The connection between BRG1, CTCF and topoisomerases at TAD boundaries

Abstract

The eukaryotic genome is partitioned into topologically associating domains (TADs). Despite recent advances characterizing TADs and TAD boundaries, the organization of these structures is an important dimension of genome architecture and function that is not well understood. Recently, we demonstrated that knockdown of BRG1, an ATPase driving the chromatin remodeling activity of mammalian SWI/SNF enzymes, globally alters long-range genomic interactions and results in a reduction of TAD boundary strength. We provided evidence suggesting that this effect may be due to BRG1 affecting nucleosome occupancy around CTCF sites present at TAD boundaries. In this review, we elaborate on our findings and speculate that BRG1 may contribute to the regulation of the structural and functional properties of chromatin at TAD boundaries by affecting the function or the recruitment of CTCF and DNA topoisomerase complexes.

Keywords: BRG1; CTCF; Hi-C; SWI/SNF;TADs; topoisomerase; topologically associated domains.

Figure 1.

A schematic figure depicting the possible connection between BRG1, CTCF and topoisomerases. In the presence of BRG1 (top panel), CTCF and topoisomerases can efficiently bind to TAD boundaries and promote proper nucleosome occupancy and uncoiling of the DNA, resulting in a strong TAD boundary. We previously reported that nucleosome occupancy around CTCF sites was reduced upon BRG1 knockdown. Therefore, we propose that upon BRG1 knockdown, CTCF and topoisomerases may interact with TAD boundary sequences, but the lack of ATP-dependent remodeling activity may alter nucleosome occupancy and affect boundary strength (middle panel). Alternatively, the binding of CTCF and topoisomerases may be perturbed, resulting in altered nucleosome occupancy and reduced boundary strength (bottom panel).