Epigenetic pioneering by SWI/SNF family remodelers

Abstract

In eukaryotic genomes, transcriptional machinery and nucleosomes compete for binding to DNA sequences; thus, a crucial aspect of gene regulatory element function is to modulate chromatin accessibility for transcription factor (TF) and RNA polymerase binding. Recent structural studies have revealed multiple modes of TF engagement with nucleosomes, but how initial "pioneering" results in steady-state DNA accessibility for further TF binding and RNA polymerase II (RNAPII) engagement has been unclear. Even less well understood is how distant sites of open chromatin interact with one another, such as when developmental enhancers activate promoters to release RNAPII for productive elongation. Here, we review evidence for the centrality of the conserved SWI/SNF family of nucleosome remodeling complexes, both in pioneering and in mediating enhancer-promoter contacts. Consideration of the nucleosome unwrapping and ATP hydrolysis activities of SWI/SNF complexes, together with their architectural features, may reconcile steady-state TF occupancy with rapid TF dynamics observed by live imaging.

Keywords: ATP-dependent remodeling; cancer; chromatin; development; gene regulation; histone; nucleosome; transcription factor.

Figure 1:. Contacts around the nucleosome.

A) The path that DNA follows around a nucleosomal histone octamer surface (not shown) with DNA super-helical locations (SHL) indicated. There are 7 SHLs on either side of the dyad axis nucleosome center (SHL 0); SHLs on only one gyre of DNA is shown for clarity, while the other gyre is a mirror image as the nucleosome is symmetrical. SHL 7 marks where DNA enters or exits the nucleosome particle. B) SHLs on one half of a nucleosome represented as an elongated wedge. In the core nucleosomal DNA interacts with histones H3 and H4, while DNA at the periphery interacts with histones H2A and H2B and DNA near the entry/exit site interacts with histone H3. The colored gradient shows increasing likelihood of DNA exposure towards the nucleosomal edges due to transient unpeeling. Red circles show locations of TFs binding to nucleosomal DNA as determined by structural studies discussed in the text.

Figure 2:. Structure of mammalian BAF complexes at enhancers and promoters.

The diagram of cBAF bound to a nucleosome, adapted from Ref, with resolved subunits indicated in colors and unassigned density outlined, and that of the PBAF-nucleosome complex from Yuan et al. with alternative subunits indicated. cBAF is typically found at enhancers and grabs a nucleosome like a C-clamp, where SMARCA4 (green) and SMARCB1 (light blue) bind to histone surfaces exposed on the faces of the nucleosome (black dotted lines) and the ATPase domain of SMARCA4 engages with nucleosomal DNA and generates torque near SHL 2 (red dotted circle). Without SMARCB1-histone contacts most of the core module may be free to flex and interact with nearby DNA or non-nucleosomal targets. The PBAF complex, which is typically found at active promoters shares many core components with cBAF with the indicated alternative subunits, and binds nucleosomes similarly.

Figure 3:. Model for promoter-enhancer interaction

We speculate that BAF is handed-off from enhancers to nucleosomes flanking promoters, facilitated by rapid release from the enhancer upon ATP hydrolysis. BAF remodeling of the promoter-proximal +1 nucleosome would then distort DNA to facilitate the transit of promoter-proximally paused RNAPII and transcription bursting.