Mechanisms by which transcription factors gain access to target sequence elements in chromatin

Abstract

Transcription factors (TF) bind DNA sequence motifs, but the presence of a consensus DNA element is not sufficient to direct TF binding to chromatin. Recent genomic data have revealed that accessibility, as measured by DNase sensitivity and the presence of active histone marks, is necessary for TF binding. DNA sequence provides the initial specification of the accessibility of DNA elements within chromatin that permits TF binding. In yeast, it is known that poly(dA-dT) tracts directly encode low-nucleosome occupancy at promoters. Recent evidence suggests that CpG islands in mammals are inherently refractory to higher-order chromatin structure and remain accessible, despite favoring nucleosome formation in vitro. Taken together, these studies support a model for how accessibility originates and then propagates throughout regulatory cascades and development.

Figure 1. DNase I intensity can be modeled using histone marks and TF binding data

DNase I hypersensitivity landscape is inferred by models that use histone modification profiles and TF profiles. Incorporating non-histone chromatin-bound factors into the model increases accuracy, which is consistent with the role of TFs having an additive effect upon DNase I hypersensitivity [5,12].

Figure 2. HSF discriminates between potential binding sites based on the pre-existing chromatin state

This region of chromosome 3R contains two strong potential HSF-binding sites (green and red arrows), measured by an in vitro protein/DNA-binding assay (PB-seq) [14]. Although the HSF-free motif (red arrow) binds with comparable affinity in vitro (PB-seq), chromatin structure restricts HSF occupancy in vivo (ChIP-seq). HSEs that are enriched for H4 acetylation and DNase I hypersensitivity during non-HS are preferentially bound by HSF in vivo (green arrow).

Figure 3. DNA sequence directs chromatin structure and allows transcription factor binding to precipitate regulatory cascades

(A) A CpG island is refractory to higher-order chromatin compaction (unraveled chromatin). A regulatory or developmental cascade is precipitated by the activation or expression of a transcription factor (yellow rounded rectangle) targeted to elements within the CpG island. Another TF remains (pink ellipse) unable to access elements with the H1 linker histone (green, interior crescents) condensed chromatin. (B) Targeting of the TF to the CpG island directly or indirectly results in the recruitment of nucleosome remodeling factors (brown crescent) and histone acetyltransferases (purple ellipse), which further decondenses the region and allows the other TF (pink ellipse) access to its cognate element. (C) Binding of the second TF (pink ellipse) directly or indirectly causes the recruitment and productive elongation of RNA Polymerase II (green pentagon) to a gene encoding a third TF, which is subsequently transcribed (transparent orange line) and translated (orange rounded rectangle). This causes further nucleosome loss, histone modifications (orange triangles), and decondensation of the Region A locus. (D) The translated protein (orange rounded rectangle), encoded by region A, is targeted in trans to Region B, which is highly acetylated and contains a transcriptionally engaged paused RNA Polymerase II. This binding event leads to the release of the paused RNA Polymerase II and activation of the gene.