Coregulation of Transcription Factor Binding and Nucleosome Occupancy through DNA Features of Mammalian Enhancers

Abstract

Transcription factors (TFs) preferentially bind sites contained in regions of computationally predicted high nucleosomal occupancy, suggesting that nucleosomes are gatekeepers of TF binding sites. However, because of their complexity mammalian genomes contain millions of randomly occurring, unbound TF consensus binding sites. We hypothesized that the information controlling nucleosome assembly may coincide with the information that enables TFs to bind cis-regulatory elements while ignoring randomly occurring sites. Hence, nucleosome would selectively mask genomic sites contacted by TFs and thus potentially functional. The hematopoietic TF Pu.1 maintained nucleosome depletion at macrophage-specific enhancers that displayed a broad range of nucleosome occupancy in other cell types and in reconstituted chromatin. We identified a minimal set of DNA sequence and shape features that accurately predicted both Pu.1 binding and nucleosome occupancy genome-wide. These data reveal a basic organizational principle of mammalian cis-regulatory elements whereby TF recruitment and nucleosome deposition are controlled by overlapping DNA sequence features.

Nucleosome fragility is associated with future transcriptional response to developmental cues and stress inC. elegans

“…2B). These data are in agreement with previous reports from yeast to humans that TFs compete with nucleosomes for access to DNA (Wang et al 2012;Ozonov and van Nimwegen 2013;Barozzi et al 2014). To further investigate the relationship …”

“…2B). These data are in agreement with previous reports from yeast to humans that TFs compete with nucleosomes for access to DNA (Wang et al 2012;Ozonov and van Nimwegen 2013;Barozzi et al 2014). To further investigate the relationship (Locke et al 2013) and computational nucleosome occupancy model scores (Kaplan et al 2009) Nucleosome fragility in C. elegans between TF binding and fragility, we broke TFBSs into groups depending on the number of TFs bound at a site.…”

Pioneer transcription factors in cell reprogramming

“…Reprogramming from fibroblast to iPSCs (mouse/human) Inducing reprogramming Takahashi and Yamanaka 2006 Binding to chromatin that is nonhypersensitive and not premarked by common histone modifications in vivo Soufi et al 2012 (continued) Myeloid and lymphoid development (mouse/human) Increasing DNA accessibility in native chromatin Ghisletti et al 2010;Heinz et al 2010;Barozzi et al 2014 GATA4 Transdifferentiation from fibroblast to iHep (mouse)…”

“…PU.1 binding induces local nucleosome remodeling followed by the deposition of the active histone modification H3K4me1 (Heinz et al 2010). PU.1 also engages other lineage-determining transcription factors (Heinz et al 2010) and promotes overall nucleosome depletion (Barozzi et al 2014). Additionally, PU.1 binding contributes to endotoxin-induced transcriptional activation in macrophages (Ghisletti et al 2010).…”

“…Although most transcription factors cannot access nucleosomal DNA by themselves, pioneer transcription factors (e.g., FoxA) can bind to nucleosomal DNA and recruit other factors to bind (Cirillo et al 2002). Along these lines, the transcription factors p53 and PU.1 and the progesterone receptor, which apparently operates with FoxA1 (Clarke and Graham 2012), preferentially target their binding motifs amid sequences with high intrinsic nucleosome occupancy rather than high-affinity motifs with low intrinsic nucleosome occupancy (Lidor Nili et al 2010;Ballare et al 2013;Barozzi et al 2014). Thus, contrary to the dogma that nucleosomes would be inherently repressive to gene activity and must be removed for factor binding, pioneer transcription factors positively use the feature of high nucleosome occupancy at enhancers as their functional binding target ( Fig.…”