Pioneer transcription factors: establishing competence for gene expression

Abstract

Transcription factors are adaptor molecules that detect regulatory sequences in the DNA and target the assembly of protein complexes that control gene expression. Yet much of the DNA in the eukaryotic cell is in nucleosomes and thereby occluded by histones, and can be further occluded by higher-order chromatin structures and repressor complexes. Indeed, genome-wide location analyses have revealed that, for all transcription factors tested, the vast majority of potential DNA-binding sites are unoccupied, demonstrating the inaccessibility of most of the nuclear DNA. This raises the question of how target sites at silent genes become bound de novo by transcription factors, thereby initiating regulatory events in chromatin. Binding cooperativity can be sufficient for many kinds of factors to simultaneously engage a target site in chromatin and activate gene expression. However, in cases in which the binding of a series of factors is sequential in time and thus not initially cooperative, special “pioneer transcription factors” can be the first to engage target sites in chromatin. Such initial binding can passively enhance transcription by reducing the number of additional factors that are needed to bind the DNA, culminating in activation. In addition, pioneer factor binding can actively open up the local chromatin and directly make it competent for other factors to bind. Passive and active roles for the pioneer factor FoxA occur in embryonic development, steroid hormone induction, and human cancers. Herein we review the field and describe how pioneer factors may enable cellular reprogramming.

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

“…In addition, motifs for Sox ( p ‐value 1 × 10 −27 ) and GATA factors ( p ‐value 1 × 10 −25 ) were enriched in these regions. Forkhead and GATA factors are established pioneer factors (Zaret & Carroll, 2011), which actively open chromatin by binding nucleosomal DNA first and enable subsequent binding of other factors, while Sox factors may also exhibit pioneering ability (Sarkar & Hochedlinger, 2013). The motifs for these regulators are found in regions bound by lamin B1 exclusively in young hepatocytes and possibly occupied by these pioneer factors in the old hepatocytes.…”

“…Foxa1 can bind and open compacted chromatin in vitro (Cirillo et al., 2002), while Foxa2 binds nucleosomal DNA in vivo (Li, Schug, Tuteja, White & Kaestner, 2011) and mediates nucleosomal depletion during differentiation (Li et al., 2012). Hence, Foxa proteins have been labeled as “pioneer” factors for their ability to bind highly condensed chromatin first, displacing linker histones, and enable access for subsequent binding of additional transcription factors (Zaret & Carroll, 2011). We also found that Foxa2 occupies considerably more regions in aged fatty liver, binding regions of decreased nucleosome occupancy at PPAR targets, and cooperating with PPAR receptors in regulation of gene expression changes that contribute to steatosis (Bochkis et al., 2014).…”

Pioneer transcription factors in cell reprogramming

“…Chromatin decompaction Fakhouri et al 2010 Mitotic bookmarking (human) Binding to mitotic chromatin Caravaca et al 2013 Hormone-dependent cancer progression (human) Recruitment of hormone receptor Zaret and Carroll 2011;Jozwik and Carroll 2012 In vitro reconstituted nucleosome or nucleosome array…”

“…Recruitment of hormone receptor Zaret and Carroll 2011;Jozwik and Carroll 2012 In vitro reconstituted nucleosome array…”

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…Methylation of lysine residues can occur on histones H3 and H4, thereby contributing to a chromatin conformation compatible with either active or repressed gene transcription, depending on the residue modified and the degree of methylation [134]. In particular, histone 3 Lys 4 monomethylation and dimethylation (H3K4Me1 and H3K4ME2) are enriched at cis-regulatory domains that are bound by ERα and FoxA1, which leads to the stimulation of transcription of target genes under estrogen hormonal control [135].…”