Chromatin and epigenetic determinants of estrogen receptor alpha (ESR1) signaling

Highlights

• ESR1 recruitment relies on chromatin openness and epigenetic signatures.

• Pioneer factors guide ESR1 binding.

• Stimulus induced epigenetic modifications define active ESR1 bound sites.

• Genetic alterations can impact the chromatin landscape relevant to ESR1.

Abstract

The oestrogen receptor alpha (ESR1) is a transcription factor that potentiates the response to diverse stimuli, including oestrogen and growth factors, in various tissue types. Its recruitment to the DNA is directly regulated by the chromatin landscape, inclusive of chromatin compaction and epigenetic modifications. In this review we discuss our current understanding of the interplay between ESR1 signaling and the chromatin landscape. We present how the chromatin landscape primes the lineage-specific response and contributes to stimuli-specific signaling. Finally, we discuss recent efforts to decipher the relationship between genetic and epigenetic as it relates to ESR1 signaling in breast cancer.

Introduction

Our genome holds the genetic code that potentiates its interaction with DNA binding proteins, including transcription factors such as the estrogen receptor alpha (ESR1) (Kumar et al., 1987, Kumar and Chambon, 1988, ENCODE Project Consortium et al., 2012, Wang et al., 2012). The vast majority of DNA motifs recognized by transcription factors are short sequences (ranging in size between 5 and 19 nucleotides long) that are commonly found across the genome (Wingender, 1988, Sandelin et al., 2004, Bilu and Barkai, 2005, Neph et al., 2012). However, the DNA in eukaryotic cells is progressively folded into a higher complexity structure called chromatin, where nucleosomes form the basic unit. This ensures that the genome can be stored within the finite space provided by the nucleus (Fussner et al., 2011) but also imposes restriction on DNA accessibility that affects DNA motif recognition by transcription factors with direct consequences on transcriptional regulation.

Nucleosomes consist of approximately 147 base pairs of DNA wrapped around an octamer of histone proteins, where two members of the four core histones, namely H2A, H2B, H3 and H4, are typically present (Luger et al., 1997). Their N-terminal tail protrudes outside from the nucleosomes which renders them accessible for post-translational modifications (PTM) by chromatin modifiers, either “writers” or “erasers” (Jenuwein and Allis, 2001, Henikoff and Shilatifard, 2011). Known PTMs include phosphorylation, ubiquitination, isomerization, deamination, ADP ribosylation, acetylation and methylation (Kouzarides, 2007). At least seven, nine and 23 different residues in the N-terminal tails of H2A or H2B, H4 and H3, respectively, can be post-translationally modified (Kouzarides, 2007, Dawson and Kouzarides, 2012). The diverse combinations of these PTMs on a single nucleosome or on a series of neighboring nucleosomes have given rise to the concept of the epigenetic code (Jenuwein and Allis, 2001), where each unique combination of PTMs associates with distinct functional features of the genome (Ernst and Kellis, 2010, Ernst et al., 2011). For instance, nucleosomes trimethylated on lysine 4 and 27 of histone 3 (H3K4me3 and H3K27me3) associate with poised promoters while the acetylation of K27 combined with H3K4me3 preferentially maps to promoters engaged in transcription (Mikkelsen et al., 2007). Mono- and di-methylation of lysine 4 of histone 3 (H3K4me1/me2) is enriched at transcription factor-bound enhancers (Heintzman et al., 2007, Lupien et al., 2008, Ernst et al., 2011), and directs cell type-specific transcription factor binding (Lupien et al., 2008, Heintzman et al., 2009, ENCODE Project Consortium et al., 2012). Genome-wide mapping of these epigenetic modifications has started to reveal the complex epigenetic nature of the human genome and is allowing for its annotation beyond coding sequences (Ernst and Kellis, 2010, Ernst et al., 2011).

Nucleosomes found across the human genome exhibit various degrees of mobility. They can also be repositioned in response to transcriptional activity (Bintu et al., 2012). This allows for the DNA found between nucleosomes, known as linker DNA, to be made accessible to DNA binding proteins such as transcription factors (Schneider and Grosschedl, 2007, Bell et al., 2011, Thurman et al., 2012). Different families of chromatin remodelers and pioneer factors can actively reposition nucleosomes (Hargreaves and Crabtree, 2011, Magnani et al., 2011b). These frequently co-localize to the chromatin with transcription factors to facilitate their binding through nucleosome remodeling (Wang et al., 2012, Li et al., 2012b). Assays such as DNase-seq or FAIRE-seq can profile the extent of chromatin remodeling resulting in openness across the genome (Song et al., 2011). Chromatin openness profiling combined with epigenetic mapping and transcription across a large collection of cell lines has led to systematic characterization of over 80% of our genome as being biochemically active and potentially involved in regulating expression (ENCODE Project Consortium et al., 2012).

In this review, we discuss how the chromatin landscape relates to ESR1 signaling. Specifically, we describe how binding is achieved through a coordinated effort involving specialized transcription factors along with histone modifications, epigenetic regulatory factors and chromatin remodelers. Finally, we discuss how defects in the epigenetic machinery can influence the development and proliferation of ESR1-positive breast cancer.