Oriented nucleosome binding by the pioneer factor ELF2

Abstract

AbstractPioneer factors are transcription factors that are important for stem cell pluripotency, cell reprogramming and differentiation, due to their ability to bind to nucleosomes at closed chromatin regions. ELF2 is an ETS family pioneer factor that has a strong preference for oriented binding on nucleosomes (Zhu et al., 2018). On nucleosomes, ELF2 preferentially binds to a composite head-to-tail dimeric motif with a 2 bp spacing between the GGAA core sequences. In this study, we investigated the interaction between ELF2 and a nucleosome using single-particle cryo-electron microscopy (cryo-EM) analysis. The ELF2-nucleosome structure shows two ELF2 proteins bound to the nucleosome cooperatively at superhelical location +4. The recognition ⍰4 helices of both ELF2 monomers dock into the major groove of DNA at the core GGAA motifs, and unwrap the nucleosome by approximately four helical turns. The unwrapping almost completely exposes one histone H2A:H2B dimer, which dissociates in a subset of particles to form an ELF2-bound hexasome. Genome-wide mapping of the ELF2 composite motifs shows that they are highly enriched downstream of transcription start sites (TSS), oriented in such a way that the TSS becomes accessible upon ELF2 binding to a nucleosome. ELF2 binding is also expected to increase the inter-nucleosome distance, and recruit chromatin remodelers that can recognize exposed histone surfaces or the hexasome. Our results suggest that ELF2 can open chromatin in an oriented fashion, facilitating chromatin remodeling and transcription initiation.