Molecular mechanisms of pioneer factor ELF2 interactions with the nucleosome

Pioneer factors are a subset of transcription factors (TFs) that can bind to nucleosomes and regulate gene expression at closed chromatin regions. Pioneer factors are important for stem cell pluripotency, cell reprogramming and differentiation. ETS family TFs are a large subfamily of TFs consisting of 29 members. The DNA binding domains (DBD) of ETS family TFs are highly conserved. ELF2 is a ETS family pioneer factor that has a strong preference for oriented binding on nucleosomes. The functionality of ELF2 in genome is, however, unknown. In this study, by further analysing previously published NCAP-SELEX data I found that ELF2 has a preference for binding onto a composite motif with 2 bp spacing on the nucleosome. I also investigated the interaction between ELF2 and a nucleosome by Cryo-EM single particle analysis. The ELF2-nucleosome structure shows that two ELF2 DBDs bind onto the nucleosome cooperatively at superhelical location (SHL) +4. The alpha-4 helix of ELF2 DNA binding domain docks into major groove DNA at preferred binding motif (GGAA) and binding of ELF2 unwraps the nucleosome by around three helical turns to expose an H2A-H2B histone dimer. To further understand the function of ELF2, I mapped the ELF2 composite binding motif on to the human genome. This shows that ELF2 composite motifs are highly enriched downstream of transcription start sites (TSS) and are oriented towards the TSS. The results indicate ELF2 is capable of unwrapping the nucleosome to increase DNA accessibility. By unwrapping the nucleosome by three helical turns, ELF2 binding to the nucleosome increases inter-nucleosome distance and could allow recruitment of chromatin remodellers. It is therefore speculated that the pioneer function of ELF2 opens up nucleosome and facilitates transcription initiation and chromatin remodelling.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Xiao, Tianyi

Advisor dc:contributor.advisor

• Taipale, Jussi

• Cryo-EM
• nucleosome
• transcription factor

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/16989157-510d-4960-b2a9-5a15e16638dc/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.112234

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/374014