Speaker
Description
Objectives
Transcription factors (TFs) are the primary drivers of gene regulation by binding to specific DNA sites with adequate affinity and stability [1]. TFs often cooperate as homodimers or heterodimers for a more delicate regulation [2]. Granyhead-like 3 (GRHL3) and Hepatocyte nuclear factor 4 alpha (HNF4α) are TFs that form heterodimers to initiate mesenchymal to epithelial transition (MET), a cell-fate alteration important in development and cancer progression [3]. In this work, we investigate the role of DNA sequence in modulating the cooperativity of transcription factors.
Methods
We developed atomistic structural models of free or nucleosomal DNA bound to human GRHL3, as well as models also including HNF4α, and performed molecular dynamics simulations.
Results
Our molecular dynamics simulations show that the two TFs cooperate when GRHL3 is bound to its native DNA sequence, but the cooperativity is disrupted by mutations in the specific DNA sequence, potentially halting MET progression.
We also investigated NF-κB p50, a TF involved in inflammation, immune response, cell division, cellular differentiation, and survival. Simulations of DNA-bound NF-κB p50 revealed homodimeric cooperativity and progressive DNA bending—suggestive of transcription-associated DNA melting. We find that the TF specificity can be established by not only the cognate DNA sequence but also by the flanking sequences upstream and downstream.
Conclusions
Our findings demonstrate that the DNA sequence is crucial for the heterodimer or homodimer cooperativity between TFs, consequently for the DNA dynamics and conformation, and gene regulation.
Acknowledgements
This project is supported by the Tübitak 2250 awarded to G.Ç., EMBO Installation Grant No:5056 and EuroHPC MareNostrum5 No:REG-2023R02-125 awarded to S.K., Tübitak 2247-A No:120C149 and Tübitak 1001 No:122Z215 awarded to D.A.
References
[1] Aykut Erbas and John F. Marko, Curr Opin Chem Biol., 53, 118–124 (2019).
[2] Jacqueline M. Matthews. Protein Dimerization and Oligomerization in Biology. Springer Science & Business Media (2012).
[3] Burcu Sengez et al., Cells, 8, 858 (2019).