A groundbreaking study led by Prof. Yosef Buganim from the Hebrew University of Jerusalem and Dr. Abdenour Soufi from the University of Edinburgh reveals how transcription factors (TFs)—key proteins that regulate gene activity—navigate DNA and chromatin structures to determine cellular identity. This discovery provides new insights into how cells establish their roles and opens pathways for advancements in regenerative medicine and cell therapy.
Transcription factors are proteins that bind to specific DNA sequences to control gene expression, guiding cells to become specific types—such as skin, muscle, or placenta cells. While TFs are known to recognize DNA sequences, the process by which they identify their precise targets across the vast genome remained unclear. This study uncovers “guided search” mechanisms, where the 3D architecture of DNA and chromatin—which packages and organizes genetic material—acts as a signpost to direct TFs to the correct genes.
Using cutting-edge technologies, the researchers examined how combinations of TFs drive distinct cell identities, such as embryo versus placenta cells. Their results revealed that transcription factors dynamically cooperate or compete, depending on the chromatin landscape, to precisely target genes critical for defining cell type.
A significant discovery was the role of chromatin topology—the folding and looping of DNA within the nucleus. TFs were shown to follow DNA patterns and chromatin loops as pathways to locate target genes or cluster at key chromatin junctions tightly packed with DNA motifs. Novel DNA elements were identified as genomic signposts that guide TFs to the correct genetic switches necessary for activating cell-type-specific genes.
The study introduces new “guided search” models, demonstrating how the spatial arrangement of chromatin directs different TFs to their relevant targets, offering a deeper understanding of how cellular identity is formed and maintained.
Prof. Buganim highlighted the potential impact of the findings: “By uncovering how transcription factors interact with chromatin architecture, we can better understand gene regulation and cellular identity. This knowledge opens exciting possibilities for regenerative medicine, enabling us to precisely control cell fate and develop therapies for diseases caused by cellular dysfunction.”
The findings pave the way for innovative strategies to manipulate gene expression, with profound implications for regenerative therapies and developmental biology.
The research, titled “Nucleosome fibre topology guides transcription factor binding to enhancers,” is published in Nature and provides a powerful framework for exploring gene regulation mechanisms. It holds great promise for understanding age-related diseases, developmental disorders, and advancing the field of cell reprogramming.
The full study can be accessed at: https://doi.org/10.1038/s41586-024-08333-9.
Researchers:
Michael R. O’Dwyer1,2, Meir Azagury3, Katharine Furlong1,2,4, Amani Alsheikh1,2,5, Elisa Hall-Ponsele1,2, Hugo Pinto6, Dmitry V. Fyodorov6, Mohammad Jaber3, Eleni Papachristoforou1, Hana Benchetrit3, James Ashmore1, Kirill Makedonski3, Moran Rahamim3, Marta Hanzevacki1,2, Hazar Yassen3, Samuel Skoda1,2, Adi Levy3, Steven M. Pollard1,4, Arthur I. Skoultchi6, Yosef Buganim3,7, Abdenour Soufi1,2,4,7
Institutions:
1) Institute of Regeneration and Repair, Centre for Regenerative Medicine, University of Edinburgh
2) Institute of Stem Cell Research, School of Biological Sciences, University of Edinburgh
3) Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School
4) Cancer Research UK Scotland Centre, University of Edinburgh
5) Health Sector, King Abdulaziz City for Science and Technology
6) Department of Cell Biology, Albert Einstein College of Medicine
7) Co-corresponding authors
The Hebrew University of Jerusalem is Israel’s premier academic and research institution. With over 23,000 students from 90 countries, it is a hub for advancing scientific knowledge and holds a significant role in Israel’s civilian scientific research output, accounting for nearly 40% of it and has registered over 11,000 patents. The university’s faculty and alumni have earned eight Nobel Prizes, two Turing Awards a Fields Medal, underscoring their contributions to ground-breaking discoveries. In the global arena, the Hebrew University ranks 81st according to the Shanghai Ranking. To learn more about the university’s academic programs, research initiatives, and achievements, visit the official website at http://new.huji.ac.il/en