Biomedical
Transcription factors organize into functional groups on the linear genome and in 3D chromatin
rnfinity
Rakesh Netha Vadnala,
Sridhar Hannenhalli,
Sridhar Hannenhalli
National Cancer Institute, National Institutes of Health,
Leelavati Narlikar,
Leelavati Narlikar
Department of Data Science, Indian Institute of Science Education and Research,
Rahul Siddharthan
Abstract
Transcription factors (TFs) and their binding sites have evolved to interact cooperatively or competitively with each other. Here we examine in detail, across multiple cell lines, such cooperation or competition among TFs both in sequential and spatial proximity (using chromatin conformation capture assays) on one hand, and based on both in vivo binding as well as TF binding motifs on the other. We ascertain significantly co-occurring (“attractive”) or avoiding (“repulsive”) TF pairs using robust randomized models that retain the essential characteristics of the experimental data. Across human cell lines TFs organize into two groups, with intra-group attraction and inter-group repulsion. This is true for both sequential and spatial proximity, as well as for both in vivo binding and motifs. Attractive TF pairs exhibit significantly more physical interactions suggesting an underlying mechanism. The two TF groups differ significantly in their genomic and network properties, as well in their function—while one group regulates housekeeping function, the other potentially regulates lineage-specific functions, that are disrupted in cancer. We also show that weaker binding sites tend to occur in spatially interacting regions of the genome. Our results suggest a complex pattern of spatial cooperativity of TFs that has evolved along with the genome to support housekeeping and lineage-specific functions.
Key Questions
What is the primary focus of this study?
The study investigates how transcription factors (TFs) organize themselves into functional groups along the linear genome and within the three-dimensional structure of chromatin to regulate gene expression effectively.
What are transcription factors, and why are they important?
Transcription factors are proteins that bind to specific DNA sequences to regulate the transcription of genetic information from DNA to RNA. They play crucial roles in controlling gene expression and cellular function.
How do transcription factors organize along the linear genome?
The study reveals that TFs form clusters at specific genomic sites, creating regions of high regulatory activity. These clusters facilitate coordinated gene expression by bringing together multiple TFs and their target genes.
What is the significance of 3D chromatin organization in this context?
In 3D chromatin, transcription factors group together at spatially connected chromatin domains. This spatial organization enables efficient communication between regulatory elements like enhancers and promoters, enhancing gene regulation.
What methods were used to study transcription factor organization?
The researchers employed advanced genomic and imaging techniques, including chromatin immunoprecipitation sequencing (ChIP-seq) and high-resolution microscopy, to analyze TF binding patterns and chromatin structure.
What are the functional implications of transcription factor clustering?
Transcription factor clustering enhances regulatory efficiency and specificity, ensuring that genes are expressed at the right time and in the right context. This organization is critical for processes like development, differentiation, and response to environmental signals.
What new insights does this study provide?
The study highlights the dual organization of transcription factors in both linear and 3D genomic contexts, demonstrating how these patterns contribute to robust gene regulation. It provides a more integrated understanding of genome organization and function.
How could this research impact future studies?
This research could pave the way for new approaches to studying genome regulation and identifying dysregulation in diseases like cancer. It may also inform therapeutic strategies targeting transcription factors or chromatin organization.
What are the broader implications of transcription factor organization?
Understanding transcription factor organization helps to elucidate fundamental principles of gene regulation, with potential applications in biotechnology, medicine, and synthetic biology for manipulating gene expression systems.
