Spatial organization of transcribed eukaryotic genes


Highly expressed long genes form TLs. Credit: DOI: 10.1038/s41556-022-00847-6

The basic process of life, known as transcription, is the process by which genetic information stored in DNA is copied by specific enzymes called RNA polymerases into RNA molecules. Despite enormous advances in our understanding of the molecular mechanisms of transcription, so far very little is known about the spatial organization of individual genes expressed. Virtually all we know is that transcription occurs inside the nucleus, where the most actively transcribed genes are located. Research by a team led by Irina Solovei at LMU’s Biozentrum, in collaboration with Leonid Mirny (MIT, Cambridge, USA) and others, has now investigated the spatial organization of transcription and the behavior of transcribed genes and discovered a mechanism that contradicts a commonly held notion.

According to the most widespread hypothesis, RNA polymerases are grouped together in a sort of stationary transcription factory, which activated genes approach and cross. It is known, however, that in gigantic specialized chromosomes, the start and end sites of transcription are spatially fixed and the expressed sequences loop. Therefore, in this case, the genes remain stationary but the RNA polymerases move along the genes

“I’ve always suspected that there couldn’t be two fundamentally different transcription mechanisms in eukaryotes. This raises the question of what moves and what stays still,” says Solovei. The biologist assumes that the resolution of modern optical microscopes is not good enough in most cases to make visible the transcription loops observed in giant chromosomes. However, in eukaryotes, frequently expressed genes are often very short – too short for the available resolution – whereas large genes are generally poorly expressed and therefore unsuitable for transcription studies.

Solovei’s team identified several long, highly expressed genes in mouse cells that could be resolved under a light microscope, and studied their structure. The scientists found that these genes unfold during transcription, pulling their ends apart and stretching sharply into the nuclear space. They thus form transcription loops similar to those of giant chromosomes.

As the researchers demonstrated, RNA polymerases move along these loops and transport nascent RNA molecules, undergoing a process of RNA maturation characteristic of eukaryotes. “The shape and expansion of transcription loops from the hosting chromosomes suggests that transcription loops are rigid structures,” Solovei explains. The authors hypothesize that highly expressed genes become rigid because they are densely decorated with multiple nascent RNAs, which, in combination with RNA-binding proteins, form large particles.

This hypothesis is supported by polymer modeling of the expressed genes carried out by the group of Leonid Mirny. By simulating the behavior of transcribed genes, the researchers showed that the modeled genes recapitulate the biological observables only by acquiring a certain rigidity. “The most striking thing for me is the sheer size of the transcription loops – up to 10 micrometers,” says Mirny. “It appears that a single long gene can unfold and cross most of the nucleus.”

“The study results show,” says Heinrich Leonhardt, Head of the Human Biology and Bioimaging Laboratory, “that even in our age dominated by molecular biology, microscopy remains an important and powerful tool for investigating fundamental biological questions.”

How transcription factors find and recognize clusters of specific DNA sequences

More information:
Susanne Leidescher et al, Spatial organization of transcribed eukaryotic genes, Cell Biology Nature (2022). DOI: 10.1038/s41556-022-00847-6

Provided by Ludwig Maximilian University of Munich

Quote: Spatial organization of transcribed eukaryotic genes (2022, February 21) retrieved February 21, 2022 from

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