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Why some genes are frequently read more than others
DNA is folded into millions of small necklaces — like beads on molecular strings — called nucleosomes. These "necklaces" allow our almost two-meter long strings of DNA to fit into a nucleus only about 0.01 mm in diameter. However, these "necklaces" actually make DNA 'unreadable'. Nucleosomes need to be temporarily "unwound" to allow genes to be copied or "read" - before a gene can produce a protein.
Wikipedia: "Gene expression is the transcription of DNA into messenger RNA using RNA polymerase. Messenger RNA then translates DNA into protein using ribosomes."
How cells ensure access to 'promoter' DNA — regions where gene transcription begins — is still not well understood. Consequently, researchers are always studying how the expression of proteins occur.
Researchers from the University of Geneva (UNIGE) and the Ecole polytechnique fédérale de Lausanne (EPFL), Switzerland, study mechanisms that control nucleosomes and then how nucleosomes affect gene expression - or how DNA becomes a protein.
How can about two meters of linear DNA contained in a mammalian cell fit into a nucleus of roughly 0.01 mm diameter? With the help of nucleosomes — the basic units made from proteins that wind a segment of DNA.
When a particular gene needs to be transcribed ("read") to create a new protein, its promoter region must be unwrapped from the nucleosome in order to be accessible to factors in the cell that initiate the transcription process.
In their research, UNIGE and EPFL researchers discovered all promoter regions can be of two distinct types – dependent on nucleosome stability.
(1) One type are the dynamic, unstable nucleosomes found in highly expressed genes — genes involved in cell growth and division.
(2) The other type contains stable nucleosomes located in less frequently expressed genes.
The interplay of these two regions is described in their work published in the journal Molecular Cell.
"It is important to understand how nucleosomes are moved, ejected or restructured, as this will affect the accessibility of promoter DNA — which in turn influences the expression of genes."
David Shore PhD, Professor, Department of Molecular Biology, Faculty of Science at the University of Geneva (UNIGE).
The dynamics of nucleosome formation and positioning in promoter regions may help us understand why some genes are highly expressed — like those involved in normal or malignant cell growth, while other are rarely expressed — like those created from stress-induced genes.
Collaborating with researchers at the Department of Computer Science (UNIGE) and the Swiss Institute of Bioinformatics at EPFL, David Shore's team undertook to characterize nucleosomes present in every gene promoter region of yeast DNA.
Yeast is a unicellular fungus used as a model organism because it functions in many ways like a mammalian cell. Yeast also possesses, as do human cells, 'fragile' nucleosomes. 'Fragile' because these nucleosomes don't resist certain enzymes as well as others. They were discovered by chance, and their nature and function had been elusive.
"We have revealed the existence of two types of promoters, which differ by the presence of 'fragile' nucleosomes."
Slawomir Kubik PhD, researcher at UNIGE, and first author of the study.
"The genome probably stays in a very compact state most of the time, with nucleosomes winding the DNA like a tight spring. We believe the presence of dynamic nucleosomes at highly expressed genes helps to unwind this spring rapidly and as often as necessary"
David Shore PhD.
Since many genes that contain 'fragile' nucleosomes are continuously at the affect of the availability of nutrients, a strategy to modify their stability may be to coordinate growth-related transcription.
Abstract
Highlights
•Yeast promoters form two groups based on the stability of their −1 nucleosome
•Distribution of two short DNA motifs is critical for promoter chromatin architecture
•Fragile nucleosomes are formed through the action of GRFs and chromatin remodelers
Summary
Previous studies indicate that eukaryotic promoters display a stereotypical chromatin landscape characterized by a well-positioned +1 nucleosome near the transcription start site and an upstream −1 nucleosome that together demarcate a nucleosome-free (or -depleted) region. Here we present evidence that there are two distinct types of promoters distinguished by the resistance of the −1 nucleosome to micrococcal nuclease digestion. These different architectures are characterized by two sequence motifs that are broadly deployed at one set of promoters where a nuclease-sensitive (“fragile”) nucleosome forms, but concentrated in a narrower, nucleosome-free region at all other promoters. The RSC nucleosome remodeler acts through the motifs to establish stable +1 and −1 nucleosome positions, while binding of a small set of general regulatory (pioneer) factors at fragile nucleosome promoters plays a key role in their destabilization. We propose that the fragile nucleosome promoter architecture is adapted for regulation of highly expressed, growth-related genes.
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