New Insights Into How Genetic Variation Affects Gene Expression

Chromatin accessibility and transcription factor binding are determined by genetic variation, according to a recent study from the University of Eastern Finland.

New Insights Into How Genetic Variation Affects Gene Expression

Image Credit: University of Eastern Finland

Proteins and DNA are the components of chromatin. Transcription factors control the density of this packing, and gene expression depends on DNA accessibility. The study's findings were released in the Nucleic Acids Research journal.

The majority of genetic variation that raises the risk of complex diseases affects parts of the gene that do not code for proteins. A particular DNA sequence found in chromatin is necessary for transcription factors to bind to it; modifications to this sequence can inhibit binding and affect the expression of a gene. It is common practice to use chromatin accessibility to locate regulatory factor binding sites.

Two genetically different mouse strains were used in the study to compare the responses to a high-fat diet, as well as the activity of regulatory regions of genes and gene expression in the liver.

These mouse strains are frequently used to investigate type 2 diabetes and obesity susceptibility. Comparing the chromatin accessibility of the mouse strains fed a regular diet with one high in fat, no differences were found. Nonetheless, notable variations in chromatin accessibility were discovered amongst the mouse strains, especially at chromosomal sites where genetic variations among the strains are situated.

Furthermore, these variations frequently happened close to genes that exhibit variable expression between strains. Therefore, transcription factor binding is influenced by genetic variation, and these modifications are manifested in changes in gene expression.

The study also looked at what kind of genomic information would be needed to predict changes brought about by genetic variation in the binding sites of individual transcription factors with any degree of reliability. The best estimate of the binding of transcription factors directly influencing chromatin accessibility was obtained by combining data on chromatin accessibility, genetic variation, and transcription factor binding regions.

However, in situations where a single genetic variation impacted multiple transcription factors’ binding sequences, the prediction's dependability was called into question. Therefore, direct measurements of the effect of genetic variation on the binding of each transcription factor are required.

This research deepens our understanding of the connections between genetics, modifications to chromatin, and transcription factor actions that direct gene expression. Additionally, the study describes how public datasets can be utilized in investigating the mechanisms behind the hereditary risk factors for complex diseases.”

Juho Mononen, University Teacher, University of Eastern Finland

Source:
Journal reference:

Mononen, J., et al. (2024) Genetic variation is a key determinant of chromatin accessibility and drives differences in the regulatory landscape of C57BL/6J and 129S1/SvImJ mice. Nucleic Acids Research. doi.org/10.1093/nar/gkad1225

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