Shaking up the fundamentals of epigenetics
Cells of multicellular organisms contain identical genetic material (the genome) yet can have drastic differences in their structural arrangements and functions. This variation of the distinct cell types comes from the differential expression of genes, which is controlled by interplay between different regulators within the cells, such as transcription factors, the transcription machinery, and the “epigenetic” modifications (which do not change the underlying genetic code) that occur on the DNA and protein factors within chromatin.
Cells of multicellular organisms contain identical genetic material (the genome) yet can have drastic differences in their structural arrangements and functions. This variation of the distinct cell types comes from the differential expression of genes, which is controlled by interplay between different regulators within the cells, such as transcription factors, the transcription machinery, and the “epigenetic” modifications (which do not change the underlying genetic code) that occur on the DNA and protein factors within chromatin.
A study co-directed by experts Montserrat Corominas, professor in the Department of Genetics and researcher at the Institute of Biomedicine of the University of Barcelona, and Roderic Guigó, researcher at the Centre for Genomic Regulation (CRG-UPF), shows that chromatin marks are irrelevant for regulating genes that are expressed in a punctual manner during development. The results of the study —featured on the cover of the October issue of the journal Nature Genetics— contrast sharply with the generally accepted view of the key roles that these epigenetic marks play in regulating gene expression.
The project was based on gene expression data from the modENCODE project, which aims to provide the scientific community with a comprehensive encyclopaedia of functional elements of the genome of model organisms. In this case, the researchers used data about the genomic expression from the nematode worm C. elegans and the fruit fly D. melanogaster.
Professor Montserrat Corominas explains: “At the beginning, we were not seeking to study the relationship between chromatin marks and gene expression during development, but rather to analyse the function of these marks in RNA processing. However, we soon saw that there were some highly-expressed genes that did not have the epigenetic marks on their chromatin, which are thought to be required to maintain such high levels of expression”.
“First —she adds—, we thought that it that this could be an experimental artifact, since it is common for developmental genes to be expressed only in a few specific cells, which could lead to the signals from the marks being diluted out and not detected”. Nevertheless, when data of the project modENCODE were analysed, the research team realized that, in fact, the genes that were regulated during development were indeed expressed even though they lacked the chromatin marks one would expect. “Great part of our work was centred on experimentally confirming these results”, highlights Professor Corominas.
Embryonic development is a well-studied process in which the precise regulation of gene expression is critical, since many genes are expressed simultaneously and in a punctual manner. The work from these two research groups in Barcelona now offers novel information for understanding this process, by focusing on a set of genes that act during development and are specific to certain tissues.
“Nowadays, we already have computer models that help us to predict the patterns of expression for genes based on their chromatin modifications. The study adds a new aspect that was previously not even contemplated, which will help us to make predictive models even more reliable”, emphasizes Roderic Guigó, coordinator of the programme Bioinformatics and Genomics at the Centre for Genomic Regulation and professor and the Pompeu Fabra University. “Results are based on the expression of genes in two model organisms. Now, we have to see whether what we observed in these two organisms also holds true for humans. If so, the results from our study will be useful for improving approaches to manipulate or modulate the levels of gene expression—which would be extremely useful for studying and treating those diseases that we know are caused by the expression of specific genes”, concludes Guigó.