Developmental Biology - Cell Identity|
Which Proteins Call The Shots
Which proteins maintain cell identity...
In our cells, some proteins are of vital importance in which genes are 'made active' or are 'turned off'. Now, research from the University of Copenhagen and the Memorial Sloan Kettering Cancer Center has uncovered which proteins influence this type of gene regulation.
All of our more than 200 cell types contain the exact same DNA. Which genes are expressed - meaning 'function' - determines each cell type. So, it is essential that the activity of each gene is controlled with great precision. A stem cell is unique in that it can develop into anything from a skin to a bone cell - but that depends, again, on which parts of the genome are expressed and telling it what cell type to become.
For several years researchers in Kristian Helin's group worked to understand mechanisms controlling whether a gene is active or inactive, how it becomes specialized and how it maintains identity — all facts crucial to understanding normal embryo development and thus how various diseases may develop due to errors in gene regulation.
In a new study from the Biotech Research & Innovation Center (BRIC), the Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) at the University of Copenhagen, and the Memorial Sloan Kettering Cancer Center in New York — researchers have achieved crucial results recently published in the scientific journal Molecular Cell that provide insight into the ways in which epigenetic mechanisms control gene activity.
"In addition, the results may have an impact on the future treatment of cancers related to the protein complex under study, which includes lymphoma, leukaemia and a specific brain cancer often seen in children."
Kristian Helin, Professor, BRIC, Director of Research, Memorial Sloan Kettering Cancer Center.
Turning Genes On and Off
One of the key protein complexes regulating genes is called PRC2. To ensure this protein complex binds in the right locations within the genome (all the genes in a body), a number of other proteins help direct PRC2 to its attachment locations. In their recently published work, the group reports on six different proteins associated with PRC2, which make up the H3K27me3 histone H3 protein, defining how all six of these proteins help direct PRC2. In fact, any one of these six proteins is all that is needed to guide PRC2 to attach.
Using 15 different combinations, researchers removed each protein from an embryonic stem cell and were able to identify the specific contribution of each. They found the ability to locate the right attachment location in the genome remained intact even if only one of the six PRC2 associated proteins remained. These six proteins are histone methylation subunits. The histone they comprise being the H3K27me3 Histone.
Our DNA is wrapped around special protein molecules known as histones. These complexes compress DNA to fit within the cell and within the cell nucleus. Histones also have long carboxyl(C) tails that contribute to interactions between histones, as well as interactions between histones and DNA .
"We assumed that each of the associated proteins was responsible for its own area to where the PRC2 complex should be guided. Instead, we saw that they all contributed to each place where the PRC2 complex binds. As long as just one of the associated proteins was left, that ability remained intact."
Jonas Højfeldt, PostDoc and study lead author.
• Non-core PRC2 subunits are collectively required for genomic targeting specificity
• Each non-core PRC2 subunit contributes to H3K27me3 deposition at PRC2 target sites
• Polycomb-like (PCL) proteins depend on SUZ12 for target-site binding
• The bulk of H3K27me3 in mESCs is dispersed and not dependent on PRC2 localization
The Polycomb repressive complex 2 (PRC2) catalyzes H3K27 methylation across the genome, which impacts transcriptional regulation and is critical for establishment of cell identity. Because of its essential function during development and in cancer, understanding the delineation of genome-wide H3K27 methylation patterns has been the focus of intense investigation. PRC2 methylation activity is abundant and dispersed throughout the genome, but the highest activity is specifically directed to a subset of target sites that are stably occupied by the complex and highly enriched for H3K27me3. Here, we show, by systematically knocking out single and multiple non-core subunits of the PRC2 complex in mouse embryonic stem cells, that they each contribute to directing PRC2 activity to target sites. Furthermore, combined knockout of six non-core subunits reveals that, while dispensable for global H3K27 methylation levels, the non-core PRC2 subunits are collectively required for focusing H3K27me3 activity to specific sites in the genome.
Jonas Westergaard Højfeldt, LinHedehus AnneLaugesen, Tülin Tatar, Laura Wiehle, Kristian Helin.
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Sep 24 2019 Fetal Timeline Maternal Timeline News
The protein complex PRC2 (left) is central to regulating genetic expression. Researchers tested several associated proteins (right) and found that all of them assisted PRC2 in binding at the correct sites. The associated protein PCL exists in three different forms, making the number of associated proteins a total of six. CREDIT Biotech Research & Innovation Centre, University of Copenhagen.