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Cells constantly remix their genes
Scientists have always believed that the location of genes was relatively fixed with each gene having a rightful place and different cell types organising genes in some unique way to produce a specific tissue type. But, genes weren't thought to move around much except during cell division. This research is the first time that gene organisation in individual cells has been studied in such detail. It provides a glimpse of how cell types might be arranged by gene location and vibration.
Published in the journal Nature, researchers examined the organization of genes found in stem cells of mice, and saw that these cells continually remix, changing gene positions as they progress though different cell stages. The work has inspired a musical collaboration, and may mean moving genes about in cells could "fine-tune" the volume of a gene to suit a cell's particular needs.
Contrary to expectations, this latest study reveals that each gene doesn't have an ideal location in the cell nucleus. Instead, genes are always on the move.
Co-first authors, Dr Takashi Nagano in the United Kingdom (UK) and Yaniv Lubling in Israel, have collected and individually analyzed information for over 4000 cells. Dr Nagano explains: "We've never had access to this level of information about how genes are organised before. Being able to compare between thousands of individual cells is an extremely powerful tool and adds an important dimension to our understanding of how cells position genes."
Collecting hundreds of thousands of pieces of information about gene positions from just one cell is a significant challenge which has relied on technology pioneered by Dr Nagano and colleagues in 2013. Called "single-cell Hi-C," Dr Nagano's team uses this technology in conjunction with statistical analyses performed by Dr Amos Tanay's team at the Weizmann Institute. A version of the Hi-C technique was recently shown to also have the potential to improve cancer diagnoses.
"We typically see that changes to gene activity have a great impact on health, disease and evolution. It's now obvious that genome organization may also have a part to play. Understanding how the genome is controlled during a constant re-shuffling is an important step towards understanding how our genomes and genes affect our lives."
The team now plans to examine whether changing the location of genes actually has a significant effect on the volume of each gene — and to study different types of cells to understand whether they move genes about less once they stop dividing. Or, do all cells behave like stem cells do.
This research has previously inspired an artistic collaboration with music producer Max Cooper and visual artist Andy Lomas, who produced the music tracks 'Chromos' and 'Coils of Living Synthesis', a video based on computational models of DNA folding generated by author Dr Csilla Varnai.
Chromosomes in proliferating metazoan cells undergo marked structural metamorphoses every cell cycle, alternating between highly condensed mitotic structures that facilitate chromosome segregation, and decondensed interphase structures that accommodate transcription, gene silencing and DNA replication. Here we use single-cell Hi-C (high-resolution chromosome conformation capture) analysis to study chromosome conformations in thousands of individual cells, and discover a continuum of cis-interaction profiles that finely position individual cells along the cell cycle. We show that chromosomal compartments, topological-associated domains (TADs), contact insulation and long-range loops, all defined by bulk Hi-C maps, are governed by distinct cell-cycle dynamics. In particular, DNA replication correlates with a build-up of compartments and a reduction in TAD insulation, while loops are generally stable from G1 to S and G2 phase. Whole-genome three-dimensional structural models reveal a radial architecture of chromosomal compartments with distinct epigenomic signatures. Our single-cell data therefore allow re-interpretation of chromosome conformation maps through the prism of the cell cycle.
Atuthors: Takashi Nagano, Yaniv Lubling, Csilla Várnai, Carmel Dudley, Wing Leung, Yael Baran, Netta Mendelson Cohen, Steven Wingett, Peter Fraser and Amos Tanay
Keywords: Chromosomes Nuclear organization
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Computer model of the folded DNA chromosomes from a single cell.
Image Credit: Csilla Varnai, PhD