New knowledge on cell differentiation mechanisms
The international FANTOM5 consortium, including scientists from Karolinska Institutet, has made major strides toward resolving common mechanisms in cell differentiation. In a new study published in the journal Science, they describe more than 400 stages of cell maturation in 33 different cell types in mouse and human.
The FANTOM5 is led from the research institute RIKEN in Japan, and gathers scientists from 114 institutions around the world. In this large-scale project, scientists have created an atlas that shows which different genes that are used in virtually all cell types that humans are composed of. The atlas was launched in March 2014, and attracted attention worldwide.
In the current study, the team has made an effort to map the transcriptional changes that occur when cells differentiate from one cell type to another cell type, both during cell development and in response to stresses or infection. Researchers investigated differentiation time series in 19 human and 14 mouse cell types, in total more than 400 stages of cell maturation. The technology used made it possible to see exactly where the genes are ‘read’ from the DNA, and to find the regulatory switches called ‘enhancers’ that are responsible for activating the reading of genes in the appropriate cells at the correct time point.
The team found that just after the cells start to differentiate or react to stimuli, there are shared patterns in gene and enhancer activity between all the studied cells types. Enhancers are activated in the first 15 minutes after stimuli. At 30 to 100 minutes, the enhancers activate a specific type of regulatory genes (transcription factors), which in turn have the ability of activated other genes and over time forming a cascade of changes.
These patterns were shared across all the studied cells, but the individual genes and enhancer that made up the patterns were specific to each cell type. This indicates that the team has found underlying rules for how cells differentiate that applies to all mammals, knowledge which may be an important part of the puzzle in understanding how the human body works in health and disease.
The FANTOM5 consortium is led by Professor Yoshihide Hayashizaki at RIKEN, and includes over 500 scientists from more than 20 countries over the whole world. The researchers from Karolinska Institutet who are members of the consortium are Andreas Lennartsson, Michelle Rönnerblad and Carsten Daub at the Department of Biosciences and Nutrition, and Peter Arner, Anna Ehrlund and Niklas Mejhert at the Department of Medicine, Huddinge. FANTOM5 was made possible through a grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology, while the EU and a number of other research funders have also contributed.
Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells
Erik Arner, Carsten Daub, Kristoffer Vitting-Seerup, Robin Andersson et al, Berit Lilje, Finn Drablos, Andreas Lennartsson, Michelle Rönnerblad et al.
Science, online 12 February 2015, doi: 10.1126/science.1259418