Humans have hundreds of different kinds of cells such as blood, kidney, liver or heart cells. All cells – except for the red blood cells – have a cell nucleus, in which the DNA with its approximately
20, 000 genes is packaged. Although the cells all have the same genetic makeup, in the different cell types different genes are active or inactive. How the genes are regulated has long been intensively researched.
“Epigenetics – link between genes and the environment”
In this context, a new concept in genetics emerged a few years ago: epigenetics. “Epigenetic factors are the link between genes and the environment,” said Dr. Carola Rintisch (MDC), explaining this phenomenon. Together with Dr. Matthias Heinig (MDC and the Max Planck Institute for Molecular Genetics, Berlin) she is the lead author of the study. Epigenetic factors regulate the activity of genes, without changing the sequence of the gene constituents. “Therefore, the next logical step was to examine the extent to which the genes can influence epigenetic factors,” Dr. Rintisch added.
The focus of the study was on histone modifications, which are among the epigenetic factors. The DNA coils around the histone proteins and, depending on how loosely or how tightly the DNA is packed around the histones, the genes can either be read out or not. The packing condition is controlled by enzymes that bind small molecules (methyl groups) to specific loci in the histones. The histone modifications caused by the different histone methylation are critical for the gene regulation. However, the role of histones and their packing conditions are still poorly understood.
Aim – to identify susceptibility for diseases
To study the impact of genetic variability on histone marks, the researchers compared the genomes of two strains of rats – one with normal blood pressure – the other with cardiovascular diseases and metabolic disorders – with the annotated histone modification maps. Already here they could determine differences in histone modification of the two strains. To determine the genetic factors that trigger the histone modifications, another 30 strains of rats were studied, all of which emerged from the two parent strains and respectively have a “genetic mosaic” of the two rat strains.
Dr. Wei Chen of the Berlin Institute for Medical Systems Biology (BIMSB) of the MDC then sequenced the processed samples from heart and liver tissues of the animals (ChIP-sequencing). In particular in the heart tissue, the researchers identified several gene regions (QTL – Quantitative Trait Loci) that affect histone modification and thus gene activity.
“Our publicly accessible records could help to identify genetic variations that suggest a susceptibility to cardiovascular and metabolic diseases,“ explained Professor Hübner. „At the same time we have shown with our approach a novel way to discover new links between genetic makeup (genotype) and the environment (phenotype).“
*Natural variation of histone modification and its impact on gene expression in the rat genome
Carola Rintisch1,*, Matthias Heinig2,1*, Anja Bauerfeind1, Sebastian Schafer1, Christin Mieth1, Giannino Patone1, Oliver Hummel1, Wei Chen1, Stuart Cook3,9,10, Edwin Cuppen4, Maria Colomé-Tatché11, Frank Johannes5, Ritsert C. Jansen5, Helen Neil6, Michel Werner6, Michal Pravenec7, Martin Vingron2, and Norbert Hübner1,8
1Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany
2Department of Computational Biology, Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany
3National Heart and Lung Institute, Cardiovascular Genetics and Genomics, Sydney Street, London, SW3 6NP, UK
4Center for Molecular Medicine, University Medical Center Utrecht, Hubrecht Institute KNAW, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
5Groningen Bioinformatics Centre (GBIC), Groningen Biomolecular Sciences and Biotechnology Institute (GBB), Linnaeusborg 7, 9747AG Groningen, The Netherlands
6Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), iBiTec-S, Université Paris-Sud, CNRS FRE3377, F-91191 Gif-sur-Yvette cedex, France
7Institut of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, CZ-14220 Prague 4, Czech Republic
8DZHK (German Centre for Cardiovascular Research), Partner site Berlin, Berlin, Germany
9Duke-NUS Graduate Medical School, 8 College Road, 169857 Singapore
10National Heart Center Singapore, 5 Hospital Drive, 169609 Singapore
11European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, NL-9713 AV Groningen, The Netherlands
Genome Res. June 2014 24: 942-953; Published in Advance May 2, 2014, doi:10.1101/gr.169029.113
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
in the Helmholtz Association
Phone: +49 (0) 30 94 06 – 38 96
Fax: +49 (0) 30 94 06 – 38 33