What is DNA Extract
When genes cannot be unpacked: mouse model established for disturbed histone metabolism
Genes are usually carefully packaged in the cell nucleus: the corresponding sections of the thread-like DNA are wrapped around small proteins - the histones - to save space. In particular, inactive genes are often packed particularly tightly. Certain enzymes - so-called histone acetyltransferases (HAT) - reduce the binding of the histones to the DNA, so that the genes can be unpacked and activated.
Professor Dr. Martin Göttlicher, the head of the GSF Institute for Toxicology (Photo: Ulla Baumgart)
Dr. Thomas Floss, Institute for Developmental Genetics (Photo: mvdh)
Opponents of HATs are histone deacetylases (HDACs), which amplify the packaging and inactivation of genes and are involved in many regulatory processes. Mice that do not produce HDACs are valuable model organisms that help understand the importance of HDACs in the development of diseases and the benefits that can be expected from HDAC-inhibiting drugs.
Scientists at the GSF - Research Center for Environment and Health, a member of the Helmholtz Association, succeeded in creating a line of mice in which the gene for the production of one of the HDACs, histone deacetylase 2 (HDAC2), is switched off. The consequences of this defect make the mice interesting for both cancer and heart research.
“There are eleven classic deacetylases. The trick is to find out which deacetylases control which processes, ”explains Professor Dr. Martin Göttlicher, head of the GSF Institute for Toxicology, who, together with scientists from the GSF Institute for Developmental Genetics (IDG), initiated the establishment of the HDAC2-deficient mouse line.
Göttlicher himself is interested in regulatory mechanisms that lead to the development of colon tumors - HDAC2 probably plays a role here. It is already known from some other tumors that the packaging reinforced by histone deacetylase apparently inactivated genes that normally drive the cells into programmed cell death (apoptosis). HDAC inhibitors could possibly reactivate apoptosis and thus stop tumor growth.
HDAC2 is also involved in other processes, e.g. the growth of heart cells. That is why the GSF scientists are also cooperating with an American research group led by Professor Jonathan Epstein (University of Pennsylvania), which is investigating this aspect in particular. Together, the scientists are now reporting in the journal Nature Medicine that HDAC2 plays a role in the development of a pathological enlargement of the heart - cardiac hypertrophy. If the heart is overloaded e.g. by stress or overexertion, it reacts by growth - it gets bigger and bigger, but not more efficient. Ultimately, this can lead to heart failure. Obviously HDAC2 is involved in this fatal spiral, because the HDAC2-deficient mice showed no enlargement of the heart even under high stress. HDAC2 intervenes in a signaling pathway that is necessary to trigger hypertrophic growth. "If you can find a way to specifically inhibit HDAC2, you may be able to develop a drug against this disease," hopes Göttlicher.
"However, one must not conclude that HDAC2 activity is exclusively disadvantageous," explains Dr. Thomas Floss (IDG), who created the mouse line with the help of the gene trap technology, which is well established at the GSF: "The mice show various impairments without HDAC2, for example they are significantly smaller than their wild-type siblings". Obviously, HDAC2 - like all histone deacetylases - intervenes in finely tuned control loops. Therefore it is probably important for potential therapeutic approaches to find inhibitors that only switch off very specific HDACs selectively. “The question is which individual HDACs one has to interfere with in order to combat diseases without disrupting other processes that are important for health,” emphasizes Göttlicher - and the GSF mice should help to solve this question.
Photos in 300 dpi resolution
Picture 1, picture 2
Online publication: Nature Medicine, February 18, 2007; | doi: 10.1038 / nm1552
Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3ß activity;
Chinmay M Trivedi, Yang Luo, Zhan Yin, Maozhen Zhang, Wenting Zhu, Tao Wang, Thomas Floss, Martin Goettlicher, Patricia Ruiz Noppinger, Wolfgang Wurst, Victor A Ferrari, Charles S Abrams, Peter J Gruber & Jonathan A Epstein
PubMed Abstract: Further
Contact to the GSF press office:
GSF - Research Center for Environment and Health, Dipl.-Ing. Heinz-Jörg Haury, Communication Department, Press Officer Tel: 089 / 3187-2460, Fax 089 / 3187-3324, E-Mail: oeanoSp @ m @ helmholtz-muenchen.de
Neuherberg, March 7, 2007
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