The functional status of chromatin is regulated by epigenetic features on the DNA, such as the methylation of specific CpG islands at gene promoter sites, which leads to the silencing of the corresponding gene region. The epigenetic attachment of acetyl, methyl, phopho, ubiquitin and other groups to various basic amino acids on the histone tails protruding from the nucleosome core form a so-called “histone code”. This regulates and fine-tunes the accessibility of the DNA bound to these nucleosome parts for specific adaptor proteins.
Beyond purely genetic changes such as mutations, deletions or fusions, these epigenetic changes are important for the development and progression of various diseases such as cardiovascular, inflammatory, degenerative and malignant diseases and provide diagnostic and prognostic information. Epigenetic changes in nucleosomes can be detected both at the cellular level and after release from the cells into the bloodstream and other body fluids.
Nucleosomes are known to be highly elevated in the blood after acute myocardial infarctionSee heart attack., trauma, autoimmune diseases and cancer. Recently, they have also been detected at greatly increased levels in COVID-19 patients with severe disease progression. Modifications of nucleosomes can be assessed by immunoassays and mass spectrometry and further characterised by ChIP-Seq approaches.
Recent ChIP-Seq studies demonstrate that the extensive genomic pattern associated with modified nucleosomes circulating in the blood is indicative of the tissue from which they originate. Therefore, the aim of our group is to develop standardised techniques to characterise epigenetic nucleosome changes and the associated DNA in defined cell cultures and in the blood of patients with acute and chronic diseases. In addition, we hope to develop robust and meaningful diagnostic tests for this new class of biomarkers.
Publications
- Holdenrieder S, Stieber P. Clinical use of circulating nucleosomes. Crit Rev Lab Med Sci, 2009; 46: 1-24.
- Gezer U, Üstek D, Yörüker EE, Cakiris A, Abaci N, Leszinski G, Dalay N, Holdenrieder S. Characterization of H3K9me3 and H4K20me3-associated circulating nucleosomal DNA by high-throughput sequencing in colorectal cancer. Tumour Biol 2013; 34: 329-36.
- Holdenrieder S, Dharuman Y, Standop J, Trimpop N, Herzog M, Hettwer K, Simon K, Uhlig S, Micallef J. Novel nucleosomics serumThe liquid component of blood freed from blood cells and clotting substances. biomarkers for the detection of colorectal cancer. Anticancer Res 2014; 34: 2357-2362.
- Stahl J, Hoecherl EF, Durner J, Nagel D, Wolf K, Holdenrieder S. HMGB1, RAGE and nucleosomes as new prognostic markers after multiple trauma. J Lab Med 2016; 40: 165-173.
- Holdenrieder S. Liquid profiling of circulating nucleic acids as novel tool for the management of cancer patients. Adv Exp Med Biol 2016; 924: 53-60.
- Völker-Albert M, Bronkhorst A, Holdenrieder S, Imhof A. Histone modifications in stem cell development and their clinical implications. Stem Cell Reports 2020; 15: 1196-1205.
- Ungerer V, Bronkhorst AJ, van den Ackerveken P, Herzog M, Holdenrieder S. Serial profiling of cell-free DNA and nucleosome histone modifications in three cell lines. Sci Rep 2021; 11: 9460.
- Cavalier E, Guiot J, Lechner K, Dutsch A, Eccleston M, Herzog M, Schomburg A, Kelly T, Holdenrieder S. Circulating nucleosomes as potential prognostic markers for COVID-19 disease severity. Front Mol Biosci 2021; 8: 600881.
