Genome-wide approaches like high-throughput DNA- and RNA-sequencing have shown that only a small part of eukaryotic genomes codes for proteins (e.g. in human only 1.5%). However, virtually the whole non-coding part is also transcribed, giving rise to thousands of non-coding RNAs (ncRNAs). The biological role of these ncRNAs has been intensively investigated over last decade, showing that they have various functions in the cell nucleus and the cytoplasm. One of the most interesting features of ncRNAs is that many of them can modulate the chromatin state in a site-specific manner. However, in most cases it is not clear how ncRNAs find their specific target sites in the genome.
Tethering via chromatin-bound proteins can be one mechanism, but is indirect and has limited discriminative power. Therefore, direct sequence-specific interactions of ncRNAs with genomic DNA are better suited. This is the case for the building of triple stranded RNA/DNA structures like triple helices (triplexes), in which the RNA binds to the major groove of the DNA double helix via Hoogsteen base pairing.
RNA:DNA triplexes have certain sequence requirements and thus allow a relaxed sequence specificity between both nucleic acids, i.e. triplex-forming RNAs can act in cis or in trans at one or several genomic loci. These features, together with the non-invasive interaction with DNA, make RNA:DNA triplex formation a very attractive targeting mechanism for ncRNAs. However, the detection of RNA:DNA triplexes in cells is very difficult and there are only a few reports describing a role of these structures in gene regulation.
AgingComb - Investigation of genome aging using high-throughput analysis of DNA replication and recombination
Numerous studies in recent years point to the importance of progressive damage to the genome during ageing. However, the molecular mechanisms that perturb genome integrity in old age are only partially understood. Within the Leibniz ScienceCampus Regenerative Aging, the research groups of Holger Bierhoff (Friedrich Schiller University Jena), Thomas Liehr, Florian Heidel (both University Hospital Jena) and Helmut Pospiech (Leibniz Institute on Aging) cooperate in this field. The cooperative project AgingComb sheds light on two central processes of DNA metabolism that affect the integrity of the genome: replication and recombination. By using the innovative 'Molecular Combing' technique, changes in the genome structure can be documented in a high-throughput process utilizing the Fiber Combing Platform of Genomic Vision. The data sets generated by this technique allow new insights into the stability of the genome and the molecular mechanisms that affect DNA replication and recombination during aging. By combining our expertise from basic research and clinical practice, we intend to generate benefits for clinical applications.
The AgingComb project is funded by the European Union's European Regional Development Fund (ERDF), which is provided by the Thuringian Ministry of Economics, Science and Digital Society.
Establishment of the nucleolus as a cellular indicator and target for healthy ageing
In our ever ageing society, age-related illnesses and loss of performance pose ever greater problems for our social and health systems. Therefore, measures for healthy aging and meaningful age diagnostics are becoming increasingly important. New studies show that ageing is closely related to changes in the structure and activity of the nucleolus, a part in the cell’s nucleus.
The present research project aims at elucidating molecular changes of the nucleolus during aging. The investigations are carried out in various model systems and on human biopsies to gain insights into human ageing and the ageing of an organism. The results will be used to derive and validate biomarkers and measures for healthy aging, which will be applicable in medicine and diagnostics. The project was conceived within the Center for Aging Research Jena (ZAJ) between Holger Bierhoff from the Friedrich Schiller University and Maria Ermolaeva from the Leibniz Institute on Aging. There is also close cooperation and scientific exchange with industrial partners from Thuringia.
The project is made possible with funding from the European Social Fund (ESF) of the European Union and with support from the Thuringian Ministry of Economics, Science and Digital Society.