Chromatin and Transcription
Chromatin describes the complex of DNA and histone proteins that can be found in the nucleus of eukaryotic cells. It provides the scaffold for the packaging of the entire genome. The basic functional unit of chromatin is the nucleosome; it contains 147 base pairs of DNA, which are wrapped around a histone octamer that consists of two copies each of histones H2A, H2B, H3 and H4. Research over the past two decades revealed that covalent modification of histone proteins and DNA can fundamentally alter the organization and function of chromatin, and that they have a crucial role in the regulation of all DNA-based processes, such as transcription, DNA repair and replication. These modifications are dynamically laid down and removed by chromatin-modifying enzymes in a highly regulated manner. Histone modifications function as docking sites for chromatin readers that specifically recognise these modifications and in turn recruit additional chromatin modifiers and remodelling enzymes. These enzymes will subsequently either add additional modifications or in case of remodellers slide nucleosomes along the DNA to generate accessible sites. Transcriptional regulation is central to cellular function and fate, highlighted by the fact that expression or inhibition of single transcription factors can alter cellular fate decisions. Ageing is accompanied by substantial changes in gene expression programs, suggesting a decline in transcriptional regulation. Recent studies in a variety of different model organism have addressed the question of how age-dependent changes are manifested by differences in transcription factor binding, histone marks, heterochromatin formation, or DNA methylation. While age-dependent alterations of these regulatory layers contribute to differences in the gene expression program, we are only beginning to understand how these layers cooperate or function on a molecular level.
To address the interplay between chromatin architecture and transcriptional regulation during the lifespan of an organism, we employ a variety of different methods, including biochemistry, cell biology and next-generation sequencing approaches.