Research Area 2: Role of PTM in transcription and epigenetic regulation

SP6 - Katrin Hoffmann
Effects of lamin B receptor deficiency on premature ageing, farnesylation, methylglyoxal (MGO) and histone modifications
SP7 - Anne Navarrete Santos
Role of protein modifications in developmental ageing and metabolic (epigenetic) programming
SP8 - Andreas SimmJochen Balbach
Epigenetic regulation of gene transcription by non-enzymatic protein modification

SP9 - Lars-Oliver KlotzChristoph Kaether
Modulation of Klotho/FOXO signalling by PTMs: effects on stress resistance and longevity

Altered gene expression profiles have been observed when comparing young and old tissues from several species. They often involve genes encoding key components of inflammation, mitochondrial function and lysosomal degradation pathways (de Magalhaes et al., 2009). Epigenetic modifications such as methylation or acetylation of chromatin contribute to altered gene expression and are hallmarks of ageing. Of note, both modifications can be disrupted or modulated by age-associated non-enzymatic processes, e.g. oxidation and/or glycation of histones. Gene expression is also affected by changes at the level of transcription factors known to regulate survival and longevity. Forkhead box O (FOXO) transcription factors are of specific interest in this context. They are negatively regulated by the insulin-IGF (insulin-like growth factor) pathway and thought to mediate the life-extending effects of reduced insulin signalling (Zhang et al., 2013). Following nutrient deprivation, FOXO transcription factors translocate to the nucleus where they transactivate genes involved in resistance to oxidative stress, energy metabolism, DNA damage repair, cell cycle arrest and apoptosis (Monsalve and Olmos, 2011). Transcriptional regulation is also dependent on structural nuclear requirements, which are provided by lamins that contribute to the formation of the nuclear laminas (Mattout et al., 2006). Interestingly, mutations in genes encoding lamins or lamin receptors are known to cause premature ageing with the underlying mechanisms being incompletely understood. In view of this, Research Area 2 will focus on the role of PTMs in epigenetic and transcriptional regulation (table 5). An important issue will be to understand whether nonenzymatic PTMs interfere with PTMs involved in physiological regulation of gene transcription. SP6 will use lamin receptor B-deficient mice (ic/ic mice) as a model of premature ageing and determine the role of non-enzymatic glycation on histone and lamin modifications and subsequent functional alterations. In SP7 it will be investigated whether AGE modifications caused by the metabolic situation of the mother lead to epigenetic reprogramming of the offspring and whether PTMs of FOXO transcription factors play a role. An established model of hyperglycaemia in rabbits will be utilised for this work. SP8 will focus on PTMs in nuclear proteins in different models of cellular senescence and tumourigenity. The role of metabolism-derived dicarbonyls, which may accumulate under age-related metabolic shifts, will be of particular interest. The consequences of histone modifications will be investigated in collaboration with several other subprojects that provide expertise in cellular signalling processes and functional assays. This project requires the application of an advanced NMR technique, which has already been established in the group. SP9 will concentrate on PTMs related to FOXO signalling pathways. In particular, it will be important to understand whether non-enzymatic glycation or oxidation will lead to ligand-independent changes of FOXO signalling and affect the Klotho-FOXO signalling axis. Klotho has been shown to extend lifespan in mice and is considered to be an anti-ageing hormone. Data from Research Area 2 will contribute to a better understanding of how PTMs contribute to epigenetic and transcriptional alterations in ageing. Experiments focus on irreversible non-enzymatic modification with a high probability of identifying new biomarkers of ageing, which subsequently will be tested in samples from epidemiological cohorts . One strength of Research Area 2 is the availability of different animal models of ageing (ic/ic mice, Klotho-knockout mice and others), which will provide insights into the normal ageing process and will foster various collaborations with other subprojects.