Life Sciences Research for Lifelong Health

Type

Events

A computational model of stem cell differentiation and ageing based on dynamic interactions between Histone modifications and DNA

Regenerative mechanisms in most tissues predominately rely on an appropriately regulated balance between self-renewal and differentiation of functional adult stem cells. Epigenetic control of gene expression is critical for the maintenance of this balance. During ageing, currently unexplained drifts in chromatin organization are observed, such as trends to global DNA hypomethylation paralleled by hypermethylation at various genomic loci. Analysing published epigenetic data from human tissue, we show that these changes are accompanied by correlated drifts in histone modification levels (in particular H3K4me3). We develop a mathematical model based on dynamic interactions between histone modifications and DNA methylation, and show that the observed epigenetic changes may originate in the limited cellular capability to inherit epigenetic information. We show that spontaneous loss of histone modifications due to fluctuations on short time scales, e.g. caused by incorporation of de novo sy nthesized histones during transcription, DNA repair and cell replication, can give rise to stochastic, and thus dysfunctional long term gene silencing by DNA methylation. Specifically, our mathematical model shows that the (experimentally established) coupling between H3K4me3 modifications and DNA methyltransferase DNMT3a, in combination with cooperative, bistable histone modification dynamics, can lead to DNA hypermethylation at specific genomic loci. Finally, motivated from hematopoietic stem cell dynamics, we extend our model by considering tissue-level organization, distinguishing between a stem cell niche and a proliferative compartment. We observe coexistence of aged and young cell phenotypes, and increasing cell heterogeneity with age. Our model highlights the fundamental role of dynamic interactions between histone modifications and DNA methylation in renewal, differentiation and ageing of somatic stem cells. To book a place or to find out more please contact kec@babraham.ac.uk

Event Time & Dates

Starts01:00 pm - 30/01/2014

Event Details

Contact Michael Hinton
LocationBrian Heap Room
SpeakerDr Thimo Rohlf
Speaker AffiliationUniversity of Leipzig

Posted

9 January, 2014