Age-related loss of gene-to-gene transcriptional network coordination among single cells

  Guy Amit  ,  Orr Levy  ,  Dana Vaknin  ,  Tom Snir  ,  Peter Castaldi  ,  Yang-Yu Liu  ,  Haim Y Cohen  ,  Amir Bashan  
Department of Physics, Bar-Ilan University, Ramat-Gan 52900, Israel
The Mina and Everard Goodman Faculty of Life Science, Bar-Ilan University, Ramat-Gan, Israel
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Division of Primary Care and General Medicine, Brigham and Women's Hospital, Boston, MA USA

A long-standing model holds that stochastic aberrations of transcriptional regulation play a key role in the process of ageing. While transcriptional dysregulation is observed in many cell types in the form of increased cell-to-cell variability, its generality to all cell types remains doubted. Here, we propose a new approach for analysing transcriptional regulation in single-cell RNA sequencing data by focusing on the global coordination between the genes rather than the variability of individual genes or correlations between pairs of genes. Consistently, across very different organisms and cell types, we find a decrease in the gene-to-gene transcriptional coordination in ageing cells. In addition, we find that loss of gene-to-gene transcriptional coordination is associated with high mutational load of a specific, age-related signature and with radiation-induced DNA damage. These observations suggest a general, potentially universal, stochastic attribute of transcriptional dysregulation in ageing.