Epigenetic and transcriptional variability contribute to the vast diversity of cellular and organismal phenotypes and are key in human health and disease. In this review, we describe different types, sources, and determinants of epigenetic and transcriptional variability, enabling cells and organisms to adapt and evolve to a changing environment. We highlight the latest research and hypotheses on how chromatin structure and the epigenome influence gene expression variability. Further, we provide an overview of challenges in the analysis of biological variability. An improved understanding of the molecular mechanisms underlying epigenetic and transcriptional variability, at both the intra- and inter-individual level, provides great opportunity for disease prevention, better therapeutic approaches, and personalized medicine.

SE and SBare funded by the UK National Institute for Health Research UCLH Biomedical Research Center (BRC84/CN/SB/5984) and the H2020 Project MultipleMS (733161). VP and AV are funded by the Joint BSC-IRB-CRG Program in Computational Biology and Severo Ochoa Award (SEV 2015– 0493).TheMRC/BHF Cardiovascular EpidemiologyUnit is supportedby the UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194), andNIHR Cambridge Biomedical Research Centre. We thank Allan Orozco for providing critical comments on the manuscript, and Laura Phipps for proofreading the text.

Peer Reviewed