TY - JOUR T1 - Evaluating the Stability and Flexibility of DNA Methylation Patterns from Stem to Differentiated Cells JF - bioRxiv DO - 10.1101/072488 SP - 072488 AU - Minseung Choi AU - Diane P. Genereux AU - Jamie Goodson AU - Haneen Al-Azzawi AU - Shannon Q. Allain AU - Stan Palasek AU - Carol B. Ware AU - Chris Cavanaugh AU - Daniel G. Miller AU - Winslow C. Johnson AU - Kevin D. Sinclair AU - Reinhard Stöger AU - Charles D. Laird Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/08/31/072488.abstract N2 - DNA methylation has been studied extensively in many developmental systems. Little attention, however, has been given to identifying methylation features that distinguish loci whose patterns are in flux in a given cell lineage from those whose patterns are stable. Here, we develop a new metric, the Ratio of Concordance Preference (RCP), to quantify and compare epigenetic flexibility and stability across loci, cell types, and developmental stages, without assuming any specific biochemical mechanisms. We apply RCP to double-stranded DNA methylation data from human and murine cells and conclude that: (i) preference for concordant DNA methylation is reduced but not eliminated in stem relative to differentiated cells; (ii) cellular differentiation is characterized by increasing preference for concordant methylation states; and (iii) while concordance preference remains substantial through embryonic totipotency and early stages of pluripotency, primordial germ cells initially have nearly no preference for concordance, perhaps reflecting the high level of epigenetic flexibility en route to production of gametes. The mechanism-free nature of RCP will enable comparison of DNA methylation systems not only across cell types and developmental stages, but also across organisms whose methylation machineries are not well understood or may differ significantly.Author Summary In storing and transmitting epigenetic information, organisms must balance the need to maintain information about past conditions with the capacity to respond to current and future information from their environments. Methylation states can be transmitted with variable levels of fidelity from parent to daughter strand: high fidelity confers strong pattern matching between the strands of individual DNA molecules and thus pattern stability over rounds of DNA replication; lower fidelity confers reduced pattern matching, and thus greater flexibility. We are interested in the strategies that various cell types, organisms, and species use to achieve balance between flexibility and stability. Here, we present a new conceptual framework, the Ratio of Concordance Preference (RCP), that can quantify the flexibility and stability of the system that gave rise to a given set of DNA methylation patterns. We confirmed previous observations that differentiated cells operate with high DNA methylation stability. In contrast, increased flexibility was inferred for a wide variety of stem cells, although substantial levels of stability remained. One exception was the near-complete, albeit transient, potential loss of stability in the precursors of eggs and sperm. Broader application of our RCP framework will permit comparison of epigenetic-information systems across cells, developmental stages, and organisms whose methylation machineries differ substantially or are not yet well understood. ER -