Epigenetic memories: structural marks or active circuits?

Abstract

A hallmark of living systems is the management and the storage of information through genetic and epigenetic mechanisms. Although the notion of epigenetics was originally given to any regulation beyond DNA sequence, it has often been restricted to chromatin modifications, supposed to behave as cis-markers, specifying the sets of genes to be expressed or repressed. This definition does not take into account the initial view of epigenetics, based on nonlinear interaction networks whose "attractors" can remain stable without need for any chromatin mark. In addition, most chromatin modifications are the steady state resultants of highly dynamic modification and de-modification activities and, as such, seem poorly appropriate to work as long-term memory keepers. Instead, the basic support of epigenetic memory could remain the attractors, to which chromatin modifications belong as do many other components. The influence of chromatin modifications in memory is highly questionable when envisioned as static structural marks, but can be recovered under the dynamic circuitry perspective, thanks to their self-templating properties. Beside their standard repressive or permissive functions, chromatin modifications can also influence transcription in multiple ways such as: (1) by randomizing or inversely stabilizing gene expression, (2) by mediating cooperativity between pioneer and secondary transcription factors, and (3) in the hysteresis and the ultrasensitivity of gene expression switches, allowing the cells to take unambiguous transcriptional decisions.

A model of dynamic stability of H3K9me3 heterochromatin to explain the resistance to reprogramming of differentiated cells

“…Cells and their epigenetic marks are open systems with permanent molecular renewal, in which no molecular complexes can be definitely locked [34,35]. Chromatin modifications were initially considered as static epigenetic marks, but have then been shown highly reversible and labile, continuously written and erased by antagonistic chromatin-modifying and -demodifying enzymes present together in the cell [36].…”

Life is a Self-Organizing Machine Driven by the Informational Cycle of Brillouin

“…In this respect, Szilard and Brillouin, who wrote their studies before the discovery of the genetic code, were particularly clear-sighted. In practice, terrestrial life uses several information-storage devices: long-term genetic (DNA) and short-term epigenetic, in the form of either chemical or structural modifications or of active circuits (Nicol-Benoît et al, 2012). The DNA that we received at the stage of the egg should be appreciated as an invaluable gift, because it contains digitally-engraved information concentrating billions of cycles of Brillouin.…”

“…The essential role of TF dimerisation could in fact be that it provides a natural mechanism to eliminate microstates: those made of DNA bound by TF monomers. This simple fact is sufficient to generate nonlinearity, indispensable to design conditional memory circuits (Nicol-Benoît et al, 2012). The need for nonlinearity is basically related to integrative networks.…”

“…It is remarkable that the only persistent molecule throughout cellular lifespan is DNA, which can be marginally repaired but is not replaced, contrary to all the other cellular components. These permanent turnovers allow the multistability of biochemical networks and the shaping of the epigenetic landscape of Waddington (Ferrell, 2012;Nicol-Benoît et al, 2012). Multistability can emerge only out of equilibrium whereas at equilibrium, only one final state is possible when starting from the same ingredients.…”

New Developments and Trends in Tissue Engineering: An Update

“…Although the notion of epigenetics was originally given to any regulation beyond DNA sequence, it has often been restricted to chromatin modifications, supposed to behave as cis-markers, specifying the sets of genes to be expressed or repressed. This definition does not take into account the initial view of epigenetics, based on nonlinear interaction networks whose "attractors" can remain stable without need for any chromatin mark [50]. Epigenetics has reborn as a new field of developmental genetics.…”