Epigenetic Regulation of the Mammalian Cell

Abstract

BackgroundUnderstanding how mammalian cells are regulated epigenetically to express phenotype is a priority. The cellular phenotypic transition, induced by ionising radiation, from a normal cell to the genomic instability phenotype, where the ability to replicate the genotype accurately is compromised, illustrates important features of epigenetic regulation. Based on this phenomenon and earlier work we propose a model to describe the mammalian cell as a self assembled open system operating in an environment that includes its genotype, neighbouring cells and beyond. Phenotype is represented by high dimensional attractors, evolutionarily conditioned for stability and robustness and contingent on rules of engagement between gene products encoded in the genetic network.Methodology/FindingsWe describe how this system functions and note the indeterminacy and fluidity of its internal workings which place it in the logical reasoning framework of predicative logic. We find that the hypothesis is supported by evidence from cell and molecular biology.ConclusionsEpigenetic regulation and memory are fundamentally physical, as opposed to chemical, processes and the transition to genomic instability is an important feature of mammalian cells with probable fundamental relevance to speciation and carcinogenesis. A source of evolutionarily selectable variation, in terms of the rules of engagement between gene products, is seen as more likely to have greater prominence than genetic variation in an evolutionary context. As this epigenetic variation is based on attractor states phenotypic changes are not gradual; a phenotypic transition can involve the changed contribution of several gene products in a single step.

Genes without prominence: a reappraisal of the foundations of biology

“…The majority of coding sequences in the human genome lead to more than one peptide per sequence through diverse splicing of exons and each of these peptides may, through multiple folding opportunities, lead to more than one protein, which may be activated in a number of ways, for example, by phosphorylation. These proteins interact with each other according to the rules of engagement (information acquired upon folding and post-translational processes) to contribute to the output of the attractor [20]. These energy dissipative processes are symmetry-breaking and potentially give rise to emergent and irreducible (to the originating DNA sequences and indeed proteins) phenotypic properties.…”

“…This implies that an epigenetic 2 mechanism for the regulation of the cell and a model for such has been proposed for mammalian cells [20] (applies to any eukaryotic cell) and compared with competing genetic regulatory mechanisms [7]. True replication, in contrast to the simple splitting of a cell into two, is favoured when it allows free energy to be consumed more effectively.…”

“…proteins derived from peptides by folding and other post-translational processes such as phosphorylation [20]. It is useful to envisage the cell/ system as comprising a state space with a dimension for each active gene product arbitrarily calibrated from zero to the maximum expressible activity.…”

“…jumps from one thermodynamic steady state to another. The attractor of a cell from a stably replicating species is termed the 'home' attractor: it has been evolutionarily conditioned to optimize the integrity of replication [20]. The state space specified by the human genotype potentially contains a very large number of attractors to consume free energy under various circumstances [7].…”

Emotion: The self-regulatory sense

“…Upon the mapping of the genome, however, the subsequent revelations about epigenetic control processes have forever altered the central dogma by elucidating the crucial role of environmental cues, intrinsic signals, and cellular memory in evolution. [186][187][188] Revelations of how supposedly "junk DNA" and noncoding RNA are actually providing ongoing regulatory switching 189,190 ; with relational ifthen rules of engagement that ensure specific gene products are brought into action when and only when appropriate, 191 and mediating the very developmental morphology of an organism 192 as well as its behavior. Revelations of how epigenetic switching yields critical modifications during cellular stress responses, 100,[193][194][195][196] plays a key role in immune functioning, 197 and serves as modulators of neuronal responses, 198 of neural development and neuroplasticity.…”