Is Metabolic Epigenetics as Ancient as Life Itself? Of Memory that Might Pre‐Date RNA and DNA
Year: 2019
Type: editorial
Abstract: Around 10 years ago one could still (and I did) regularly hear people saying “Epigenetics, huh, they really don't know what they're talking about…”. In 2013 there was a small, but extremely interesting Keystone Symposium that doubtless slipped under the radar of media that reach educated and interested non-specialists. February in Santa Fe, new Mexico, at around 2200 m above sea level, is an ideal setting for focusing meeting attendees on the business at hand! That business was essentially presenting intriguing emerging insights into the link between nutrition, epigenetics and human health (as the symposium was titled https://tks.keystonesymposia.org/index.cfm?e=Web.Meeting.Program&MeetingID=1212). What we were witnessing was the birth of a new discipline, and although this might not be “official” yet, “metabolic epigenetics” would be a fitting name for it. In November 2019 at the EMBO/EMBL Symposium “Metabolism Meets Epigenetics” (https://www.embo-embl-symposia.org/symposia/2019/EES19-11/index.html), another fascinating meeting, it was clear that many epigenetic effects are starting to make great sense. Basically, they can tune, or even radically change, the behaviour or phenotype of cells and whole organisms in response to metabolic demands and constraints. Histone acetylation and methylation were arguably the most-mentioned epigenetic “marks”, as it were, bridging to metabolism via the metabolic intermediates, respectively, acetyl coenzyme A (Acetyl-CoA) or S-Adenosyl methionine (SAM) and S-Adenosyl-L-homocysteine (SAH). For example (and oversimplified in the interest of brevity), Acetyl-CoA is a key product of carbon metabolism, being made very early on from the glycolysis of carbohydrates or beta-oxidation of fats and lipids (via pyruvate). As such it is a good “signal” for the cell to switch from a quiescent state to one of growth and multiplication: as glycolysis or beta-oxidation really get going, not all of the resultant Acetyl-CoA goes into the Krebs cycle (tricarboxylic acid cycle) to produce reducing equivalents NADH and FADH2 and the energy-carrier GTP; some – via histone acetyl transferases (HATs) – starts to acetylate histones of growth genes, hence activating them or upregulating their expression. In addition, relative ratios or concentrations of NAD:NADH, FAD:FADH2, ADP:ATP, GDP:GTP and possibly even glucose itself seem to act in concert with acetyl and methyl donors to achieve a combination of large changes and fine-tuning: intermediate metabolites hence act as a complex and highly refined signaling network to regulate gene expression in response to changing nutritional environments. What is more, some of these modifications persist over several generations as epigenetic memory. Perhaps even more provocatively, as presented at the symposium, histones might even act as a “sink” for soaking up basic metabolites, an example being histone methylation, which shifts the equilibrium between SAM and cysteine to favour cysteine, a key metabolite, not least because it is needed for making one of the cell's principal antioxidant: glutathione. In this issue of BioEssays, Razvan Stan et al. expand the range of non-genetic modifications in the cell to protein conformations,1 hypothesizing that regulatory proteins modulate metabolism (and reproduction) via a molecular memory that acts as the interface between them and the environment. Citing examples of non-linear behaviour (hysteresis) in response to ligands, as well as prions and post-translational phosphorylation, for instance, the authors propose that signalling networks can adapt in real time within a single cell, and harbour a “memory” of metabolic events. Why, indeed, should epigenetics be limited to DNA/histone modifications and non-coding RNAs? Focusing now on proteins as “memory carriers”, it seems to me that another part of biology is also becoming clearer from studies on metabolic epigenetics: the origin and evolution of the most primitive life on Earth. It is no coincidence that, according to latest theories, primitive metabolism was at the heart of ancient self-organizing systems that became life as we know it. Though not as ancient as the probable redox chemistry that might have sparked life (e.g., green rust or iron-sulphur compounds), inorganic phosphate has left a trace in the evolution of energy gradients used in cells. Orthophosphate and acetyl phosphate (perhaps the “acetyl” is also no coincidence) are proposed to be primordial energy currencies. And the fact that many biological systems can run on inorganic phosphate, as well as the organic GTP and ATP energy currencies, might be an ancient trace of early beginnings of metabolic epigenetics – not in the form of DNA modifications (DNA came much later), but rather protein phosphorylation that we see today as a very important post-translational modification. Could modulation of protein activity via phosphorylation – in response to metabolically relevant changes in cellular “high-energy phosphate” concentration – be the primordial form of epigenetics? Today we consider epigenetics as modifications to DNA and histones, and binding of non-coding RNAs, that affect gene expression. However, this view is strongly conditioned by the prevailing dogma of DNA as the genetic material, the “memory” of a cell, and epigenetic modifications that directly impact DNA as the “nuances” of that memory. I speculate that the present-day role of phosphate in cells might be a clue to a primordial type of heritable metabolic memory based on proteins – one that also extends to protein conformation – before nucleic acids had become the genetic material. Conformational changes in protein loops and helices as a result of phosphorylation have long been known and predicted.2 Though often subtle, they clearly modulate the role of proteins in regulatory and signalling pathways.3 Indeed, post-translational modifications in general may be considered candidates for an ancient metabolic modulation and memory system. Primordial epigenetics? I welcome comments! Andrew Moore Editor-in-Chief
Source: BioEssays
Author: Andrew Moore
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2994671640