Review of 'Lipids contribute to epigenetic control via chromatin structure and functions'

The manuscript entitled "Lipids contribute to epigenetic control via chromatin structure and functions" provides a timely review of current research bridging the frontiers of lipidomic and epigenetic regulation. The topic and the ideas behind this review are of high importance and innovative. However, despite the fact that the review includes the most important issues of the current knowledge of how certain lipid species may contribute to epigenetic control, some aspects need refinement concerning terminology and interpretation:

1) The current understanding of "lipids" in the field of lipidomic research defines "lipid classes" and "lipid" species within lipid classes (e.g. ester- or ether bonds mostly due to variation of fatty acid chain length, double bonds, cis/trans configuration or hydroxylation). Unfortunately, the authors do not mention lipid classes and species. Instead, they use variable terminologies, e.g. "specific lipid molecules; shotgun analysis of total lipids....contain common types of lipids; lipids at the edge of the cellular compartment; lipid functions as energy storage molecules; what makes lipids such an effective cellular compartment; lipid carbon chain function of lipids inside the nucleus; PC is the most abundant lipid in cell membranes; etc.". The authors should be more specific and relate their wording more precisely to lipid classes and species and to the related biochemical pathways.

Similarly, instead of e.g. "proteomics has identified lipid synthesis enzymes", the authors should be more specific as related to synthetases, hydrolases, and transferases of fatty acids, phospholipids/lysophospholipoids, sphingolipids, or certain lipid mediators (Mediator Lipidomics).

If the authors follow this advice, they will recognize, that these enzymes represent an important functional principle to regulate precursor/product and mediator lipidomic effects in epigenetic control. Interestingly the minor lipid species with the shortest half-life are the most important and potent ones.

2) The authors should also consider to include acetylation into table 2 as the starting point of "Lipid modifications of histone proteins...", since all of the molecular lipid species mentioned, are starting-, intermediate-, or end-products of the Fatty Acid Synthase (FAS)-complex. Thus, histone acetylation/deacetylation could be considered as a regulatory principle behind precursor-(acetate), intermediate-(propionate, butyrate, malonate, succinate), and product-(palmitate) epigenetic control.

This would also allow to distinguish the effects of endogenous FAS-pathway intermediates from absorbed exogenous dietary precursors, intermediates and end products especially in metabolic overload disorders related to "Diabesity".

3) Similarly, the authors should better integrate the aspects of farnesylation and geranylation as intermediates of the cholesterol synthesis pathway, which also starts with acetate but ends with cholesterol. In addition, there is considerable published evidence, that other intermediates of this pathway including mevalonate, dolichols, GPI-anchor synthesis, etc. influence DNA-processing, cell cycle, proliferation and differentiation. The authors may summarize this aspects in a similar table as shown in table 2 for FAS-metabolites.

Moreover, miRNAs related to Lipidomic genes, e.g. SREBP1/2 may also contribute to epigenetic control. This latter aspect is still missing in the current manuscript.

If the authors re-interpret their current considerations on the basis of the points raised here under 2) + 3), the influence of lipid species from both , the FAS-pathway and the cholesterol synthesis pathway in epigenetic control, the concept behind the review may become clearer. 

4) Concerning S-adenosine methionine (SAM) and DNA-methylation the authors should also mention that the homocysteine metabolism is critically influenced by choline/betaine, which explains the coincidence of hyperhomocysteinemia and enhanced PC-synthesis under fibrate therapy (choline steeling mechanism).

5) The statement "Erythrocytes contained lower amounts of tightly bound neutral lipids (e.g.cholesterol)", is not correct.

On a molar basis erythrocytes contain the highest cholesterol levels of all blood cells, and contain double the amount of cholesterol as compared to PCs.

6) If the authors mention "phospatidylethanolamination", they should also include phosphatidylcholination and phosphatidylserination as important regulators of terminal LC3-activation in the control of autophagy and apoptosis.