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Is post-transcriptional regulation of gene expression (for example regulation by microRNAs) a type of epigenetic gene expression regulation?

I think we can categorize it as epigenetic since the DNA sequence is not changed, but I have never come across that terming in any papers. Does someone have any idea, or know of any papers that categorize post-transcriptional regulation as epigenetic?

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miRNAs and other post-transcriptional regulators are very well "genetic". They are encoded by genetic elements, are expressed and are affected by mutations. Just because this mode of regulation was not well known previously, it should not be classified as an epigenetic mechanism while the traditional protein based transcription factors (TF) are not.

Epigenetics, as it is originally defined (the "formal definition") is about mechanisms that can perpetuate the state of a cell to its next generation. Inheritance of gene expression programmes is therefore epigenetic. Although the gene expression programmes themselves can be implemented via different factors including protein and RNA based regulators, they would not necessarily constitute the epigenetic mechanisms that lead to inheritance of this state.

rg255's point of view is that any mechanism that causes a variation in the functional aspects of the genome without altering the genome sequence itself, would be epigenetic. This is technically correct but in that case all gene expression regulators including TFs should constitute epigenetic mechanisms.


Now, the main issue is where to draw the line between gene regulation and epigenetics?

In my opinion, the epigenetic mechanisms are one of the ways to regulate the gene expression. Although histone modifications and DNA methylation regulate gene expression and also confer heritability to the gene expression programme, the heritability can be implemented without them as well.

You can imagine a cell as a vessel which runs a system of biochemical reactions. This system can have multiple steady states (for e.g. multiple fates of a stem cell). To perpetuate a state, the new cell just needs to have the right initial conditions. This can be proved mathematically too. Such a system can be implemented via the traditional transcription factors as well. So what is epigenetic?

IMHO epigenetic was a loose term to denote something that people were not fully aware of, at that time. Anything that was not directly mediated by transcription factors was termed as epigenetic, including long distance regulators, non-coding RNA etc.


BOTTOMLINE

I would not classify non-coding RNAs as "epigenetic" for the very reason that they are encoded by genes and have more or less a direct effect on the target genes, just like TFs (which are apparently not epigenetic). As for the papers, there were many papers that used to assign these under epigenetic mechanisms, but that is IMO just too vaguely arbitrary. (Ironically, I happened to come across miRNAs and lncRNAs while I was doing a summer project on epigenetics and was reading relevant papers.)

What should be considered epigenetic would be a subject of another debate.

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  • $\begingroup$ How can you implement functionally non-fatal heritable mechanisms without the presence of histone modifications and methylation? The conservative epigenetics definition revolves around heritable mechanisms (not loose), the contemporary epigenetics definition is now loose encompassing fields which we understand better than we did in previous years (noncoding RNAs, chromatin architecture included). $\endgroup$ – FoldedChromatin Aug 17 '16 at 8:57
  • $\begingroup$ How can you implement functionally non-fatal heritable mechanisms without the presence of histone modifications and methylation?... It is theoretically possible and there are examples too but I cannot remember them at this moment. The point is that you are thinking from a top-down point of view (looking at the world from a human/animal/eukaryotic point of view). A self sustaining system does not need histone modifications. Look at the cell cycle, for example. $\endgroup$ – WYSIWYG Aug 17 '16 at 8:59
  • $\begingroup$ I meant an experimental system. I would be very interested in seeing such an implementation in a eukaryotic system where the mechanisms have been completely removed (not cases such as ipsc where the marks are procedurally removed and re-established by the system) and the system is able to propagate without these mechanisms. $\endgroup$ – FoldedChromatin Aug 17 '16 at 9:07
  • $\begingroup$ @KoustavPal That would be very difficult to implement because the cells have evolved to be dependent on that complexity and it would not be possible for the cell to survive if you strip that off from it. However, a self sustaining system can exist without these mechanisms (exist just because of the GRN). It is likely that histone modifications etc came later in the course of evolution. Prokaryotic organisms don't even have typical histones! $\endgroup$ – WYSIWYG Aug 17 '16 at 9:11
  • $\begingroup$ GRN?. Ofcourse they had to come later, you might find this on prokaryotic memory interesting, I read something similar or this one a long time ago (nature.com/nature/journal/v460/n7252/abs/nature08112.html), my point with the original question was a system which has evolved a regulome around these features would find it very hard to survive without them, although a system without them wouldn't need them at all. So that sort of makes the statement moot. We are talking about very different systems altogether, with entirely different contexts, the statement to me implies $\endgroup$ – FoldedChromatin Aug 17 '16 at 9:26
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On epigenetic and genetic effects:

Changes to the genome can be of two key types: genetic and epigenetic. Genetic changes are those which cause changes in the nucleotide sequence. Epigenetic are changes to the genome that do not involve making changes to the nucleotide sequence, e.g. post-transcriptional processing.

"Functionally relevant changes to the genome that do not involve a change in the nucleotide sequence. Examples of mechanisms that produce such changes are DNA methylation and histone modification, each of which alters how genes are expressed without altering the underlying DNA sequence".

Epigenetics is also generally used to refer to the study of variation induced by heritable non-genetic factors that affect the genome, such as maternal and paternal effects. The two subtly different definitions are responsible for some of the common confusion.

"Today, epigenetics refers to the study of heritable changes in gene expression without the change in gene sequence. ".

On microRNA

There is some contention around whether miRNA is specifically an epigenetic mechanism - you've used it as an example - post transcriptional modifications would generally be considered epigenetic effects. See the paper from which the following extract comes which covers "classical" mechanisms too:

"Whether miRNA regulation is an epigenetic mechanism in its own right is unclear"

Also see whatisepigenetics.com:

"At least three systems including DNA methylation, histone modification and non-coding RNA (ncRNA)-associated gene silencing are currently considered to initiate and sustain epigenetic change."

And part of the conflict is perhaps because miRNA's are seemingly involved in the control of epigenetic processes:

"Epigenetics is defined as mitotically and meiotically heritable changes in gene expression that do not involve a change in the DNA sequence. Two major areas of epigenetics—DNA methylation and histone modifications—are known to have profound effects on controlling gene expression. DNA methylation is involved in normal cellular control of expression, and aberrant hypermethylation can lead to silencing of tumor-suppressor genes in carcinogenesis. Histone modifications control the accessibility of the chromatin and transcriptional activities inside a cell. MicroRNAs (miRNAs) are small RNA molecules, ~22 nucleotides long that can negatively control their target gene expression posttranscriptionally. ....

Taken together, miRNAs can be considered important players in the epigenetic control of gene expression."

From a quantitative geneticist standpoint, if it affects phenotypic variation by altering genomic properties but there is no variation in the DNA sequence, then miRNA based post-transcription modification is a source of epigenetic variance. It seems that, for molecular biologists, post-transcription modification by miRNA falls outside of the classical definition of epigenetic effects, but I've not seen any literature explaining why nor classifying it as a genetic effect.

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  • $\begingroup$ The point is not that the field of molecular biology has a different definition. What I want to point is that if miRNAs are considered epigenetic then why not TFs? As per your definition TFs/spilicing regulators/RNA binding proteins/riboswitch/protein kinases etc should also be considered epigenetic. $\endgroup$ – WYSIWYG Aug 18 '16 at 10:01
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You should check out this article by Adrian Bird, titled Perceptions on Epigenetics

Excerpts from the article:

Should heritability be mandatory in a contemporary view of epigenetics?

...

To explain why, it is necessary to introduce a third, somewhat informal, ‘definition’ of epigenetics that has crept into widespread use. This incarnation of epigenetics encompasses the biology of chromatin, including the complex language of chromatin marks (see page 407), the transcriptional effects of RNA interference (see page 399) and, for good measure, the effects of the higher-order structure of chromosomes and the nucleus (see page 413)

Finally he goes on to propose a new definition:

The following could be a unifying definition of epigenetic events: the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states

If we consider that this definition might also be a possible definition for what epigenetics is, then yes RNAi would fall under the broader bounds of epigenetics

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I disagree with rg255 on this. Most if not all of posttranscriptional modification is encoded in the actual DNA sequence. Those microRNAs for example can be determined by reading the DNA bases or finding the encoded enzymes that do RNA editing (like C to U by TPR enzymes). The DNA sequence already encodes all the information that will determine if it will get modified or not.

Epigenetic regulation on the other hand are encoded on the histones and other proteins associated with DNA and can by definition not be understood by reading the sequence (e.g. acetylation and methylation). This information does not code for proteins or transcripts.

EDIT: A quick Pubmed search underlines what most scientists think is epigenetic Pubmed search. You see loads of methylation/histone research but miRNA or transcription factors are nowhere to be seen.

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    $\begingroup$ the regulation of a gene's expression is an epigenetic process, regardless of whether the ability to do such regulation comes from genetic information $\endgroup$ – rg255 Aug 17 '16 at 8:27
  • $\begingroup$ The expression of a gene is modified post transcription, not because a nucleotide was changed elsewhere in the genome, but because that nucleotide exists $\endgroup$ – rg255 Aug 17 '16 at 8:33
  • $\begingroup$ e.g. expression of gene X may be regulated to be differently expressed in two cell types, each cell has the same sequence of DNA, but one part of that DNA gives instructions about regulation of gene X in specific cells - there are no differences in sequence between the cells, but there is a difference in expression, therefore it is epigenetic $\endgroup$ – rg255 Aug 17 '16 at 8:34
  • $\begingroup$ @rg255 then the TFs are also epigenetic. Every gene expression regulator is epigenetic that way. $\endgroup$ – WYSIWYG Aug 17 '16 at 8:38
  • $\begingroup$ if it creates variance in the genome, but does not come from variance in the sequence, it's epigenetic $\endgroup$ – rg255 Aug 17 '16 at 8:40

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