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Is post-transcriptional regulation of gene expression an epigenetic process?


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?


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.


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.


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


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.


Epigenetic and Posttranscriptional Regulation of CD16 Expression during Human NK Cell Development

The surface receptor FcγRIIIA (CD16a) is encoded by the FCGR3A gene and is acquired by human NK cells during maturation. NK cells bind the Fc portion of IgG via CD16a and execute Ab-dependent cell-mediated cytotoxicity, which is critical for the effectiveness of several antitumor mAb therapies. The role of epigenetic regulatory mechanisms controlling transcriptional and posttranscriptional CD16 expression in NK cells is unknown. In this study, we compared specific patterns of DNA methylation and expression of FCGR3A with FCGR3B, which differ in cell type-specific expression despite displaying nearly identical genomic sequences. We identified a sequence within the FCGR3A promoter that selectively exhibits reduced methylation in CD16a + NK cells versus CD16a - NK cells and neutrophils. This region contained the transcriptional start site of the most highly expressed CD16a isoform in NK cells. Luciferase assays revealed remarkable cell-type specificity and methylation-dependent activity of FCGR3A- versus FCGR3B-derived sequences. Genomic differences between FCGR3A and FCGR3B are enriched at CpG dinucleotides, and mutation of variant CpGs reversed cell-type specificity. We further identified miR-218 as a posttranscriptional negative regulator of CD16a in NK cells. Forced overexpression of miR-218 in NK cells knocked down CD16a mRNA and protein expression. Moreover, miR-218 was highly expressed in CD16a - NK cells compared with CD16a + NK cells. Taken together, we propose a system of FCGR3A regulation in human NK cells in which CpG dinucleotide sequences and concurrent DNA methylation confer developmental and cell type-specific transcriptional regulation, whereas miR-218 provides an additional layer of posttranscriptional regulation during the maturation process.

Copyright © 2018 by The American Association of Immunologists, Inc.

Figures

NK cells acquire CD16a during…

NK cells acquire CD16a during normal maturation. (A) Mononuclear cells (MNCs) from adult…

DNA methylation and isoform-specific expression…

DNA methylation and isoform-specific expression within the promoter regions of FCGR3A and FCGR3B…

Analysis of DNA methylation- and…

Analysis of DNA methylation- and lineage-specific activity of FCGR3 promoter sequences. A) Illustration…

Identification of miR-218 as a…

Identification of miR-218 as a potential regulator of FCGR3A . (A) Expression ratio…

MiR-218 negatively regulates CD16a in…

MiR-218 negatively regulates CD16a in primary human NK cells. Primary human NK cells…


79 Regulation of Gene Expression

By the end of this section, you will be able to do the following:

  • Discuss why every cell does not express all of its genes all of the time
  • Describe how prokaryotic gene regulation occurs at the transcriptional level
  • Discuss how eukaryotic gene regulation occurs at the epigenetic, transcriptional, post-transcriptional, translational, and post-translational levels

For a cell to function properly, necessary proteins must be synthesized at the proper time and place. All cells control or regulate the synthesis of proteins from information encoded in their DNA. The process of turning on a gene to produce RNA and protein is called gene expression . Whether in a simple unicellular organism or a complex multi-cellular organism, each cell controls when and how its genes are expressed. For this to occur, there must be internal chemical mechanisms that control when a gene is expressed to make RNA and protein, how much of the protein is made, and when it is time to stop making that protein because it is no longer needed.

The regulation of gene expression conserves energy and space. It would require a significant amount of energy for an organism to express every gene at all times, so it is more energy efficient to turn on the genes only when they are required. In addition, only expressing a subset of genes in each cell saves space because DNA must be unwound from its tightly coiled structure to transcribe and translate the DNA. Cells would have to be enormous if every protein were expressed in every cell all the time.

The control of gene expression is extremely complex. Malfunctions in this process are detrimental to the cell and can lead to the development of many diseases, including cancer.

Prokaryotic versus Eukaryotic Gene Expression

To understand how gene expression is regulated, we must first understand how a gene codes for a functional protein in a cell. The process occurs in both prokaryotic and eukaryotic cells, just in slightly different manners.

Prokaryotic organisms are single-celled organisms that lack a cell nucleus, and their DNA therefore floats freely in the cell cytoplasm. To synthesize a protein, the processes of transcription and translation occur almost simultaneously. When the resulting protein is no longer needed, transcription stops. As a result, the primary method to control what type of protein and how much of each protein is expressed in a prokaryotic cell is the regulation of DNA transcription. All of the subsequent steps occur automatically. When more protein is required, more transcription occurs. Therefore, in prokaryotic cells, the control of gene expression is mostly at the transcriptional level.

Eukaryotic cells, in contrast, have intracellular organelles that add to their complexity. In eukaryotic cells, the DNA is contained inside the cell’s nucleus and there it is transcribed into RNA. The newly synthesized RNA is then transported out of the nucleus into the cytoplasm, where ribosomes translate the RNA into protein. The processes of transcription and translation are physically separated by the nuclear membrane transcription occurs only within the nucleus, and translation occurs only outside the nucleus in the cytoplasm. The regulation of gene expression can occur at all stages of the process ((Figure)). Regulation may occur when the DNA is uncoiled and loosened from nucleosomes to bind transcription factors ( epigenetic level), when the RNA is transcribed ( transcriptional level), when the RNA is processed and exported to the cytoplasm after it is transcribed ( post-transcriptional level), when the RNA is translated into protein ( translational level), or after the protein has been made ( post-translational level).


The differences in the regulation of gene expression between prokaryotes and eukaryotes are summarized in (Figure). The regulation of gene expression is discussed in detail in subsequent modules.

Differences in the Regulation of Gene Expression of Prokaryotic and Eukaryotic Organisms
Prokaryotic organisms Eukaryotic organisms
Lack a membrane-bound nucleus Contain nucleus
DNA is found in the cytoplasm DNA is confined to the nuclear compartment
RNA transcription and protein formation occur almost simultaneously RNA transcription occurs prior to protein formation, and it takes place in the nucleus. Translation of RNA to protein occurs in the cytoplasm.
Gene expression is regulated primarily at the transcriptional level Gene expression is regulated at many levels (epigenetic, transcriptional, nuclear shuttling, post-transcriptional, translational, and post-translational)

Prokaryotic cells can only regulate gene expression by controlling the amount of transcription. As eukaryotic cells evolved, the complexity of the control of gene expression increased. For example, with the evolution of eukaryotic cells came compartmentalization of important cellular components and cellular processes. A nuclear region that contains the DNA was formed. Transcription and translation were physically separated into two different cellular compartments. It therefore became possible to control gene expression by regulating transcription in the nucleus, and also by controlling the RNA levels and protein translation present outside the nucleus.

Most gene regulation is done to conserve cell resources. However, other regulatory processes may be defensive. Cellular processes such as developed to protect the cell from viral or parasitic infections. If the cell could quickly shut off gene expression for a short period of time, it would be able to survive an infection when other organisms could not. Therefore, the organism evolved a new process that helped it survive, and it was able to pass this new development to offspring.

Section Summary

While all somatic cells within an organism contain the same DNA, not all cells within that organism express the same proteins. Prokaryotic organisms express most of their genes most of the time. However, some genes are expressed only when they are needed. Eukaryotic organisms, on the other hand, express only a subset of their genes in any given cell. To express a protein, the DNA is first transcribed into RNA, which is then translated into proteins, which are then targeted to specific cellular locations. In prokaryotic cells, transcription and translation occur almost simultaneously. In eukaryotic cells, transcription occurs in the nucleus and is separate from the translation that occurs in the cytoplasm. Gene expression in prokaryotes is mostly regulated at the transcriptional level (some epigenetic and post-translational regulation is also present), whereas in eukaryotic cells, gene expression is regulated at the epigenetic, transcriptional, post-transcriptional, translational, and post-translational levels.

Review Questions

Control of gene expression in eukaryotic cells occurs at which level(s)?

  1. only the transcriptional level
  2. epigenetic and transcriptional levels
  3. epigenetic, transcriptional, and translational levels
  4. epigenetic, transcriptional, post-transcriptional, translational, and post-translational levels

Post-translational control refers to:

  1. regulation of gene expression after transcription
  2. regulation of gene expression after translation
  3. control of epigenetic activation
  4. period between transcription and translation

How does the regulation of gene expression support continued evolution of more complex organisms?

  1. Cells can become specialized within a multicellular organism.
  2. Organisms can conserve energy and resources.
  3. Cells grow larger to accommodate protein production.
  4. Both A and B.

Critical Thinking Questions

Name two differences between prokaryotic and eukaryotic cells and how these differences benefit multicellular organisms.

Eukaryotic cells have a nucleus, whereas prokaryotic cells do not. In eukaryotic cells, DNA is confined within the nuclear region. Because of this, transcription and translation are physically separated. This creates a more complex mechanism for the control of gene expression that benefits multicellular organisms because it compartmentalizes gene regulation.

Gene expression occurs at many stages in eukaryotic cells, whereas in prokaryotic cells, control of gene expression only occurs at the transcriptional level. This allows for greater control of gene expression in eukaryotes and more complex systems to be developed. Because of this, different cell types can arise in an individual organism.

Describe how controlling gene expression will alter the overall protein levels in the cell.

The cell controls which proteins are expressed and to what level each protein is expressed in the cell. Prokaryotic cells alter the transcription rate to turn genes on or off. This method will increase or decrease protein levels in response to what is needed by the cell. Eukaryotic cells change the accessibility (epigenetic), transcription, or translation of a gene. This will alter the amount of RNA and the lifespan of the RNA to alter the amount of protein that exists. Eukaryotic cells also control protein translation to increase or decrease the overall levels. Eukaryotic organisms are much more complex and can manipulate protein levels by changing many stages in the process.

Glossary


Control of RNA Stability

Before the mRNA leaves the nucleus, it is given two protective “caps” that prevent the end of the strand from degrading during its journey. The 5′ cap, which is placed on the 5′ end of the mRNA, is usually composed of a methylated guanosine triphosphate molecule (GTP). The poly-A tail, which is attached to the 3′ end, is usually composed of a series of adenine nucleotides. Once the RNA is transported to the cytoplasm, the length of time that the RNA remains there can be controlled. Each RNA molecule has a defined lifespan and decays at a specific rate. This rate of decay can influence how much protein is in the cell. If the RNA decays more rapidly, translation has less time to occur, so less protein will be produced. Conversely, if RNA decays less rapidly, more protein will be produced. This rate of decay is referred to as the RNA stability. If the RNA is stable, it will be detected for longer periods of time in the cytoplasm. Binding of proteins to the RNA can influence its stability (Figure 3).

Figure 3 The protein-coding region of mRNA is flanked by 5′ and 3′ untranslated regions (UTRs). The presence of RNA-binding proteins at the 5′ or 3′ UTR influences the stability of the RNA molecule.


RNA Stability and microRNAs

In addition to RBPs that bind to and control (increase or decrease) RNA stability, other elements called microRNAs can bind to the RNA molecule. These microRNAs , or miRNAs, are short RNA molecules that are only 21–24 nucleotides in length. The miRNAs are made in the nucleus as longer pre-miRNAs. These pre-miRNAs are chopped into mature miRNAs by a protein called dicer . Like transcription factors and RBPs, mature miRNAs recognize a specific sequence and bind to the RNA however, miRNAs also associate with a ribonucleoprotein complex called the RNA-induced silencing complex (RISC) . RISC binds along with the miRNA to degrade the target mRNA. Together, miRNAs and the RISC complex rapidly destroy the RNA molecule.


Abstract

Seed dormancy is a developmental checkpoint that prevents mature seeds from germinating under conditions that are otherwise favorable for germination. Temperature and light are the most relevant environmental factors that regulate seed dormancy and germination. These environmental cues can trigger molecular and physiological responses including hormone signaling, particularly that of abscisic acid and gibberellin. The balance between the content and sensitivity of these hormones is the key to the regulation of seed dormancy. Temperature and light tightly regulate the transcription of thousands of genes, as well as other aspects of gene expression such as mRNA splicing, translation, and stability. Chromatin remodeling determines specific transcriptional outputs, and alternative splicing leads to different outcomes and produces transcripts that encode proteins with altered or lost functions. Proper regulation of chromatin remodeling and alternative splicing may be highly relevant to seed germination. Moreover, microRNAs are also critical for the control of gene expression in seeds. This review aims to discuss recent updates on post-transcriptional regulation during seed maturation, dormancy, germination, and post-germination events. We propose future prospects for understanding how different post-transcriptional processes in crop seeds can contribute to the design of genotypes with better performance and higher productivity.


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Is post-transcriptional regulation of gene expression an epigenetic process? - Biology

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Evolution Connection

Alternative RNA SplicingIn the 1970s, genes were first observed that exhibited alternative RNA splicing. Alternative RNA splicing is a mechanism that allows different protein products to be produced from one gene when different combinations of exons are combined to form the mRNA (Figure). This alternative splicing can be haphazard, but more often it is controlled and acts as a mechanism of gene regulation, with the frequency of different splicing alternatives controlled by the cell as a way to control the production of different protein products in different cells or at different stages of development. Alternative splicing is now understood to be a common mechanism of gene regulation in eukaryotes according to one estimate, 70 percent of genes in humans are expressed as multiple proteins through alternative splicing. Although there are multiple ways to alternatively splice RNA transcripts, the original 5'-3' order of the exons is always conserved. That is, a transcript with exons 1 2 3 4 5 6 7 might be spliced 1 2 4 5 6 7 or 1 2 3 6 7, but never 1 2 5 4 3 6 7.

There are five basic modes of alternative splicing.


The (slightly) bigger picture: epigenetic processes in a cellular context

Impressive high-throughput technologies that will be touched on in the next article in this series have provided linear maps of epigenetic marks. Although these maps are very insightful, keep in mind that the next logical step would be to move on to 3D representations that link epigenetic processes to cell signalling cascades and environmental clues. Although epigenetic mechanisms take place in the nucleus, they can occur in response to environmental signals, such as hormones, nutrients, stress and cell damage. This indicates that extracellular and cytoplasmic factors are also at stake in epigenetic regulation.

How exactly non-epigenetic cues induce cells to alter their epigenomes is an important question that needs answering. How is it possible that genes are generally under stringent epigenetic control, and only get activated and transcribed when needed?

Certain cellular signalling pathways have already been earmarked as candidate regulators of epigenetic remodelling. Not surprisingly, they tend to be factors with already established roles in cell lineage commitment, growth and development.

Then what makes epigenetic regulation distinct from classic signal transduction? The latter refers to direct changes in gene expression due to altered levels, post-translational modifications, or actions of transcription factors, in response to the extracellular environment or state of the cell. Once gene transcription has been changed, a new epigenetic signature might be established to stabilise the signal transduction, thereby rendering it heritable and independent of the initial triggering signal.

Of course, that is not all: as enzymes of the epigenetic machinery can be regulated by signalling molecules, but might at the same time affect the activity of signalling molecules, the interplay between classic regulatory signals and epigenetic control is – you guessed it – complex and likely often intertwined. Indeed, certain signal transduction effectors such as transcription factors and signalling molecules have been found to interact with chromatin modifying enzymes.

In the next article in this series, I will discuss some experimental techniques that have helped us better understand these processes.

Sources/further reading:

Portela A, Esteller M (2010) Epigenetic modifications and human disease. Nat Biotechnol 28: 1057-1068.

Mohammad HP, Baylin SB (2010) Linking cell signaling and the epigenetic machinery. Nat Biotechnol 28: 1033-1038.


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