Epigenetics
Genes are genetic recipes. Edits that alter the recipe are epigenetic.
The term epigenetics is a portmanteau of genetics and epigenesis; coined by English geneticist Conrad Waddington in 1942 before details of genetics were known. Waddington meant epigenetics as a notion of how genes might interact with their environment to alter a phenotype: the visible traits of a cell or organism. While Waddington’s gist was generally correct, the definition of epigenetics has become more gene specific.
That gene expression may be suppressed by DNA methylation was discovered in 1975. It was not until the 1990s that the term epigenetics became common in research circles.
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“Epigenetic mechanisms provide the key to understanding the size and organization of eukaryotic genomes.” ~ American biochemist Nina Fedoroff
Epigenetics involve factors outside DNA sequencing by which life experiences are encoded into cells, and which may be passed on to cell offspring when a cell divides. Epigenetics provides for cellular memory that lives on in descendant cells.
Single-celled paramecia have 2 distinct mating types, called even (E) and odd (O). Sex between E and O occurs by conjugation: reversible cell fusion, during which partners exchange genes before separating into progeny cells.
Although offspring all start with identical, mixed genomes, each cell retains the memory of the mating type of its parent. It does so via epigenetics. Small RNA molecules communicate mating type between parent and progeny cells.
Epigenetics refers to regulating, modifying, or suppressing gene expression without altering DNA sequence, which instead would be a genetic mutation. Epigenetic effects also include changes to the chromatin proteins associated with DNA, whereby expression may be silenced or engendered.
“Chromatin marks are highly specific and localized. They are induced by the signals cells receive during embryological development or in response to changed environmental conditions. Once induced, the information about cellular activities that is carried in a chromatin mark can often he transmitted in the cell lineage long after the inducing stimulus has disappeared. The chromatin-marking systems are therefore part of a cell’s physiological response system, but they are also part of its heredity system.” ~ Israeli geneticist Eva Jablonka & English evolutionary biologist Marion Lamb
Epigenetics also encompasses modulating epigenetic effects. As such, epigenetics involves an interleaved context-dependent network that tempers gene expression. All epigenetic mechanisms are interrelated.
Genetically identical cells living in the same environment can display markedly different traits. Both extracellular triggers and internal influences can drive a cell to change its lifestyle or fate.
“Genes do not automatically stay “on” or “off” once activated or repressed. Rather, those states of gene expression require the continual activities of the specific regulators to maintain that state of expression.” ~ American molecular biologist Mark Ptashne
Epigenetic marks are an ongoing dynamic. Lifestyle and mental well-being have an epigenetic effect which is inherited by offspring.
“We inherit more than just genes from our parents. Acquired environmental adaptations are passed to our offspring.” ~ Italian geneticist Nicola Iovino
Memories are mental products, but they have physical correlates. Memories are epigenetically encoded via de novo protein synthesis. This holds for all organisms. These gene expression programs – memories – are readily transmitted to offspring.
“Epigenetic processes mediate long‐term memory formation.” ~ German molecular biologist André Fischer
Stress of any sort makes a deleterious mark that long outlasts its source. Conversely, meditation and a calm mind promote healthier genetic expression and boost the immune system.
Biologically based survival lessons are inherited. For instance, smells that signal danger are epigenetically encoded and transmitted to future generations.
“Epigenetic changes are crucial for the development and differentiation of the various cell types in an organism, as well as for normal cellular processes.” ~ English cytologist Alex Eccleston et al
Epigenetic activity guides organism development. This provides adaptive flexibility. The onset of mammalian puberty is epigenetically triggered. Epigenetic changes continue throughout an individual’s life.
Families tend to have similar epigenetic patterns. Handedness and sexual orientation are both familial epigenetic phenomena. Homosexual men have a different epigenome than heterosexuals.
Sexual orientation is implanted via epigenetic changes related to testosterone exposure during fetal development. These epigenetic marks are passed from one generation to the next.
“Epigenetics explores how genetically identical entities, whether cells or whole organisms, display different characteristics, and how these are inherited.” ~ French geneticist Jonathan Weitzman
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“The cells themselves must be influenced ultimately by that mysterious force which we call life.” ~ American physician Duncan Bulkley
Epigenetics is an integral part of the cell life cycle. All somatic cells retain the full complement of DNA present in germline cells and stem cells.
A stem cell generates a different cell type by invoking epigenetic alterations. The specialized functions of somatic cells are programmed epigenetically. That a somatic cell may differentiate into a different cell type in exigent circumstance is an epigenetic exercise of intelligence.
“Various cell types respond differently to the environment by using distinct circuits of genomic reprogramming.” ~ Italian biochemist Paolo Sassone-Corsi
Cells regularly adapt to changes in their environment by regulating gene expression, thus modulating cellular behaviors. Cell memory and intelligence are expressed by epigenetic responses.
Organisms have an array of strategies to recognize and restrain invasive foreign DNA, such as those introduced by viruses. One way is by remembering previous gene expression and tracking expression changes. This epigenetic memory silences foreign genes from one generation to the next.
“Novel protein-coding genes can arise either through re-organization of preexisting genes or de novo.” ~ French geneticist Anne-Ruxandra Carvunis et al
Occasionally, new genes are expressed. This activation is passed on as an epigenetic memory. Hence, a eukaryote may adopt a foreign gene, by a decision process not yet understood.
Plants and animals both produce many thousands of RNA molecules that do not code for proteins. Instead, these molecules may communicate the present state, and memories, thereby selectively silencing or promoting gene expression.
These RNA epigenetic messengers may travel from cell to cell, stifling or activating genes as they go. Hence, an epigenetic response to a stimulus may be carried far and wide from its point of origin.
For good or ill, epigenetic effects store an organism’s life experiences in chromatin. Behavior patterns, depravations, addictions, and illnesses, both physical and mental, are encoded epigenetically. Autism stems from epigenetic inheritance.
An organism lives an integrated experience. Hence, epigenetic marks are not isolated occurrences. Epigenetic changes may be different for different cell types, even as they emanate from the same experience.
Brain and nerve cells are affected by epigenetics. But the brain is not the origin of many behaviors, including those commonly considered as conscious choices. Impulses of all sorts are epigenetically encoded cellular imperatives from regions distant from the brain.
For better or worse, epigenetics provides the mechanism for lessons learned, neglected, or ignored. Being a creature of habit is embedded in cells. (As the mind-body is an entangled energetic gyre, trying to suss cause-and-effect between mind and body is like trying to untangle a gnarled enigma with imaginary tweezers.)
“The external world, inclusive of food, toxins, carcinogens, and many other day-to-day factors, has a significant impact on cellular regulation.” ~ American geneticist and cytologist Amber Willbanks et al
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Genes influence the behaviors of a cell and traits of an organism through the proteins and other molecules constructed from them. Getting from nucleotide code to bioproduct is a convoluted process where much can come out differently than DNA dictates.
Transcription comes first: making an RNA copy from DNA. Most epigenetic regulation happens by inhibiting transcription in very specific ways.
During translation, the RNA template is used to create a polypeptide, which is then folded up into an active protein during post-translational processing. These processes can render a functional protein quite different than what would be expected from reading the DNA recipe.
Hence, the genetic code alone provides only a partial picture of inheritance. Due to epigenetic influences, actions during protein synthesis and genomic activity during cell differentiation are as much effect as cause.
Germline cells erase epigenetic memory at critical points during development, thereby resetting the epigenome. But the erasure is commonly incomplete. Certain epigenetic indications escape reprogramming and are transmitted to offspring. By this, parental life experiences are passed to progeny.
“Genes have adapted to allow for the correct balance of memory versus flexibility.” ~ Indian epigeneticist Sandip De & American epigeneticist Judith Kassis
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Epigenetics is the story of a cell’s life experiences, of markings that are passed from one generation of cell to the next. Epigenetically, the offspring of organisms are simply an extension of cellular memory.
Most traits are the product of multiple genes, or even epigenetic tweaks to gene complexes. Few traits are traceable to a single gene. Even then, epigenetics factors in.
Genetic Evolution
A long-standing presumption about evolution is that increased complexity in organisms owed to a greater number of genes that encode information about development and growth. In other words, evolution was partly an outcome of quantitative genetic growth. Evidence has shown otherwise.
“Most animals have a similar number of genes encoded in their DNA.” ~ geneticist Miloš Tanurdžić
The number of genes in an organism is merely a historical artifact, not a telltale indicator of evolutionary ‘progress’, whatever that may be intended to mean. Instead, complexity and diversity were largely achieved via various epigenetic mechanisms.
“Gene regulation is responsible for the evolution of diversity.” ~ Miloš Tanurdžić
A related misconception has been that genetics itself evolved – particularly, a greater sophistication in gene complexes or in regulatory mechanics. Not at all. Primordial sponges that lived 800 million years ago had all the genetic savvy that humans have today.
“Gene regulatory complexity was fundamental for the evolution of multicellularity and diverse forms and functions.” ~ Miloš Tanurdžić
“The regulatory landscape used by complex bilaterians was already in place at the dawn of animal multicellularity.” ~ evolutionary and molecular biologist Federico Gaiti et al
The upshot is that genes themselves say little about an organism. It is their employment – involving epigenetics – that matter.
Further, whatever evolution genetics itself underwent has, so far, eluded detection. As with the origin of life, the inception of genetics is lost in the mists of time.
Junk Debunked
“So much “junk” DNA in our genome.” ~ Japanese American geneticist Susumu Ohno in 1972
The academic discipline known as genetics arose from an interest in comprehending heredity. Hence the presumption that the molecular knowledge base of life was merely a currency for inheriting traits. That genetics is a fountain of ongoing cellular activity is a recent idea.
At the beginning of the 20th century Wilhelm Johannsen created the terms phenotype and genotype to correlate traits to genes on a one-to-one correspondence. Research proceeded on that basis, to expanding dismay. Bewildered by the apparent disorder of DNA in humans, geneticists declared much of it useless, as it did not fit their preconceptions.
“We were using the idea of “junk” in the genome in the sixties in Cambridge.” ~ South African biologist Sydney Brenner
This simpleminded misattribution continued as dogma for decades. Relentless exploration of DNA begat more questions than answers. As complications piled up, the tidy notion of genes unraveled.
Beginning in the 1st decade of the 21st century, DNA sequences previously considered junk – those that do not code for proteins – were found to regulate access and employment of genetic coding.
“What was dismissed as junk because it was not understood may well turn out to hold the secrets to human complexity and a guide to the programming of complex systems in general.” ~ John Mattick
Only 1.5% of the human genome consists of protein-coding genes. The rest is now called intergenic: DNA sequences between genes. All told, 8.2% of the human genome is presently presumed functionally employed.
Intergenic DNA and RNA play critical roles in regulating genetic expression; the development of cells and organisms, and their intelligence system; enhancing biomolecular performance; and ensuring biological propriety and health. Among other diseases, autism correlates with anomalies in intergenic DNA.
Among other employments, intergenic DNA is read to produce small certain RNA molecules which inhibit protein production by shutting down a ribosome’s protein assembly line. This technique is used when cells are stressed and need to instigate quick responses. RNA molecules can be manufactured much faster than proteins.
Genes are the coding of heritable traits in only the vaguest sense. Such vagary does not serve scientific inquiry.
It makes little sense to have distinctions without meaningful difference: genetic versus intergenic versus epigenetic. All are essential facets of using the artifactual knowledge base by which cells manage their affairs.
Genetics terminology is an instance of historical continuity obscuring understanding, as umbrella terms have been reinterpreted through time to mean different things to different people.
Meanwhile, new terms are piled on to an obsolete paradigm. This jungle of jargon is ill-serving.
The commonly bandied term noncoding is even vaguer than gene, as it encompasses a far more amorphous realm of greater magnitude than protein templates. Further, the notion is inconsonant, as so-called noncoding DNA/RNA functionally codes for regulation rather than production.
In many instances, functionality was simply overlooked. If researchers discovered a sequence that did not correspond to preconception, it was labeled “noncoding” and dismissed. Such disregard was blithe: a product of ignorant assumption of how DNA works. A 2013 survey of protein production uncovered 193 proteins produced by supposed noncoding sequences.
“The fact that proteins came from DNA sequences predicted to be noncoding means that we don’t fully understand how cells read DNA, because clearly those sequences do code for proteins.” ~ Indian molecular biologist Akhilesh Pandey
In essence, noncoding is merely a replacement for nucleotides previously dismissed as junk; a belated turn of muck into brass, albeit with equally vacuous terminology.
In conventional parlance, long noncoding RNA (lncRNA) differs from small noncoding RNA by the arbitrary distinction of being an identifiable sequence greater than 200 nucleotides. The same goes for microRNA (22 nucleotides), and circular RNA (circRNA), a recently discovered enigma. Naming solely by how something looks under a microscope is hardly helpful, especially when looks bely a plethora of functions among cast members.
“The vast majority of trait-associated DNA variations occur in regions of the genome that were once labeled as “junk DNA” because they do not code for proteins. We now know that these regions harbor genetic elements that control where, when, and to what extent specific genes are expressed to make functional RNA and protein products. Therefore, most trait-associated DNA variants are thought to alter not the gene itself, but rather, the regulatory elements that control the process of gene expression.” ~ American geneticist Terrence Furey & Indian geneticist Praveen Sethupathy
When cells divide, chromosomes are distributed to daughter cells. Centromeres – specialized chromosome regions – ensure that the chromosomes correctly segregate.
The human DNA for centromeres transcribes to a long noncoding RNA. Instead of producing a protein itself, the RNA product recruits and binds 2 proteins so that a centromere functions properly.
Research into erstwhile “junk” is proving to be an exploration of an incredible web of molecular knowledge with staggering intricacy – the font of life’s unicity.
“The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation.” ~ The ENCODE Project Consortium
Epialleles
“Epialleles are heritable, nongenetic (epigenetic) differences in DNA methylation.” ~ American geneticist Laura Zahn
Inheritance of most characteristics in complex organisms involves a confluence of factors, part genetic and part environmental: nature and nurture. While alleles provide a genetic basis for trait variation, epialleles are analogous epigenetic factors that afford divergence from straightforward gene expression.
Epialleles are alleles but include the characteristic marks that may affect expression of an allele. But even epialleles leave the inheritance picture incomplete, as many, if not most, epigenetic effects are from chemical attachments outside of the gene being epigenetically regulated.
Mechanisms
“Processes in free-living cells are modulated to fit the environmental conditions. The possible programs a given cell can execute are defined by the cell’s genome, and the optimal program is selected based on the level of environmental signals sensed by the cell. Regulation of gene expression is a main component in the selection of the optimal program. Gene regulatory networks are based on simple building blocks such as promoters, transcription factors and their binding sites on DNA. Simple elements of transcription regulation form a highly flexible toolbox that can generate diverse functions.” ~ Hungarian geneticist Alexander Hunziker et al
There are an epic number of epigenetic options: transcription codon choice, gene silencing, histone and chromatin remodeling, RNA regulation, X chromosome inactivation, paramutation, bookmarking, imprinting, reprogramming, translocation and transvection, among others. Their application to alter gene expression is interrelated, forming a tensor network of relations and effects.
This brief survey introduces a few of the mechanisms which illustrate the intelligent, intricate, and delicate nature of cell life which affect an organism in ways both subtle and profound.
Methylation
“DNA methylation is one of a number of epigenetic mechanisms that can determine which proteins are made in different cell types without changing the underlying DNA sequence.” ~ English geneticist Hannah Long et al
Epigenetically regulated regions have characteristic markings from specific chemical attachments. One such marking is methylation, which is a frequently employed method for epigenetic inheritance. A methyl group (CH3) attaches to either cytosine or adenine, stifling the associated gene so that the it will not properly express in a cell or its offspring.
DNA methylation is not an on-off switch; instead, strands may be methylated to varying degrees.
“Methylation may serve as an agent of evolution.” ~ American epigeneticist Gregory Hannon
Methylation can drive changes in DNA sequence. In such a scenario, methylation acts as prototyping for genic reprogramming. If the methylated change is productive, DNA may be recoded to produce the new desired output.
Methylation patterns vary depending upon cell type and function. Methylation marks are important in determining how a cell develops and how it behaves when mature.
“DNA methylation is essential for the survival of the embryo, and its occurrence is dynamically regulated during development.” ~ French geneticists Sylvain Guiber & Michael Weber
Mammalian cells are wiped clean of their methylation marks and reprogrammed in 2 instances: for germline and embryonic stem cells. The reason for this erasure and reinscription remains mysterious – perhaps to anticipatorily clarify signal quality. Germline cells go on to serve a reproductive role. Embryonic stem cells are the basic cell type for differentiation into distinct duties during development.
“These 2 cell types represent the output of the 2 reprogramming waves, and as such are the basis or ‘ground state’ for all that will follow, over the life of the individual cell and the organism itself.” ~ French geneticist Antoine Molaro
Breeding Urges
Many animals breed seasonally. Hormonal changes invoke and extinguish breeding urges.
Breeding timing is tied to melatonin, a nocturnally produced hormone that accounts for day length, and so serves as a biological clock. Melatonin changes alter the level of methylation of a regulatory DNA region in the hypothalamus, a brain region active during periodic biological imperatives, including hunger and sleep, as well as mating and parenting behaviors.
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For mammals, the more methylated a DNA strand is, the less active its expression. Methylation of the sequence which encodes glucocorticoid receptors is exemplary.
Glucocorticoid receptors relay signals from stress hormones in the blood into the portions of the brain that control behavior. Methylation of the glucocorticoid receptor code affects anxiety level and handling of stress.
Twice in the lives of mammal cells, methylation marks are wiped clean and then reprogrammed. The purpose of this erasure and reinscription is not known.
DNA methylation patterns alter as a person ages. These changes can contribute to age-related diseases, including cancer.
Methylated regions can cumulatively lose methyl groups, turning strands back on that increase the risk of infection and diabetes. Osteoarthritis results from reduced methylation of a destructive enzyme. Demethylation in an aging brain causes cognitive decline.
Methylation can be reversed by demethylation at any age. Plants appear particularly adept at employing methylation and demethylation to suit their expression needs.
Methylation is only one facet of a complex epigenetic regulatory network which includes many mechanisms.
There is a huge amount of flexibility in what can be done to reach different endpoints from the same DNA blueprint. Hormones play a key role in shaping the genetic basis of traits. ~ American evolutionary biologist Robert Cox
Honeybee Memories
“The development of different bees from the same DNA in the larvae is one of the clearest examples of epigenetics in action.” ~ English biochemist Mark Dickman
Honeybees in a colony are caste-bound. The queen prolifically produces offspring sisters. A few are fated to follow as queens, while a vast multitude of workers collect and store food, tend to the young, and maintain the hive.
Royal jelly is fed to larvae via secretions by worker bees. How much royal jelly a larva receives determines her future role in life. Royal jelly consumption affects hormone signaling, which alters gene expression patterns via methylation and histone modification.
A worker bee finds an ample food supply that is communicated to fellow foragers. She must quickly learn that route, then later just as easily forget it to better retain new routes. Honeybees have a methylation system that is instrumental in storing and erasing memories.
So too mammals. Neural DNA methylation promotes associative learning.
Other insect species, including ants, have active methylation systems; but not fruit flies, which have been by far the genetics study subject of choice. Hence, researchers long overlooked the significance of epigenetics.
Seeds & Embryos
Procreation in higher mammals begins with a zygote; the initial cell formed from the fertilizing union of 2 gamete cells during sexual reproduction. A zygote is the source of both the embryo and the placenta. The placenta nourishes a developing embryo but is not part of the growing offspring.
Seeds are similar. An endosperm nourishes the embryo.
Flowering plants and placental mammals are the only known organisms that employ genetic imprinting: identifying regulating genetic expression by the sex of the parent.
When horses and donkeys mate, they produce sterile mules. This owes to imprinting bias toward paternal genes.
In plants, the paternally derived gene copy carries the methylation, but this copy is not always the one that is inactivated. Hence, in plant imprinting, methylation tells how a gene was inherited, not whether the gene should be expressed.
Methylation Variation
Methylation technique and effect varies. Both plants and higher mammals silence the genes of repetitive elements, albeit using different techniques.
Duplicate plant genes are individually methylated. This is more precise than in mammals, where repetitive elements are silenced by methylating chromatin, the gene packaging. In contrast, honeybees do not methylate repetitive elements.
Methylating the body of a gene which encodes amino acids variably regulates expression. In contrast, methylating the promoter site stifles gene expression.
Plant and insect genes are often methylated in a way that modulates, but does not deter, expression. Regulating but not silencing expression is used for long-term mammal memory, particularly during brain development. Otherwise, methylation that stifles gene expression is common in mammals.
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Methylation illustrates how evolution reuses the same materials and mechanisms in different ways. With coherent intelligence applied in creating combinatorial regulatory networks, organic chemistry has provided an incredibly flexible toolkit for variety and adaptability.
“The key players orchestrating DNA methylation all work together in an elegant way.” ~ American epigeneticist Scott Rothbart
Histone Alteration
“Histone modifications are important markers of function and chromatin state, yet the DNA sequence elements that direct them to specific genomic locations are poorly understood.” ~ American geneticist Graham McVicker et al
Histones are the proteins that package DNA in an orderly way into nucleosomes. Histones tightly bind to inactive DNA sequences. The binding is loosened where sequences are actively engaged in protein synthesis.
The strength of binding between a histone and DNA may be epigenetically impacted. Histones may be biochemically altered by removing an acetyl group (deacetylation), or via methylation, which blocks gene expression by preventing transcription.
Impacting a histone may have a knock-on effect, as histone behaviors are often coordinated. Histones of related DNA sequences communicate. How a histone complex carries on a conversation depends on how its constituents are chemically modified.
Like methylation, a histone epigenetic effect is passed on to descendant cells. Methylation and histone modification are often harmonized.
Histone regulation plays a major role in controlling organism development.
Rite of Spring
Plants commonly must endure a prolonged cold spell to provoke flowering. Vernalization is the term for an angiosperm requiring a cold winter to flower in spring.
Vernalization is a form of state memory, via epigenetics, particularly histone alteration. The flow of epigenetic activity that ultimately regulates flowering varies depending upon the season and the developmental stage that a plant is in.
A seed has no need to know of flowering. The epigenetics associated with vernalization have been reset.
As a plant grows, memories of its development are preserved from one cell generation to the next. Those memories are stored epigenetically.
Having grown strong during summer into fall in its 1st year, and then survived the winter, a plant is prepared to bring forth the next generation. The epigenetic marks in its cells tell it so.
RNA Regulation
“RNA has become widely suspected as the culprit behind almost every case of epigenetic regulation. There continues to be a shift in how we conceptualize this remarkably versatile macromolecule, once regarded primarily as mere intermediary of the “central dogma” stating that information moves unidirectionally from DNA to RNA to protein.” ~ Chinese American geneticist Jeannie Lee
DNA is used to make RNA. RNA is used to make proteins. Proteins are the principal actors of biological functions.
That is the classical script for RNA. But many types of RNA have other functions besides protein coding. Those functions involve RNA communiqués that alter protein production or gene expression. There is an ever-growing compendium of regulatory agents involved. 2 worth noting are RNAi and microRNA.
RNA interference (RNAi) affects which genes are active, and how active genes are. RNAi limits expression, sometimes to the point of silencing a gene, by cleaving its target: messenger RNA (mRNA).
microRNA
microRNA (miRNA) are a diverse class of short noncoding regulatory RNA molecules that inhibit expression by binding to microRNA response elements (MREs), thereby decreasing the stability of messenger RNA (mRNA) or limiting the efficacy of protein translation.
microRNAs work in middle management: regulating protein manufacture. They help a cell maintain balance by not making unnecessary proteins and help prevent build-up of potentially harmful proteins.
An evolutionarily ancient avenue of genetic regulation, microRNA pathways are well conserved in eukaryotes.
The repertoires of plant and animal microRNAs evolved independently, with different ways of working. Animal microRNAs are specific in the binding, while plant microRNAs may bind at both coding and noncoding regions.
microRNA offers combinatorial regulation. A microRNA may have different mRNA targets, and any given site subject to regulation may be targeted by multiple microRNAs.
Modest alterations by microRNAs can have a butterfly effect, including changing the appearance of an organism.
microRNA activity is essential to learning. Associative memories which impart survival skills can be epigenetically passed on to offspring. microRNA is the likely physical mechanism for inheriting primal memories.
(A physical molecule cannot encapsulate a meaningful memory, but its hd energy gyre can. Many mental attributes, such as memory and stress, have physical counterparts. Here is an instance.)
microRNA plays a role in numerous diseases, including cancer. Some protect against cancer, while others promote it.
Other RNAs may compete in binding to microRNAs. By this, MREs mediate relevant communication, allowing different types of RNA to converse and build regulatory networks which act epigenetically.
X Inactivation
X inactivation (aka lyonization) silences gene expression for 1 of the 2 X chromosomes that mammalian females possess.
There are many cell divisions prior to X inactivation, but it happens early in embryonic development. The timing of X inactivation affects development.
For many animal species, after some fetal development, X inactivation varies cell by cell. Some work the mom X, while others the dad X. This confers genetic variety. The timing and specifics of X inactivation is one contributor to identical female twins not being entirely identical.
Cells retain their lineage whether X-inactivated or not. In maternal tissue sustaining a fetus, paternal X chromosomes are inactivated, as with marsupials.
Calico and tortoiseshell cats, which are always female, show their X linkage by their patchwork coats: the light, dark, and orange areas detail the pseudo-random X inactivation of hair cell lineages.
Not all double-X genes are inactivated: 15–25% escape inactivation. These are housekeeping genes: sequences for the basic cellular processes required by all cells.
X inactivation initiates at the X Inactivation Center (XIC), a specific spot on the X chromosome. Several actors play roles on the XIC stage. The X inactivation script has an intricate plot.
A leading X-inactivation actor in placental mammals is Xist: a X-inactive-specific transcript. Xist is not a protein production template. There is no Xist protein. Instead, Xist is an odd messenger RNA: while processed like other mRNAs, Xist stays untranslated.
“Xist evolved from a protein-coding gene. The loss of protein-coding function of the proto-Xist coincides with the four flanking protein genes becoming pseudogenes. This event occurred after the divergence between eutherians and marsupials, which suggests that mechanisms of dosage compensation evolved independently in both lineages.” ~ French geneticist Laurent Duret et al
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“Xist is not sufficient. There have to be other factors, on the X chromosome itself, that activate Xist and then cooperate with Xist RNA to silence the X chromosome.” ~ American geneticist Sundeep Kalantry
Xist acts to lyonize the X chromosome to which it is attached, in a multiple-stage process of smothering. Xist identifies its target regions by recognizing their folded shape. As Xist copies are made, they plaster the target chromosome.
Then Xist RNA attracts histones and methylating factors. Finally, the Xistified X chromosome is crunched into a compact blob: a Barr body, named after its discoverer, Canadian physician Murray Barr.
Duplication of the Xist gene on another chromosome inactivates that chromosome.
Sometimes translocation occurs: chromosomal bits get dislodged, such as a genetic bit of X with Xist on it; an abnormal rearrangement happens, and another gene gets inactivated, at least partially.
Translocations happen in around 1 in 500 human newborns, and also occur with genes other than Xist-covered bits. Some translocations are harmless. But unfortunate translocations can cause Down syndrome, infertility, or cancer.
Marsupial X Inactivation
Marsupials are 334 extant species of mammal that carry their young in a pouch. Well-known marsupials include kangaroos, koalas, and opossums.
Marsupial X inactivation is a more ancient evolutionary state than the more modern mammal lineage – eutherians (placental mammals) – that diverged from marsupials.
Marsupials work the maternal X. The paternal X is largely inactive.
Marsupials lack Xist. Because of that, marsupials lack the benefit of genetic variety from the selective X inactivation that transpires in placental mammals.
Xist is a most significant difference between marsupials and placentals.
Protein Post-Production
Proteins interact with each other, work together, and perform individual steps in chain reactions, sometimes collaboratively. Affecting protein production and/or interactions can have profound effects on cellular activity.
As macromolecules, proteins can be influenced at multiple interaction sites. A protein’s active (enzymatic) site is a small fraction of its surface. This means that most of a protein’s surface is available for binding to other proteins, and for changing the shape or activity of a protein. Binding at a place other than an active site is allostery.
Allostery
Allosteric site binding among proteins results in numerous interactions, not only between those proteins, but also with others not physically connected. These interactions may affect protein functioning and may be affected by allosteric regulation.
“Allostery is the process by which biological macromolecules (mostly proteins) transmit the effect of binding at one site to another, often distal, functional site, allowing for regulation of activity.” ~ American molecular biophysicist Hesam Motlagh et al
Allostery functions as a dynamic interrelated network, creating ensemble behavior in affected proteins. Allostery effectively entangles proteins into a regulated web, behaving like the protein equivalent of quantum nonlocality.
The biomechanics of allostery are only partly understood; but allostery works via conformational changes in the proteins involved, and thermodynamics within the effective domain of the allosteric network.
Drugs often function via allostery. Further, allostery provides for adaptive evolution outside any changes in genetic code.
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From archaic bacteria to humans, practically all cells can tweak proteins by changing their chemical properties after production. This capability provides ready, adaptive flexibility, enabling cells to react quickly to changing conditions or needs.
2 post-translational modifications – phosphorylation and lysine acetylation – are intracellular communication signals that can have epigenetic effect. Lysine acetylation affects histone employment with a downstream epigenetic effect. Phosphorylation influences expression of protein-building genes by adding a phosphate group. This can alter proteins involved in building other proteins.
Epigenome
“The epigenome (the constellation of all epigenetic modifications in the nucleus) constitutes a primary interface between environmental factors and the genome.” ~ American molecular biologist James Shapiro
The somatic cells in a multicellular organism collaborate in building a body and keeping it going. Most are specialized, each with slightly different genomes.
During the continual replication that occurs throughout the human body during a lifetime, the 200 different kinds of cells are reproduced by reading different scripts written in DNA. There is a 2nd layer of instructions embedded in the special proteins that package the DNA of a genome. This 2nd layer – the epigenome – controls access to genes; allowing each cell type to activate (express) its own special genes, while blocking access to much of the rest of the genome, because the particular cell type does not need that knowledge.
A genome comprises regulatory genes whose protein products – transcription factors – control the activity of other genes. There is also a subset of master regulatory genes that control the lower-level regulators. Gene regulation is hierarchically networked and interrelated.
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Transcription factors have to commute to work. Finding the work site is nontrivial. These proteins amble about chromosomes, attaching to specific DNA sequences along the way, until they hit their target. Other proteins bound to the chromosome act like roadblocks, slowing the search. Once the binding site is found, a transcription factor slides over it several times, checking the target out before binding to it.
The master transcription factors act on each other’s genes in a way that sets up a circuitry. The output of this circuitry shapes the initial cascade of epigenomes spun from a fertilized egg.
Though epigenetics forms an interactive entangled network, the organization of epigenomes emanate from information inherent in the genome. Systemic genetic entanglement is a fact of life.
“The field long has been focused on identifying genes that manufacture proteins. The epigenome is just as important.” ~ Chinese geneticist Ting Wang
Wood Work
In trees, transcription factors take control of a cascade of genes that controls the production of wood by differentiating cells into the needed components in the proper proportions. The primary controller protein for wood production regulates gene expression on multiple levels, ensuring proper growth.
What is unusual about the controller in poplars and rockcress is its residence in the cytoplasm, outside the cell nucleus. This is odd, as transcription factor proteins are otherwise always in the nucleus. In this instance, a nucleus-based transcription factor comes and ushers the cytoplasmic controller protein into the nucleus to begin wood work.
Lifestyle Epigenetics
“Gene expression is modulated by lifestyle and environmental factors.” ~ Mexican toxicologist Jorge Alejandro Alegría-Torres
A man contributes to its offspring’s genetic inheritance, but a fetus develops within a woman’s womb, which strongly influences fetal gene regulation and expression.
A fetus is not the only one genetically affected. Fetal DNA can persist in its mother for the rest of her life. That DNA may benefit a mother’s health or stir adversity.
All mammal mothers undergo a range of hormonal change prior to and after birthing. Stimulating the hypothalamus, oxytocin promotes affection. In healthy animals, these and other changes combine to engender maternal behaviors.
Most furred mammal mothers, including rodents and dogs, lick their pups. Pups mothered by generous lickers fare better under stress than those stingily succored. Neglected rat pups who don’t get loving licks become neglectful mothers.
The psychological effects of parenting can be profound and lifelong. The quality of parenting, especially mothering, creates a perpetuating generational cycle. This has been repeatedly observed in rodents and primates, including people.
A foster pup, going from a poor licker of a mother to a good one, develops a better stress response; one more like that of its foster upbringing than its biological mother.
While epigenetic effects tend to persist, the permanence of methylation is in flux during early development. The earlier methylation goes unabated, the more pronounced and pervasive its impact. Epigenetic alterations account for differences in stress response in identical twins.
Social interactions of every sort affect gene regulation, as they are a form of stress. From fish to humans, competitive interactions influence testosterone levels with consequential impact on gene activity.
Altered genetic expression from stress is passed to the next generation. Chronically stressed pregnant women bear children with greater proclivity to physical, psychological, and behavioral disorders owing to greater sensitivity to stress.
Fathers as well as mothers pass the effects of their diet, temperament, and lifestyle to their offspring.
Epigenetically inherited stress increases the risk of depression, obesity, and autoimmune diseases. Dampened glucocorticoid-receptor-gene activity renders people more aggressive and impulsive. This makes men particularly inclined to abusiveness that perpetuates through generations.
It makes no difference the source of stress – physical or psychological – for parent or offspring; such distinction is clinical anyway. Existence is holistic; so too health and illness.
Methylation patterns vary with diet. Early malnutrition can create a host of problems, such as hyperactive stress response, with wide-ranging effects that last throughout life.
Exposure to pollutants, including alcohol and tobacco, can have lasting epigenetic effects which may be passed to offspring who are never exposed to the triggering pollutant. Such effects can last for generations.
Many chronic diseases are epigenetically endowed as a culmination of lifestyle. Autoimmune diseases, such as rheumatoid arthritis, are exemplary.
“Common diseases are due to many changes with small effects on a handful of genes.” ~ American geneticist Peter Scacher
The speed at which the epigenome changes relates to lifespan, both in individuals and across species. For animals, eating less slows the rate of epigenomic change.
Cancer
“Cancer is due to errors in the mode of living.” ~ Duncan Bulkley
Cancer is an umbrella term for diseases characterized by uncontrolled cell growth. Cancer essentially emanates from environmental stimulus, though genetic expression tilts the risk for the disease.
Several epigenetic alterations characterize cancer, including lowering histone levels, which help activate the growth and ensure the survival of cancer cells. Cancer is a product of defective gene regulation, though the progression of cancer often has genetic repercussions as well.
Comparative Epigenetics
While significant in all life forms, epigenetic inheritance plays a stronger adaptive role in other life forms than it does in mammals. Insects, plants, and yeast transfer extensive adaptations epigenetically.
Cold numbs even nerve cells. Signaling slows down. Amazingly, octopi in the frigid waters near Antarctica adapted without any genetic change from those in tropical seas. An enzyme that specializes in editing mRNA alters the blueprints for octopus nerve cells by adjusting nerve cell timing for ambient water temperature. This epigenetic trait has been conserved through evolutionary time. Cold-water survivability is so handy that it independently evolved in several octopus lineages (convergent evolution).
Plant Epigenetics
“Plants have a more complex and redundant array of epigenetic mechanisms than animals.” ~ Nina Fedoroff
Plants and fungi lack the early segregation of germline that is characteristic of multicellular animals. Epigenetic inheritance offers an avenue of adaptability via an ample assortment of actions. RNA sequences carry guidelines for epigenetic activity from one generation to the next. Plants use epigenetics to regulate various developmental processes, including vernalization, flowering, stem cell maintenance, and in response to hormonal and environmental stresses.
“A plant’s reproductive success depends critically on the precise timing of flowering in the springtime.” ~ American epigeneticist Karissa Sanbonmatsu
Plants only flower after a certain number of cold weather days. They plan their blooms by remembering the number of days since winter set in. Noncoding RNAs are the physical mechanism for this memory.
Other functions are accomplished by chromatin remodeling, including histone modification and replacement of canonical histones with variants.
Paramutation alters gene expression. In paramutation, one allele induces a heritable change in a homologous allele at the same locus. This is a common floral epigenetic technique, but rare in animals. Paramutation is meiotically inheritable, and so violates Mendel’s law of segregation.
Plant parts select which genes to express. A certain part may revert to an ancestral gene rather than the parent version adopted in the rest of the plant.
There is a tradeoff between growth and defense in many organisms, but this is especially pronounced in plants. The more resources devoted to defense against pathogens the slower the growth rate.
Plants in a pathogen-rich habitat tend to be stunted. This environmental adaptation is passed on epigenetically: no gene mutation occurs for this tradeoff to be carried by offspring. By conveying critical information to seedlings, this epigenetic head start improves the odds of survival for next-generation plants.
Plants assiduously avoid inbreeding. When closely related individuals do mate, offspring tend to be less fit.
This inbreeding depression has long been attributed to genetics: reduction in gene variability. In plants, epigenetics also plays an active part in reducing fitness from inbreeding. This lessens the likelihood that inbred plants will further propagate and weaken a population.
Epigenetic inheritance is both more common in plants than animals and more stable: lasting for hundreds of generations. Epigenetic inheritance in plants is as stable as genetic inheritance. Plant epigenetic reprogramming is much less pervasive and thorough than in animals, so epigenetic marks linger unscathed. Nonetheless, for flexible adaptation, marks remain reversible.
