"Epigenetic regulation of alternative splicing" aka "Splicing without Darwin.

Introduction

Alternative splicing (AS) is a post-transcriptional gene regulation mechanism that generates multiple mature messenger RNA (mRNA) isoforms from a single gene. AS is a highly dynamic process that is regulated by a variety of factors, including transcription factors, RNA-binding proteins, and epigenetic modifications.

Epigenetic regulation of AS

Epigenetic modifications are chemical changes that occur to DNA or histones that do not alter the underlying DNA sequence. Epigenetic modifications can affect gene expression by regulating the binding of transcription factors and RNA-binding proteins to DNA.

There is growing evidence that epigenetic modifications play a role in regulating AS. For example, DNA methylation and histone modifications have been shown to affect the splicing of specific genes.

Long non-coding RNAs (lncRNAs) (Junk RNA)

lncRNAs are a class of non-coding RNAs that are longer than 200 nucleotides. lncRNAs have been shown to play a variety of roles in gene regulation, including AS.

Some lncRNAs can interact with splicing factors and regulate the splicing of specific genes. Other lncRNAs can act as competitive endogenous RNAs (ceRNAs) and inhibit the splicing of specific genes.

Conclusion

Epigenetic modifications and lncRNAs are two important factors that regulate AS. Further research is needed to understand the mechanisms by which these factors regulate AS and how they contribute to human health and disease.

Here are some additional points that are mentioned in the article:

* AS is a complex process that is regulated by a variety of factors.

* Epigenetic modifications and lncRNAs are two important factors that regulate AS.

* Further research is needed to understand the mechanisms by which these factors regulate AS and how they contribute to human health and disease.

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Epigenetics is the study of changes in gene expression that are caused by factors other than changes in the DNA sequence as required by neo darwinism which requires random nucleotide mutations.

Left :The ToE has mutations 

Right: epigenetic factors sit on top of the DNA with no sequence changes or mutations. It's non Darwinian.

These changes can be inherited from parents to offspring, and they can be influenced by environmental factors such as diet, stress, and exposure to toxins.

Epigenetic changes can cause a variety of changes in the phenotype, or physical appearance, of an organism. For example, they can affect the development of organs and tissues, the function of enzymes, and the response to disease.

In some cases, epigenetic changes can lead to adaptation, or the ability of an organism to survive and reproduce in a particular environment. For example, studies have shown that epigenetic changes can help plants to adapt to drought conditions.

There are several ways in which epigenetic changes can cause adaptation. One way is by changing the expression of genes. For example, a gene that is normally turned off may be turned on in response to an environmental challenge. This can lead to the production of new proteins that help the organism to cope with the challenge.

Another way in which epigenetic changes can cause adaptation is by affecting the way that DNA is packaged. DNA is wrapped around proteins called histones, and the way that the histones are arranged can affect whether or not a gene is expressed. Epigenetic changes can alter the way that histones are arranged, which can lead to changes in gene expression.

Epigenetic changes are a relatively new area of research, and scientists are still learning about how they work and how they can affect adaptation. However, it is clear that epigenetic changes play an important role in the ability of organisms to survive and reproduce in changing environments.

Here are some examples of how epigenetics can cause adaptation:

• Famine resistance: In times of famine, plants that have epigenetic changes that allow them to store more food are more likely to survive and reproduce.

• Cold tolerance: In cold climates, animals that have epigenetic changes that allow them to produce more heat are more likely to survive.

• Disease resistance: Animals that have epigenetic changes that allow them to fight off disease are more likely to survive and reproduce.

Alternative splicing is a process in which different combinations of exons are used to produce different proteins from the same gene. This can happen in a variety of ways, including the use of different splice sites, the addition or removal of introns, or the use of different regulatory elements.

NeoDarwinism is a theory of evolution that states that evolution is driven by natural selection, which acts on genetic variation in a population. While alternative splicing can lead to the production of different proteins, it does not require natural selection. In fact, alternative splicing can occur in a variety of organisms, including bacteria and archaea, without natural selection.

Therefore, alternative splicing is a phenomenon that can occur independently of NeoDarwinism. This does not mean that alternative splicing is alternative splicing is thought to play a role in a variety of Lamarckian evolutionary processes, such as the development of new genes and the adaptation to new environments.

Here are some additional points to consider:

* Alternative splicing is a common process. It is estimated that up to 90% of human genes can undergo alternative splicing.

* Alternative splicing can produce a wide variety of different proteins. In some cases, the different proteins produced by alternative splicing can have very different functions.

* Alternative splicing is thought to be important for a variety of biological processes, including development, cell differentiation, and disease.

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The discovery of alternative splicing did initially drew doubts on evolution, as it seemed to contradict the idea that genes are stable and unchanging over time. Alternative splicing is a process that allows different combinations of exons to be included in a final mRNA transcript, which can then be translated into different proteins. This means that a single gene can produce multiple different proteins, each with its own unique function.

The prevalence of alternative splicing varies widely across different species. In humans, for example, it is estimated that up to 95% of genes undergo alternative splicing. This suggests that alternative splicing is a major mechanism for generating diversity in the proteome, the collection of all proteins produced by an organism.

The evolutionary significance of alternative splicing is still being investigated, but it is clear that it can play a role in adaptation. For example, alternative splicing has been shown to be involved in the development of different cell types, the response to environmental changes, and the fight against disease.

Overall, the discovery of alternative splicing has provided new insights into the complexity of gene regulation and the potential for evolution. It is now clear that genes are not static entities, but can be dynamically modified to produce different proteins in response to different needs. Here are some additional points about the role of alternative splicing in evolution:

• Alternative splicing can be used to generate new proteins that are better suited to a particular environment or challenge.

• Alternative splicing can also be used to fine-tune the function of existing proteins.

• Alternative splicing can be a way for organisms to adapt to new environments or challenges.

• Alternative splicing is a complex process that is still not fully understood.

• More research is needed to understand the full role of alternative splicing in evolution.

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Article snippets:

2018 Dec 1

Epigenetic regulation of alternative splicing

Alternative splicing (AS) serves as an additional regulatory process for gene expression after transcription, and it generates distinct mRNA species, and even noncoding RNAs (ncRNAs), from one primary transcript.

Generally, AS can be coupled with transcription and subjected to epigenetic regulation, such as DNA methylation and histone modifications

In addition, ncRNAs, especially long noncoding RNAs (lncRNAs), can be generated from AS and function as splicing factors (“interactors” or “hijackers”) in AS

Recently, RNA modifications, such as the RNA N6-methyladenosine (m6A) modification, have been found to regulate AS

It was said by the director Eisenstein Sergei that the sum of frame A and frame B will produce C, which contains an absolutely new concept in the film field. This concept is “montage”, which is also known as “splicing”.

Similarly, in molecular biology, splicing means the editing of precursor messenger RNA (premRNA) transcripts to yield mature messenger RNAs (mRNAs) or noncoding RNAs (ncRNAs)

Splicing removes introns and joins exons together through a series of complicated reactions catalyzed by spliceosomes.

Generally, RNA splicing includes constitutive splicing (CS) and alternative splicing (AS).

AS refers to the process that selectively splices a set of sites in a premRNA to form variable mature mRNAs, thereby producing proteins with different structures and functions

This process occurs for ~95% of transcripts and creates diverse proteins by varying exon composition from a single mRNA

AS effectively increases transcriptomic and proteomic diversity and significantly influences many kinds of cellular processes, as well as tissue specificity or development and disease development

AS is important for generating proteome complexity from a limited number of genes

The primary transcripts produced from gene transcription undergo AS, with introns being removed and particular exons included or excluded, resulting in the maturation of mRNAs or ncRNAs

The generation of ncRNAs from AS was recently reported, further confirming AS as an efficient and economical mode of regulating gene expression.

exon skipping (SE, cassette exon),

SE is the most prevalent mode, with exons included in mRNAs under certain conditions but omitted from mRNAs under different conditions, similar to the differential frame choice between “TRAILER” and “FEATURE” in films.

Splicing was primarily discovered in 1977, followed by basic chemistry research to verify the existence of splicing genes

Small nuclear ribonucleoproteins (snRNPs) are RNA-protein complexes that combine with premRNA to form spliceosomes, which are key to the AS process.

One landmark event was the 1993 Nobel Prize, which was awarded for the discovery of split genes, i.e., the splicing process.

Deciphering the mechanisms of AS is important for understanding the regulatory network in AS and developing applications for therapeutic approaches in the future.

AS is a dynamic process that occurs simultaneously with and is inseparable from transcription

Emerging research has placed AS in a key position in genetic information flow, which indicates that transcription regulators could also subsequently influence AS decisions.

DNA methylation and histone modifications determine eukaryotic chromatin structures under conditions in which certain histone marks recruit splicing factors through chromatin-binding proteins.

Regulation of AS by lncRNAs

The spliceosome comprises at least five kinds of snRNAs (U1, U2, U4/U6 and U5) and more than 200 snRNPs as the AS machinery

Vast numbers of transcripts in humans cannot be further translated into proteins

However, ncRNAs seem to affect diverse biological processes by modulating mRNA transcription, splicing, stability, transportation and epigenetic modification

A plethora of long noncoding RNAs (lncRNAs) have been shown to pivotally regulate AS during disease, and the fine-tuning mechanisms extend across all steps of gene expression, including epigenetic sensu lato, co/posttranscriptional control, miRNA maturation and protein stability

To a large extent, various types of lncRNAs participate in modulating AS patterns, including NATs, UCEs and piRNAs.

N6-methyladenosine (m6A) is the most prevalent and significant modification of eukaryotic transcripts, affecting various aspects of biological processes, including RNA splicing

The methylation process is reversible because of the existence of demethyltransferases, such as FTO and ALKBH5, which serve as “Erasers”

Essentially, m6A modification could contribute to mRNA fate determination by recruiting m6A recognition proteins named “Readers”

Perturbation of the dynamic status of m6A could affect the levels of a large number of RNAs, since the methylation-related molecules were located in nuclear speckles and confirmed to interact with splicing factors that may be involved in modulating AS

Above all, m6A modification could mediate fine-tuning by decreasing the cognate combination of SFs and changing the secondary RNA structure to alter the interaction capacity between SFs and m6A-methylated RNAs

Conclusions

By reprogramming genome expression to confer proteomic and transcriptomic diversity, AS is becoming one of the most important dynamic regulatory processes for adaptation to a changing microenvironment

Therefore, it is not surprising to see so many mechanisms of AS regulation by epigenetic networks, such as the modification of DNA, RNA and histone proteins

The main topics for the study of AS are as follows: history of mRNA splicing, components of the spliceosome, introns/exons in alternative splicing, spliceosome complex regulation, diseases related to splicing and potential therapeutic approaches to splicing-induced diseases

In conclusion, further exploration of AS is needed to elucidate the full landscape of AS, the complete regulatory networks that control AS, such as ncRNAs or m6A modifications, and the function of the vast majority of AS events associated with diseases or disorders.

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