Epitranscriptomics - Complex code points to Design

Epigenetic markers on RNA are necessary for life

https://cen.acs.org/business/start-ups/Epitranscriptomics-new-RNA-code-race/97/i7

Excerpts: "There was a similar reaction to epigenetics more than a decade ago, when it became clear that chemical modifications regulating genes are frequently out of whack in cancer. Companies rushed to develop drugs against proteins responsible for making, removing, and recognizing chemical modifications on genes—often referred to as the writer, eraser, and reader proteins. With the discovery of parallel writer, eraser, and reader proteins working on RNA, epitranscriptomics is looking like a promising, untapped area for drug discovery.

...But there’s another parallel to epigenetics that’s less optimistic: thus far, epigenetic drugs have been a disappointment. “Epigenetics turned out to be a lot more complicated than the community originally thought,” says Chuan He, a professor of chemistry at the University of Chicago.

Scientists knew that METTL3 placed a methyl on a specific nitrogen in adenosine, one of the four building blocks of RNA. This modified building block is called N6-methyladenosine, or m6A for short. Beyond m6A, chemists had cataloged some 150 different chemical modifications to RNA in bacteria, plants, and animals. If He could find an enzyme that removed the methyl groups, it would suggest that there was an undiscovered RNA control system in cells, analogous to epigenetic controls in DNA.

That technique allowed the creation of the first map of m6A. The results were stunning. “We thought that m6A was going to be all over the place, kind of random,” Jaffrey says. Instead, the researchers saw that methyl marks tended to cluster near an area called the stop codon, and only on certain mRNA transcripts. “It was so specific, it just knocked our socks off.”

An even closer inspection revealed that many of the mRNAs containing m6A were linked to differentiation and development, the same functions that were affected in Fray’s stunted plant embryos. “We were amazed,” Jaffrey says.

 

Work by Stanford University geneticist Howard Chang helped change that attitude. Chang showed that without METTL3, mouse and human embryonic stem cells grow uncontrollably and never undergo their normal maturation process, called differentiation, in which they change into specialized cells, such as muscles, neurons, or white blood cells (Cell Stem Cell 2014, DOI: 10.1016/j.stem.2014.09.019). A few months later, Rechavi’s group published a similar study, with an added step showing that mouse embryos missing METTL3 died before birth.

It was becoming clear that m6A was not just some random mark on a transcript. Even though the methyl group is physically small, it has a big effect on RNA. The modifications can coax RNA to assume a different 3-D structure. He’s lab also began studying newly discovered proteins dubbed readers, which have small pockets that bind m6A. He showed that one reader specifically binds m6A to flag an mRNA for destruction. Another reader binds m6A to help spur protein production. He’s elucidation of these reader proteins increased interest in epitranscriptomics for scientists and investors, says Larry Lasky, a partner at the Column Group, a venture capital firm. “It started to look and smell like epigenetics.

In addition to the m6A erasers, a growing body of work is uncovering the importance of the m6A readers. Earlier this month, He’s lab showed that an m6A reader protein called YTHDF1 is an important control switch in the immune system and that inhibiting it might dramatically boost the efficacy of existing checkpoint inhibitors, a popular class of cancer immunotherapy (Nature 2019, DOI: 10.1038/s41586-019-0916-x). “I think a lot of immunotherapy companies will jump into epitranscriptomics once they read the paper,” He says.

And this isn’t the first known link between epitranscriptomics and immunotherapy, Accent’s Copeland says. His firm has been studying an enzyme called ADAR1—which stands for adenosine deaminase acting on RNA—that modifies adenosine bases in RNA. Studies from academic labs show that some tumors depend on ADAR1 in ways that normal cells do not. One study suggests that blocking ADAR1 could make certain drug-resistant cancers vulnerable to checkpoint inhibitors (Nature 2018, DOI: 10.1038/s41586-018-0768-9).
Other labs entering the fray are uncovering new proteins that read, write, and erase RNA modifications, with links to additional types of cancer and other diseases. The scope of epitranscriptomics could be enormous. “That’s what excites us about the field,” says Blundy, Storm’s CEO. “There are many, many RNA pathways that are regulated through modifications.” ”

My comment: There are only a few different types of epigenetic markers on DNA but the number of different epigenetic markers on RNA is about 150. DNA is needed for producing functional programmable RNA molecules. Readers, writers and erasers point to a designed cellular system, where changes don't occur just randomly but by accurate mechanisms induced by nutrition, stressors, sensory stimuli, climate, pheromones etc. Erasers make this system dynamic and reversible.

You may have heard about a theory claiming that changes in organisms occur by random chance and selection. These newest findings on RNA epigenetics refute those hollow claims.

Race is not a biological construct

Differences between 'racial' groups are minimal and differences within groups are huge

https://www.dailymail.co.uk/health/article-6710147/Scientists-say-race-does-not-determine-health-doctors-say-fueling-racial-prejudice.html

Excerpt: "Race is not a legitimate category to use in medicine, top scientists declared at the world's biggest science conference this week.

In the US, African Americans are told to watch out for hypertension, white people for multiple sclerosis, Asians for heart disease, Hispanics for diabetes, and so on.

But on Friday, leading biologists said those general warnings are based on 'bad science' and do no more than fuel 'racial prejudice'.

Among them, anthropologist Keith Hunley of the University of New Mexico presented a new map of genomes around the world, finding few differences between the clusters of racial groups that are often cited in medical research.

By lumping people into distinct broad categories, he and others warned, we risk 'hyping' certain inherited health risks for some and underestimating them for others - while sewing division, stereotypes and ignorance within society.

'We have this notion that there are variants that are unique to certain groups, that there are genes that are unique to certain groups. And that's almost never the case,' Dr Hunley said as he described his presented his paper at the American Association for the Advancement of Science conference.

'When you're looking at a trait that all humans have they're just variable in frequency. There's also variation among groups in their ability to metabolize certain drugs.'

The debate over the genetics of race started in 1972, when geneticist Richard Lewontin found differences between racial groups were 'of virtually no genetic or taxonomic significance.'
He made his statement after studying blood samples of people from seven racial groups, and found 85 percent of the differences in genes was seen within groups, and only 15 percent between groups.

In 2011, Stanford University geneticist Noah Rosenberg mapped out the data we have into pie charts, which suggested racial groups barely differ in their genetic make-up.

Rather than a Venn diagram with many separate circles and a few overlaps, it looks more like a series of circles laid on top of each other, with a few edges that jut out.

There are staunch critics of this view, including geneticist Professor David Reich, who says there are average genetic differences between racial groups that cannot be denied. What's more, they argue, there's not much we can do about it: in an ideal world we will all have access to our genetic profile to see our precise risks, but right now that's not feasible.

However, fuel was added to the fire at this year's AAAS conference in Washington, DC, which featured four new papers decrying race as a biological factor.

'Race is not biological,' said Dr Amelia Hubbard, a biological anthropologist with a new paper on how we teach race and genetics in schools.

'We have to think about how we as Americans, especially those teaching in classrooms, think about race,' Hubbard added at a press briefing with Hunley and other biologists.

'It is tied to social and cultural norms.' Dr Hubbard, of Wright State University in Ohio, claims this debate has been settled by research, but 'old ideas' still linger within mainstream medicine.

Calcium supplements, for example, are marketed to white patients, who are believed to have a higher risk of osteoporosis.
 

'If you look on the FDA label on calcium supplements there's still a really old disclaimer sort of statement about the research that was done in 1971,' Dr Hubbard said.

'And if you look into the research, it wasn't complete. It basically puts people of different races into different kinds of risk based on a study of cadavers of people of two races.

'It wasn't even good science in the first place, and it was a long, long time ago, but it has continued to be perpetuated.'

There are medical conditions that are more common among some racial groups than others. Uterine fibroids, for example, are more common in African American and Hispanic women, while bladder cancer is more common in Caucasians.

But Dr Joseph L Graves Jr, a firebrand evolutionary biologist and author of The Race Myth, said many of the differences we do see are not driven by genetics but by environmental factors - including distress from racial stereotyping.

'Take, for example hypertension,' Dr Graves said. 'I looked at the genes associated with hypertension in genetic variants and showed that they were actually in higher frequency in persons of European descent, as opposed to persons of African descent.

'And so, if your model was genetic, you would expect that Europeans would have greater incidences of hypertension. In fact we see the opposite.'

Above all, he points to racism and the stress of racial tensions as a factor driving that difference.

He uses himself, an African American man at the top of his academic field, as an example of how society can affect health.

'There are numerous examples about how institutional racism kills people. In African American people of higher incomes are more likely to die from stroke than people of lower incomes - the exact opposite of persons of European descent.

'Because people do not expect me to be there, I take home a much higher burden of stress every day.'

He says he attends more funerals now that he is working at a 'minority university', North Carolina A&T State University, with a higher proportion of African American faculty.

'Every day there is another person, and when I was at a majority [university] that never happened.'

Dr Hubbard agreed.

‘[We need to be] teaching not only why race is not biological but how the perception does impact people.

‘There’s a ton of scientific lit demonstrating that the effects of racism through stress and epigenetic tagging is being carried through generations.
‘By remaining silent you’re not really remaining neutral.’"

My comment: There is no genetic basis for race determination. Genetically (DNA) all people are 99.9 % similar. The 0.1% difference is strongly related to hereditary diseases. When we have a careful look at DNA strands associated with human skin color, we can notice that there are only a few true genomic gene alleles differing within people. These genes are:

• HERC2 - two genomic alleles but 14 transcripts (splice variants)
• OCA2 - one genomic allele but 4 transcripts (splice variants)
• MC1R - 4 transcripts (splice variants)
• ASIP - 2 transcripts (splice variants)
• SLC45A2 - one genomic allele but 5 transcripts (splice variants)
• IRF4 - 5 transcripts (splice variants)
• TYR - 3 transcripts (splice variants)
• TYRP1 - 7 transcripts (splice variants)
• GRM5 - 5 transcripts (splice variants)
• HYAL1 - 9 transcripts (splice variants)
• HYAL3 - 6 transcripts (splice variants)

As we can see, there are only three DNA genes (associated with skin color variation) having a couple of different gene alleles. The actual differences are in transcripts (64 different versions) which means different splice variants. These are results from alternative splicing which is regulated by epigenetic factors and mechanisms.  

Histone Modifications Regulate Alternative Splicing Mechanism

The role of Histone Code in protein diversity seems to be very significant

https://www.frontiersin.org/articles/10.3389/fgene.2019.00122/full (18th Feb 2019)

Excerpt: "Alternative splicing is a process that can generate multiple mRNA isoforms from a single gene by splicing pre-mRNA molecules in different ways. As an important process of gene expression, alternative splicing ensures the diversity of gene expression products. It has been estimated that alternative splicing occurs in approximately 90% human genes. Alternative splicing is reported to closely correlate with apoptosis, embryonic development and even a series of diseases. Although great efforts have been made on studying alternative splicing, the mechanisms of cell type-specific and stage-specific alternative splicing are still unclear.

Recently, Shindo et al. (2013) found that the alternative splicing of the BIN1 gene in IMR90 cell was regulated by the cooperation of H3K36me3, H3K4me3, H2BK12ac, and H4K5ac. These results strongly indicate that histone modifications play important roles in RNA splicing regulation and are key clues for revealing the regulatory mechanism of alternative splicing.
 

Based on these experimental results, several computational methods have been proposed to predict the alternative exons in exon skipping event based on histone modifications. The pioneer work was proposed by Enroth et al. (2012), in which a rule-based model was developed to classify included and excluded exons based on histone modification combinations. Later on, based on Enroth et al.’s (2012) dataset, Chen et al. (2014) proposed a quadratic discriminant (QD) function method and obtained an accuracy of 68.5% for classifying the included and excluded exons in the exon skipping event. More recently, a random forest based method was developed for the same aim and obtained an accuracy of 72.91% in the 10-fold cross validation test (Chen et al., 2018b). These results strongly indicate that histone modifications play important roles in RNA splicing regulation and are key clues for revealing the regulatory mechanism of alternative splicing. These results indicate that we should find the novel splicing code from the epigenome information.

Conclusion

Based on the Pearson correlation coefficients, the casual relationships of histone modifications in the process of RNA splicing were deduced by constructing their Bayesian networks. The results indicate that the inclusion or exclusion of exons is influenced by combinatorial patterns of histone modifications. Some of the histone modifications contribute directly to RNA splicing (e.g., H3K36me3 and H3K79me1), while other histone modifications indirectly contribute to the RNA splicing.

The result that H3K36me3 and H3K79me1 can affect RNA splicing is consistent with previous studies which have demonstrated that H3K36me3 and H3K79me1 are enriched in included exons. The H3K36me3 can regulate alternative splicing by interacting with polypyrimidine tract-binding protein (PTB). By interacting with the Tudor domain of TP53BP1, the H3K79me1 was also reported to interact with that interacts with snRNP.

By relaxing the chromatin structure, the H3 and H4 acetylation were also reported to regulating inclusion or exclusion of the skipping exon. Besides the histone modifications located in exon regions, histone modifications located in intragenic regions can also influence RNA splicing by regulating RNAPII elongation rates, or by directly binding to splicing factors and hence mediating their binding to pre-mRNA."

My comment: Histone code is a complex database being able to store epigenetic information that strongly affects DNA transcription, pre-mRNA splicing and post-transcriptional modifications of mRNA. It's clear that the histone code regulates organismal characteristics. By using histone epigenetic markers cells are able to convert digital (marker) information to analog information. The histone code is an indication of Intelligent Code of life, complex biological information that is designed by our Creator. The histone code is maintained by writers, readers and erasers which points to Intelligent Design. However, there is no mechanism for evolution, because epigenetic mechanisms only regulate pre-existing biological information. Don't get lost.

Bacterial adaptation to changing conditions is regulated by epigenetic mechanisms

Methylation endows the bacterium with the flexibility needed to adapt its pattern of gene expression to changing environmental conditions

https://www.news-medical.net/news/20190213/Microbiologists-identify-enzyme-that-makes-Helicobacter-so-adaptable.aspx

Excerpt: "The bacterial pathogen Helicobacter pylori owes its worldwide distribution to its genetic adaptability. Ludwig-Maximilians-Universitaet (LMU) Munich microbiologists have identified an enzyme that plays a vital role in the flexible control of global gene expression in the species.

The cosmopolitan bacterium Helicobacter pylori, which colonizes the mammalian gastrointestinal system, is responsible for one of the most common microbial infections in humans. Many Helicobacter infections provoke no overt symptoms, while others induce various types of gastrointestinal disorders, such as gastric ulcers. However, the most serious consequence of infection with H. pylori is that the microorganism can induce the development of cancer of the stomach. 

One of the most striking features of the species is its genetic diversity. Research groups led by microbiologists Professor Sebastian Suerbaum and Professor Christine Josenhans at LMU's Max von Pettenkofer Institute have been exploring the significance of this feature for its ability to survive in its human hosts. They now report the identification of a particular enzyme that plays an important role in coordinating the regulation of gene expression in the pathogen. The protein belongs to the class of enzymes known as DNA methylases, whose function is to attach a chemical tag known as a methyl group (CH3) to specific sequence motifs in DNA. Methylation of DNA in bacteria was first described as the self-protective arm of a primitive immune system, which recognizes unmethylated DNAs as foreign and selectively destroys them. However, it is now known that DNA methylation systems in bacteria play a variety of other roles in relation to the control of gene activity. Moreover, this function is apparently so crucial for the survival of H. pylori in the stomach that the newly identified methylase is found in every one of the over 450 strains of the species investigated in the new study. In contrast, many other members of the same enzyme family are found in only a small subset of the strains examined. The new findings are described in a paper that appears in the journal Nucleic Acids Research. Lead author of the report is doctoral student Iratxe Estibariz.
 

In virtually all domains of life, methyltransferases play a crucial role in 'epigenetic' processes (i.e. regulatory mechanisms that depend on alterations in the chemical structure but not the sequence of nucleotide bases in DNA) that enable organisms to adapt rapidly to changes in environmental conditions. Methylation of DNA as a mode of regulating gene expression was originally discovered in humans - where methylation of specific DNA sequences serves to render the genes affected resistant to activation. "However, the role of epigenetics in bacteria has been little studied so far," says Sebastian Suerbaum. 

Together with Christine Josenhans' group, he has now shown that the methyltransferase JHP 1050 has a very significant effect on gene expression in H. pylori. Genetic inactivation of the enzyme results in defects in cell growth and shape, and negatively affects the bacterium's capacity to adhere to host cells. "Our work demonstrates that practically all the biological properties that are relevant to the interactions between H. pylori and its human hosts - bacterial metabolism, motility and stress resistance, interaction with host cells - are all regulated by global methylation, and it shows that this process endows the bacterium with the flexibility needed to adapt its pattern of gene expression to changing environmental conditions," says Christine Josenhans."

My comment: DNA is just passive form of information also within bacteria. The role of epigenetics in bacteria has been little studied so far but what we already know, is that epigenetic mechanisms and factors play a major role in bacterial adaptations. This means that transcription factors and their binding sites are regulated by methylation profiles and these are mediated by non coding RNAs. Bacteria are also capable of RNA editing, which means incredibly complex repair and masquerading mechanisms. Biological information is multi-layered and extremely complex. This all points to Design and Creation.  

Insects Could Disappear Within A Century

Mass insect extinction within a century threatens 'catastrophic' collapse of nature’s ecosystems, scientists warn

https://www.independent.co.uk/news/science/insect-extinction-nature-climate-change-francisco-sanchez-bayo-sydney-science-a8773326.html

Excerpt: "Pesticide use is driving an “alarming” decline in the world’s insects that could have a “catastrophic” impact on nature’s ecosystems, researchers have warned.

More than 40 per cent of insect species are at risk of extinction with decades, with climate change and pollution also to blame, according to a global scientific review.

Their numbers are plummeting so precipitously that almost all insects could vanish within a century, the study found.

An overhaul of the agricultural industry is “urgently needed” to “allow the recovery of declining insect populations and safeguard the vital ecosystem services they provide,” wrote co-authors from Sydney and Queensland universities.

The biologists conducted a systematic review of 73 historic reports of insect declines across the world.

Ten per cent of known insect species have already become extinct, compared to one per cent of vertebrates, they found. Of the insects that remain, 41 per cent are in decline.

Over the past 30 years, the total mass of all insects dropped an average of 2.5 per cent annually. The “dramatic” fall suggest none will be left in 100 years, warned Francisco Sanchez-Bayo, of the University of Sydney’s School of Life and Environmental Sciences.

“The rate of decline is really huge,” he told BBC Radio 4’s Today.

Butterflies and moths are among the worst affected, along with bees and dung beetles. Researchers said “a considerable proportion” of aquatic fly species had also been lost already.
 

The review highlighted four key drivers of extinction: habitat loss caused by agriculture, urbanisation and deforestation; pollution; biological factors such as invasive species and diseases; and climate change.

Agriculture was the “main culprit” in 40 per cent of the studies reviewed, with researchers highlighting “the way we apply pesticides” as a particular threat.

“We have been doing agriculture for thousands of years and we have never seen these declines,” said Dr Sanchez-Bayo. “The introduction of systemic insecticides has been in a big change in the way we do agriculture these days." "

My comment: Use the following keywords to reveal the actual reason for rapid extinction of insects: 'insect loss of genetic variation' OR 'insect loss of genetic diversity'. You can replace the word 'insect' with 'butterfly' or 'bees' etc.

Evolution never happened. All kind of organisms are rapidly losing genetic diversity. For example in human genome, there are 628,685 gene-disease-associations but the number of random beneficial mutations is ZERO.

SNPs based on cDNA sequence could be artifacts of RNA editing

SNP databases are not reliable sources for mapping genetic mutations

https://www.researchgate.net/publication/7660913_Identification_of_RNA_editing_sites_in_the_SNP_database

Excerpt: "The relationship between human inherited genomic variations and phenotypic differences has been the focus of much research effort in recent years. These studies benefit from millions of single-nucleotide polymorphism (SNP) records available in public databases, such as dbSNP. The importance of identifying false dbSNP records increases with the growing role played by SNPs in linkage analysis for disease traits. In particular, the emerging understanding of the abundance of DNA and RNA editing calls for a careful distinction between inherited SNPs and somatic DNA and RNA modifications.

In order to demonstrate that some of the SNP database records are actually somatic modification, we focus on one type of these modifications, namely A-to-I RNA editing, and present evidence for hundreds of dbSNP records that are actually editing sites. We provide a list of 102 RNA editing sites previously annotated in dbSNP database as SNPs, and experimentally validate seven of these. Interestingly, we show how dbSNP can serve as a starting point to look for new editing sites. Our results, for this particular type of RNA editing, demonstrate the need for a careful analysis of SNP databases in light of the increasing recognition of the significance of somatic sequence modifications."

My comment: cDNA samples are sequenced by using mRNAs that often have gone through several epigenetic based sequence level modification events.The most common RNA editing mechanisms are alternative splicing and RNA A-to-I editing. According to some estimates, A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes.

What does this mean? Most of the SNP databases are based on edited pre-mRNAs and mRNAs and they don't tell us anything about true chromosomal, genomic (gDNA) changes. gDNA sequencing is expensive and it takes a lot of time.
 

RNA editing can be done in several complex ways:

If the product is mRNA, some of the codons in the open reading frame (ORF) of the gene specify different amino acids from those in the protein translated from the mRNA of the gene.

The reason is RNA editing: the alteration of the sequence of nucleotides in the RNA

• after it has been transcribed from DNA but
• before it is translated into protein

RNA editing occurs by two distinct mechanisms:

• Substitution Editing: chemical alteration of individual nucleotides.These alterations are catalyzed by enzymes that recognize a specific target sequence of nucleotides (much like restriction enzymes):
• cytidine deaminases that convert a C in the RNA to uracil (U);
• adenosine deaminases that convert an A to inosine (I), which the ribosome translates as a G. Thus a CAG codon (for Gln) can be converted to a CGG codon (for Arg).
• Insertion/Deletion Editing: insertion or deletion of nucleotides in the RNA.These alterations are mediated by guide RNA molecules that
• base-pair as best they can with the RNA to be edited and
• serve as a template for the addition (or removal) of nucleotides in the target

These discoveries help us see DNA tests in a new light. Especially this is important for the case of these monozygotic twins having different skin, hair and eye color. Seems that so called somatic mutations are in fact epigenetic mRNA modifications.