LncRNAs transmit epigenetic information for embryonic stem cell differentiation

Thousands of different lncRNAs transmit organismal traits from parents to offspring - lncRNAs are 'poorly conserved' which means that we have nothing to do with apes

https://www.frontiersin.org/articles/10.3389/fgene.2020.00277/full

Excerpts: "Long non-coding RNA (lncRNA), a class of non-coding RNAs with more than 200 bp in length, has been shown to act as essential epigenetic regulators of stem cell pluripotency and specific lineage commitment."

"Long non-coding RNA refers to a family of non-coding RNAs with more than 200 bp in length and is transcribed by RNA polymerase II, usually 5′ capped, spliced and polyadenylated (Kung et al., 2013; Quinn and Chang, 2016). LncRNA can be transcribed from different genome regions, including introns, exons, intergenic connections, and other areas. Currently, there are about 30,000 lncRNAs identified in human and mice (Frankish et al., 2019), but only a handful part of them have been recognized for their function."

"Here, we provide an updated overview on how lncRNA epigenetically regulates PSC (pluripotent stem cell) function."
 

Mechanisms of lncRNA in regulating stem cell pluripotency. Nuclear lncRNAs regulate the expression of pluripotent genes via chromatin remodeling. While lncRNAs in cytosol mainly act as post-transcriptional regulators. They work as miRNA sponges to affect gene expression or signaling pathway.

"Previous studies have demonstrated that lncRNAs are crucial regulators for regulating stem cell pluripotency (Chen and Zhang, 2016; Rosa and Ballarino, 2016)."

"We will discuss the role of lncRNA in cell lineage commitment and focus on how lncRNA regulates PSC differentiation into adipocytes, osteogenic, muscle, cardiomyocytes, neurons, skin, and blood cells."

"The lncRNA adipogenic differentiation-induced non-coding RNA (ADINR) is induced by adipogenesis and positively regulates both PPARγ and CEBPA expression by recruiting PA1 (a component of the MLL3/4 complex) to the CEBPA promoter and impacting H3K4me3 and H3K27me3 histone modification (Xiao et al., 2015)."
https://link.springer.com/article/10.1007/s00018-018-3000-z

Excerpt: "Many nuclear lncRNAs interact with histone modifiers (writers, readers, and erasers) and/or other chromatin-associated proteins, thus acting as epigenetic regulators."

https://www.nature.com/articles/s41467-019-13688-z

"However, unlike protein-coding genes, which are largely conserved in mammals, vast majority of human lncRNAs are non-conserved, and many of them are probably lineage-specific."

Summary and conclusions:

• lncRNAs transmit epigenetic information, especially for histones, from parents to offspring.
• There are thousands of different lncRNAs in human sperm.
• Most of human traits and characteristics are regulated by histone epigenetic information = histone code.
• DNA is just passive information and it doesn't determine organismal traits.
• It's very pseudoscientific to compare human/chimp protein coding DNA (~97% similarity) and draw evolutionary conclusions.
• lncRNAs are poorly conserved (only 20-30% similarity) between humans and apes

The theory of evolution has major flaws. The modern synthesis has got causality in biology wrong, DNA doesn't determine organismal traits. DNA is just passive data base. Evolution never happened. Don't get lost, my friends.

Epigenetic mechanisms behind organismal change - Nothing to do with random mutations

It's a classical mistake to confuse between ecological adaptation and evolution

Everyone has heard of mantra touted by evolution believers: "Evolution happens because of random mutations and selection that weeds out harmful changes and preserves beneficial ones." Simple and easy. In this way the pseudoscientific heresy can be taught even for toddlers. But modern science has revealed that these doctrines are false science and that ecological adaptation has nothing to do with random mutations. 

Ecological adaptation and phenotypic change is ALWAYS based on two mechanisms:

1. Epigenetic regulation of pre-existing information.
2. Loss or corrupted information that leads to re-organization of information.

Epigenetic regulation can be influenced by several factors such as nutrition, climate, stress, sensory stimuli, toxicants, etc. These are already well understood biological facts:

a. How diet and nutrition affects organismal change?

https://www.pnas.org/content/113/52/15042

Histone deacetylases control module-specific phenotypic plasticity in beetle weapons

Excerpt: "We found that epigenetic regulators, such as histone deacetylases (HDACs) and polycomb group (PcG) proteins, contribute specifically to the plastic expression of male mandibles...Nutritional conditions during early development influence the plastic expression of adult phenotypes. Among several body modules of animals, the development of sexually selected exaggerated traits exhibits striking nutrition sensitivity, resulting in positive allometry and hypervariability distinct from other traits."

Keywords: 'nutrition epigenetic regulation', 'diet and methylation'

b. How climate impacts on epigenetic modifications?

DNA methylation as a possible mechanism affecting ability of natural populations to adapt to changing climate

https://academic.oup.com/icb/advance-article-abstract/doi/10.1093/icb/icaa049/5848649?redirectedFrom=fulltext

Excerpt: "This review highlights the significance of environmental temperature on epigenetic control of phenotypic variation, with the aim of furthering our understanding of how epigenetics might help or hinder species’ adaptation to climate change. It outlines how epigenetic modifications, including DNA methylation and histone/chromatin modification, (1) respond to temperature and regulate thermal stress responses in different kingdoms of life, (2) regulate temperature-dependent expression of key developmental processes, sex determination, and seasonal phenotypes, (3) facilitate transgenerational epigenetic inheritance of thermal adaptation, (4) adapt populations to local and global climate gradients, and finally (5) facilitate in biological invasions across climate regions."

Keywords: 'climate epigenetic regulation'

c. How stressors contribute to epigenetic changes?

https://www.researchgate.net/publication/316751947_Mechanical_stress_affects_methylation_pattern_of_GNAS_isoforms_and_osteogenic_differentiation_of_hAT-MSCs

Mechanical stress affects methylation pattern of GNAS isoforms and osteogenic differentiation of hAT-MSCs

Excerpt:"Mechanical stress exerts a substantial role on skeletal-cell renewal systems, whereas accumulating evidence suggests that epigenetic mechanisms induce changes and differential gene expression. Although the underlying mechanisms remain to be fully elucidated, our study suggests that the influence of the long term mechanical stimulation elicits epigenetic modifications controlling osteogenic differentiation of human adipose tissue multipotential stromal cells (hAT-MSCs) and contributes to an accelerating in vitro osteogenesis."

Keywords: 'stress epigenetic regulation'

d. How sensory stimuli influences epigenetic regulation and gene expression?

https://newscenter.lbl.gov/2013/03/04/olfactor-receptors-epigenetics/

Do We Owe Our Sense of Smell to Epigenetics?

Excerpt: "A nerve cell’s initial choice of a specific allele, or form of the gene, is likely probabilistic. Once the choice is made, the challenge is to explain how the chosen allele is locked in: how does the cell silence the competing genes? The answer lies with an epigenetic mechanism – one that works outside genetic processes – to spatially rearrange the chromosomes."

Keywords: 'brain signals sensory epigenetic regulation'

e. How toxicants affect epigenetic regulation?

https://epigeneticsandchromatin.biomedcentral.com/articles/10.1186/s13072-017-0154-0

Excerpt: "In this review, we have reported and discussed recent evidence that strongly supports the idea that the zebrafish can be a valuable animal model for exploring both individual and transgenerational epigenetic variations induced by a wide variety of environmental stimuli."

Keywords: 'toxicants epigenetic regulation'

Summary and conclusions: Change in organisms is a clearly observable fact in nature. A good question is: Why change is happening and what it results in? These previous examples elucidate that there are complex epigenetic mechanisms behind the organismal change and adaptation. Rich biodiversity is based on these epigenetic mechanisms and factors. However, epigenetic modifications often lead to harmful DNA mutations. This is why all living organisms are experiencing rapid genetic degradation. Evolution never happened. Don't get lost, my friends.

Epigenetic factors control mouse embryo development

Epigenetic regulators arrange for the many different types of cells in the body

https://www.bionews.org.uk/page_151203

Excerpt: "Key epigenetic factors regulating cell diversity in mouse embryos have been revealed in new research.

Scientists at the Max Planck Institute for Molecular Genetics in Berlin, Germany have used new techniques to determine the function of some key epigenetic regulators in the development of mouse embryos. Their work, published in Nature, found epigenetic regulator PRC2 is necessary for limiting the number of germline progenitor cells – cells that will develop into sperm or eggs.

'With the combination of new technologies we addressed issues that have been up in the air for 25 years,' said, senior author, Professor Alexander Meissner. 'We now understand better how epigenetic regulators arrange for the many different types of cells in the body.'

A fertilised egg cell develops into a whole organism, producing many specialised tissues and organs, while the genetic information inside each cell remains the same. Epigenetic marks play a role in making this happen by changing the 'packaging' of DNA without altering the DNA sequence. This 'instructs' cells what cell type to become by switching on or off certain gene.

Crucial regulator proteins control the location and timing of these epigenetic marks. Adding further complexity, these regulators are present in all cells but do different tasks depending on the cell type and timing. Until now it has not been possible to study these regulator proteins in detail.
 

The team used CRISPR/Cas9 genome editing in fertilised eggs to remove single genes which code for epigenetic factors and observed the effects on development. After six to nine days they examined anatomical changes to the embryo and analysed gene expression in almost 280,000 individual cells.

Researchers said the single-cell analysis gave a 'high-resolution view' not possible from observing the embryo's appearance. Switching off a single regulator often led to a ripple effect causing changes to the activation of many genes in the network. Removing PRC2, a known epigenetic modifier, had a big impact on the embryo, causing an excessive number of germline progenitor cells, loss of shape and death.

Professor Meissner describes the potential of this new approach: 'Our method lets us investigate other factors such as transcription or growth factors or even a combination of these. We are now able to observe very early developmental stages in a level of detail that was previously unthinkable'.
This work also paves the way for more detailed investigations into epigenetic regulation, which is not only relevant for the development of embryos but also the formation of cancer."

My comment: This study proves again how the cell uses DNA as passive information. The DNA strands are controlled by epigenetic mechanisms and factors. Regulator proteins such as PRC2 are classified as epigenetic factors. Transcription of any protein is also completely controlled by epigenetic mechanisms. DNA has no control over cellular processes, embryonic development, body shape or body plan. Think about the huge complexity of these epigenetic regulators: These regulators are present in all cells but do different tasks depending on the cell type and timing. Perfect timing needs perfect coding and programming? Where's the code? Who is the programmer? These kind of complex mechanisms point to Intelligent Creator, not blind evolution. Don't get lost my friends.

Several recent reports suggest a key role for epigenetics in the development of antibiotic resistance in bacteria

Genetic changes fail to explain bacterial antibiotic resistance

https://aac.asm.org/content/64/2/e02225-19

Excerpts: 

"Despite extensive research, well-documented biochemical mechanisms and genetic changes fail to fully explain mechanisms underlying antibiotic resistance. Several recent reports suggest a key role for epigenetics in the development of antibiotic resistance in bacteria. The intrinsic heterogeneity as well as transient nature of epigenetic inheritance provides a plausible backdrop for high-paced emergence of drug resistance in bacteria."

"Adaptive resistance. When bacteria are subjected to increasing subinhibitory concentrations of an antibiotic, they develop adaptive resistance to the antibiotic. The characteristic feature of adaptive resistance is the rapidity with which the resistance phenotype emerges and reverts to a susceptible phenotype upon the withdrawal of the antibiotic. The survival rate of bacteria in subinhibitory concentrations of antibiotics cannot be explained by genetic mutations as expected mutation rates that lead to resistance are lower than the observed survival rates. Genetic changes also cannot explain the high reversion rates because for the bacteria to revert to susceptible phenotype, compensatory or back mutations are needed, and these are known to occur at a very low rate. Adaptive resistance is the consequence of the presence of heritable phenotypic variations even in genetically identical bacteria from isogenic populations. Culture-based evolution studies, investigation of genetic knockout and transcriptomes, and modeling-based studies suggest that epigenetic inheritance and stochastic heterogeneity in gene expression patterns are responsible for this phenomenon"

 

"Epigenetic inheritance is dynamic in nature and thus can explain the transience of adaptive resistance. The resistance which develops when bacteria grow in the presence of nonlethal concentrations of antibiotics could be the consequence of changes in the epigenetic landscape of the bacterial genome. As soon as the antibiotic stress is removed from the environment, the epigenetic changes are no longer sustained on the genome of the subsequent generations, and, thus, they retrogress to a susceptible phenotype."

"Phase variation.Bacteria can survive highly dynamic environments by rapidly modulating the expression of certain genes in a switch-on/switch-off manner, and this reversible switch is called phase variation. There are several ways by which phase variation is brought about, such as DNA inversion, methylation/demethylation of gene promoters or other regulatory sequences, slipped-strand mispairing, homologous recombination, and transposition. Changes in methylation profiles of DNA regulate phase variation in bacteria, but the reverse is true as well, wherein phase variation leads to regulation of the expression of methyltransferases or changes in their target specificities."

"Methylated cytosines act as mutational hot spots.Cytosine undergoes spontaneous deamination to uracil. Since the presence of uracil is atypical in genomic DNA, it gets excised by uracil-DNA glycosylase, initiating the base excision repair pathway. But spontaneous deamination of 5-methylcytosine (m5C) yields thymine, which is not easily recognized by the DNA repair machinery and thus may not get excised or repaired. This results in fixing of the mutation in the genome. The frequency of deamination of m5C is 2 to 4 times higher than that of cytosine. Methylated cytosines are regarded as hot spots for cytosine to thymine mutations in bacteria although very-short-patch (VSP) mismatch repair may reduce the frequency of such mutations."

"A recent report analyzing whole-genome sequences of thousands of bacteria suggests that cytosine methylation may increase the rate of C-to-T transitions by over 50-fold."

"Methylation of cytosine provides a stable framework for the emergence of mutations which can potentially be either deleterious or beneficial for bacteria under antibiotic stress, depending on the site of mutation. Studies investigating the synergy between antibiotic stress-induced error-prone polymerases and C-to-T transitions of methylated cytosines may help us better understand the specific role of methylation-mediated genetic changes in regulating antimicrobial resistance."

"CONCLUSION AND FUTURE PERSPECTIVES

Since well-documented biochemical or genetic changes fail to fully explain mechanisms underlying antibiotic resistance, it is becoming increasingly evident that we need to shift our focus to newer, nonclassical mechanisms such as epigenetic regulation. The biological role of epigenetic modifications in modulating gene expression and other cellular processes is being increasingly recognized. New epigenetic modifications are being discovered in both prokaryotes and eukaryotes, including phosphorothioation in bacterial DNA backbone  and acetylation of cytidine in eukaryal mRNA. Since it has been established that modifications in eukaryotic mRNAs can modulate a variety of cellular processes, it may not be too speculative to suggest that such modifications in bacterial transcripts may be linked to critical functions in the bacterial life cycle. Even though m6A modification in bacterial mRNAs has been identified, the epigenetic writers (the enzymes that add the epigenetic tag to the nucleotide), readers, etc., for this modification are yet to be identified. The influence of epigenetics on the heterogeneity among members of isogenic bacterial populations merits detailed studies.
While the literature from the last decade reviewed here unambiguously indicates a role for epigenetics in antibiotic resistance among bacteria, we believe that precise mapping of epigenetic tags on bacterial genomes and their functional analysis will help create a paradigm shift in our understanding of this field. Furthermore, epigenetic modifications on bacterial genomes represent new diagnostic markers as well as novel drug targets."

My comment: Bacterial antibiotic resistance has been an example of evolution for several decades. Modern science has now revealed that it's not about evolution. Epigenetic modifications are mechanism based dynamic changes that often result in errors in DNA. Bacterial antibiotic resistance has nothing to do with evolution. Like any change and adaptation in organisms living in nature, antibiotic resistance is due to epigenetic modifications, in this case in bacterial mRNA (m6a). These changes, however, often result in DNA alterations that are sometimes intentional but mostly are harmful and deleterious because bacterial genome's GC content gradually turns to AT content. Again, mechanisms for devolution are well understood. Evolution never happened. Don't get lost.