Hopping molecule clusters control genes in Energy efficient way

Cells can respond as quickly as possible to signals from the outside


Research at the University of York has revealed that genes are controlled by 'nano footballs' -- structures that look like footballs but 10 million times smaller than the average ball.

Excerpt: "By placing tiny glowing probes on transcription factors -- special chemicals inside cells which control whether a gene is switched 'on' or 'off' -- researchers gained a remarkable new insight into the way in which genes are controlled.

Crucially, they discovered that transcription factors operate not as single molecules as was previously thought, but as a spherical football-like cluster of around seven to ten molecules of roughly 30 nanometres in diameter.

The discovery of these nano footballs will not only help researchers understand more about the basic ways in which genes operate, but may also provide important insights into human health problems associated with a range of different genetic disorders, including cancer.

The research, supported by the Biotechnology and Biological Sciences Research Council (BBSRC) and published in eLife was carried out by scientists from the University of York, and the University of Gothenburg and Chalmers University of Technology, Sweden.

The researchers employed advanced super-resolution microscopy to look at the nano footballs in real time, using the same type of yeast cells utilised in baking and brewing beer.

Professor Mark Leake, Chair of Biological Physics at the University of York who led the work, said: "Our ability to see inside living cells, one molecule at a time, is simply breathtaking.

"We had no idea that we would discover that transcription factors operated in this clustered way. The textbooks all suggested that single molecules were used to switch genes on and off, not these crazy nano footballs that we observed.

The team believe the clustering process is due to an ingenious strategy of the cell to allow transcription factors to reach their target genes as quickly as possible.

Professor Leake said: "We found out that the size of these nano footballs is a remarkably close match to the gaps between DNA when it is scrunched up inside a cell. As the DNA inside a nucleus is really squeezed in, you get little gaps between separate strands of DNA which are like the mesh in a fishing net. The size of this mesh is really close to the size of the nano footballs we see.

"This means that nano footballs can roll along segments of DNA but then hop to another nearby segment. This allows the nano football to find the specific gene it controls much more quickly than if no nano hopping was possible. In other words, cells can respond as quickly as possible to signals from the outside, which is an enormous advantage in the fight for survival."

Genes are made from DNA, the so-called molecule of life. Since the discovery that DNA has a double helix shape, made in the 1950s by pioneering biophysics researchers, much has been learned about transcription factors which can control whether a gene is switched on or off.

If a gene is switched on, specialised molecular machinery in the cell reads off its genetic code and converts it into a single protein molecule.Thousands of different types of protein molecules can then be made, and when they interact that can drive the building of all of the remarkable structures found inside living cells.

The process of controlling which genes are switched on or off at any particular point in time is fundamental to all life. When it goes wrong, this can lead to serious health problems. In particular, dysfunctional switching of genes can result in cells which grow and divide uncontrollably, which can ultimately lead to cancer.

This new research may help provide insights into human health problems associated with a range of different genetic disorders. The next stages will be to extend this research into more complicated types of cells than yeast -- and ultimately into human cells."

My comment: Genes are controlled by several epigenetic factors, like these nano molecule clusters. The cell is able to produce even thousands of different proteins by using only one sequence of the DNA by a very clever mechanism called alternative splicing. These nano footballs point to Intelligent Design. The cell can re-use them on several locations along the needs of adaptation. Here we have again a mechanism that refutes hollow claims of random mutations and selection. All change in organisms is based on epigenetic regulation of existing biological information or loss of it. That's why there's no mechanism for evolution. Don't get misled.


Epigenetic alterations result in harmful mutations

Modifications in methylation patterns lead to harmful genetic mutations


Excerpts: "Diverse epigenetic modification patterns can affect the types and frequencies of genetic alterations at the neighboring chromatin regions. Integrative analysis of whole genome sequencing with epigenome sequencing have identified how the epigenetic landscape influences the accumulation of genetic alterations during hepatocarcinogenesis. The analysis also showed that several cancer driver genes are mutated either by genetic or epigenetic alterations. Genetic mutations that are affected or substituted by epigenetic alterations include single nucleotide variant (SNVs) mutations, small insertions and deletions (indels) and DNA copy number variations (CNVs). We have summarized recent findings that demonstrate molecular links between genetic mutations and epigenetic modifications.
Because diverse mutational mechanisms are at play during tumorigenesis, the SNV patterns of each tumor are different and reflect the nature of the tumor-inducing conditions. HCC shows high frequencies of C to T, C to A and T to C nucleotide substitutions. Among these, C to T transitions at CpG dinucleotide sequences are caused by the relatively elevated rate of spontaneous deamination of 5-methyl-cytosine in tumors. Thus, the DNA demethylation levels of tumor cells could influence the mutation frequencies induced by the deamination process. In addition, the significant upregulation of the APOBEC family in HBV- and HCV-HCC promotes C to T and C to A mutations by deaminating cytidine to uracil (C to U), coupled with the base excision repair and DNA replication processes. Besides APOBEC enzymes, several cellular and viral proteins also affect base substitutions epigenetically. A methyl-CpG-binding protein, MBD4, can affect the C to T transition rate, probably by regulating accessibility of the methylated C for deamination or repair enzymes.

DNA methylation status also has a strong effect on chromosomal integrity. Global DNA hypomethylation is observed in HCC and can induce activation of transposons and chromosomal instability, thus contributing to the generation of a large number of CNVs during hepatocarcinogenesis. Hypomethylation-associated reactivation of repetitive elements such as LINE-1, ALU and juxtacentromeric SAT2 is frequently observed in HCC along with copy number variations caused by insertions and deletions. Intriguingly, the loss of repetitive DNA appears tightly associated with its hypomethylation.

Acetaldehyde and free radicals generated by metabolizing alcohol induce DNA damage and oxidative stress, which often accelerate monocyte activation and telomere shortening. The alcohol-derived risk factors (acetaldehyde and free radicals) seem to function mainly as a mutagen affecting DNA integrity; however, its role in epigenetic regulation in liver cells is now being discovered."

My comment: We've been taught that epigenetic modifications don't contribute to the DNA but as we can see, this is not the case. It's obvious that changing methylation patterns (also called as methylation profiles) result in changes in DNA sequences. The most typical factors impacting on methylation patterns by abnormal way are oxidative stress, viruses, alcohol, smoking and environmental toxins. Shifting diet types also cause alterations in epigenetic patterns possibly leading to harmful genetic mutations. Life habits are the most significant reason for rapidly increasing repertoire of disease-causing genetic mutations in the human DNA. There are already 208,368 of them at population level. The annual increase was about 20,000. But modern scientists are not aware of beneficial random mutations. That's why there are no mechanisms for evolution. All change in organisms is based on epigenetic regulation of existing biological information OR loss of it. Don't get misled. 


This is why scientists should focus on Epigenetics

This is why Mendelian laws are not valid anymore

1. "A few years later, the situation became even worse with the discovery of alternative splicing. In alternative splicing, a given ‘split gene’ can code for various different proteins, depending on whether this or that exon is expressed at a given time (for instance a certain exon is expressed in embryos, another one is expressed in the adult organism)."

The most significant EPIGENETIC factors modulating the alternative splicing machinery:
a. microRNAs  b. DNA methylation  c. Histone markers

2. "Other phenomena are also quite challenging for the notion of a gene as ‘no more than a coding sequence’: assembled genes (where germinal sequences, often designated as ‘genes’, are assembled to make a single somatic gene, a situation commonly found in immunogenetics: all antibodies are coded by assembled genes); inversion of the reading frame (meaning that the same DNA sequence can be transcribed in both directions, resulting in different proteins)."

Especially microRNAs (EPIGENETICS) mediate the production of antibodies.

3. "Partial overlapping of the reading frames (the same sequence translated in different frames can give up to two or even three different proteins)."

Transcription of overlapping reading frames is regulated by EPIGENETIC mechanisms:
a. DNA methylation  b. microRNAs  c. Histone markers

4. "Multiple initiation and termination sites of transcription (producing a multiplicity of RNA molecules out of which proteins will eventually be synthesized)."

This is based on EPIGENETIC mechanisms.

5. "Non-universality of the genetic code (e.g., a slightly different code for nuclear genes and cytoplasmic genes: this means that the same sequence, in the same organism, can lead to different proteins)."

Because protein production is mediated by several EPIGENETIC mechanisms.

6. "This is only a partial list. Today, many molecular processes are known that challenge the traditional ‘one gene-one protein’ dogma. In reality, it seems hopeless to provide a general definition of the gene on the basis of exclusively molecular criteria."

7. "The discovery of non-coding RNA has maybe been the most impressive discovery in molecular biology since 2000. Recent data show that 98.5% of our genome is not translated into proteins, but more than 70% is transcribed into RNA (EPIGENETICS). Furthermore, 70,000 promoter regions (EPIGENETICS) (the sites where proteins bind to control gene expression) and 400,000 enhancers (EPIGENETICS) (regulatory sites that affect the expression of distant genes) have been discovered in the human genome. These findings suggest that the information contained in our genome goes far beyond the usual picture of 20,000–25,000 protein-coding genes. (My comment: 19,600) There are many more functional units than those protein-coding genes. Given this situation, one might think that the word ‘gene’ could be abandoned, and replaced by more precise terms."

My comment: The DNA sequences, often designated as 'genes', are very raw material for several epigenetic mechanisms that control cellular processes. All change in organisms is based on epigenetic regulation of existing biological information OR loss of it. That's why there are no mechanisms for evolution. Life is not driven by DNA's gene sequences. Genes are driven by life(style).


Smoking causes changes in methylation profiles - First step in lung cancer development

Genetic mutations caused by epigenetic alterations


Excerpt: "Scientists at the Johns Hopkins Kimmel Cancer Center say they have preliminary evidence in laboratory-grown, human airway cells that a condensed form of cigarette smoke triggers so-called "epigenetic" changes in the cells consistent with the earliest steps toward lung cancer development.

Epigenetic processes are essentially switches that control a gene's potentially heritable levels of protein production but without involving changes to underlying structure of a gene's DNA. One example of such an epigenetic change is methylation—when cells add tiny methyl chemical groups to a beginning region of a gene's DNA sequence, often silencing the gene's activation. (My comment: Even an addition/removal of one methyl group might significantly influence the protein interactions and the identity of the cell.)

"Our study suggests that epigenetic changes to cells treated with cigarette smoke sensitize airway cells to genetic mutations known to cause lung cancers," says Stephen Baylin, M.D., the Virginia and D.K. Ludwig Professor for Cancer Research and professor of oncology at the Johns Hopkins Kimmel Cancer Center. Details of the scientists' experiments are described in the Sept. 11 issue of Cancer Cell.

For two decades, scientists have known some of the genetic culprits that drive lung cancer growth, including mutations in a gene called KRAS, which are present in one-third of patients with smoking-related lung cancers, according to Baylin. Genetic and epigenetic changes also occur when normal cells undergo chronic stress, such as the repeated irritation and inflammation caused by decades of exposure to cigarette smoke and its contents.
Baylin and Johns Hopkins scientist Michelle Vaz, Ph.D., first author on the study, suspected that the interplay of epigenetic and genetic changes may occur when normal lung cells develop into cancer, but, Baylin says, the timing of such changes was unknown.

To create the effect of tobacco smoke on cells, Vaz, Baylin and their colleagues began their studies with human bronchial cells, which line the airways of the lungs, and grew them in a laboratory. Every day for 15 months, the scientists bathed the cells with a liquid form of cigarette smoke, which they say is comparable to smoking one to two packs of cigarettes daily.

The scientists recorded the molecular and genetic changes in the smoke-exposed cells over 10 to 15 months, which the scientists say may be similar to 20 to 30 years of smoking, and compared the changes to bronchial cells that had not been exposed to the liquid smoke.

After 10 days of smoke exposure, the scientists found an overall increase in DNA damage responses to so-called reactive oxygen species within the cells. Reactive oxygen species, also called free radicals, are chemicals that typically contain oxygen, are known to be found in cigarette smoke, and cause DNA damage in cells.

Between 10 days and three months, the cells exposed to smoke had a two- to four-fold increase in the amount of an enzyme called EZH2, which works to dampen the expression of genes. Baylin and other scientists have shown that EZH2 and its effects can precede abnormal DNA methylation in gene start sites.

After EZH2 enzymes rise, their levels taper off, and then, the scientists found two to three-fold increases in a protein called DNMT1, which maintains DNA methylation in the "start" location of a variety of tumor suppressor genes that normally suppress cell growth. When these genes are silenced a barrier is removed that might otherwise stop the cells from growing uncontrollably—a hallmark of cancer.

A host of other genes (My comment: mediated by non coding RNA molecules), which control many other cellular processes do not show such abnormal DNA methylation after smoke exposure.

Baylin says certain genes that control cell growth 
(My comment: mediated by non coding RNA molecules) get turned down periodically during certain stages of life, including embryogenesis, when organisms are growing and developing rapidly. These genes can normally be turned on when cells need to stop growth and allow cells to mature. Chronic cigarette smoke exposure, as noted in many human cancers, tends to block these cell maturation genes from properly turning on, says Baylin.

At the end of six months, the amount of EZH2 and DNMT1 enzymes had tapered off in the cells exposed to the smoke. However, the impact of the two methylation-regulating enzymes was still seen at 10 to 15 months, when scientists found decreased expression of hundreds of genes—many of which are key tumor suppressor genes such as BMP3, SFRP2 and GATA4—in the smoke-exposed cells and a five- or-more-fold increase in the signaling of the KRAS oncogene that is known to be mutated in smoking-related lung cancers.

However, no mutations were found in the KRAS gene itself or the tumor suppressor genes during the 15-month period of cigarette smoke exposure. These abnormally methylated and silenced genes, says Baylin, would have blocked the increase in KRAS signaling if the genes had been properly activated under smoke-free circumstances.

The scientists also found that the timing of epigenetic and genetic events may be key to lung cancer development. They tested this by inserting mutations into the KRAS gene in the DNA of cells exposed to the cigarette smoke condensate for six months as well as those exposed for 15 months. The scientists found that the inserted mutation transformed cells into cancer in only the 15-month cells, where methylation was fully established, but not in the six-month-exposed cells.

Vaz and Baylin say the results suggest that early epigenetic changes triggered by chronic cigarette smoke exposure can build up over time and make the airway cells increasingly sensitive to responding to mutations that initiate cancer.

They say that smokers can best lower their risk of cancer by quitting altogether, and the sooner a smoker quits, the lower their lung cancer risk may be. Their analysis of data in previous studies done by The Cancer Genome Atlas group have shown that the types of abnormal methylation levels they found are lower in smokers who have quit for more than 10 years than those who have not quit.

It may be possible to use de-methylating drugs, they say, for people with higher than normal risk for lung cancer, such as people who have had surgery for early forms of the disease. Such drugs are currently used in clinical trials for certain types of cancer and are standard therapy for a type of pre-leukemia condition.

The scientists caution that their model, as is the case with any laboratory model, may not be exactly what occurs in people during a lengthy period of smoking, but they say it's a first step in understanding the epigenetic processes that may occur early in the transformation of cells into lung cancer."

My comment: This is a typical example of genetic alterations driven by life habits. Cells are exposed to free radicals and oxidation by several other factors that result in aberrant methylation patterns that sensitize cells to genetic mutations. A minority of these genetic errors are ended up to germ line cells. This is one significant reason for human genetic degradation. It is an inevitable phenomenon but people are catalyzing it with poor nutrition, smoking, alcohol consumption and other bad life habits.

Organisms in nature are also experiencing alterations in methylation patterns. This same phenomenon exposes cells to genetic errors that weaken the gene pool. All changes in organisms are based on epigenetic regulation of existing biological information OR loss of information. That's why there are no mechanisms for evolution. Don't get lost.


Supercomputer models one second of human brain activity

It took 40 minutes for a supercomputer with 705,024 processor cores and 1.4 million GB of RAM to simulate ONE second of human brain activity

Excerpt: "The most accurate simulation of the human brain to date has been carried out in a Japanese supercomputer, with a single second’s worth of activity from just one per cent of the complex organ taking one of the world’s most powerful supercomputers 40 minutes to calculate.

Researchers used the K computer in Japan, currently the fourth most powerful in the world, to simulate human brain activity. The computer has 705,024 processor cores and 1.4 million GB of RAM, but still took 40 minutes to crunch the data for just one second of brain activity.

The project, a joint enterprise between Japanese research group RIKEN, the Okinawa Institute of Science and Technology Graduate University and Forschungszentrum J├╝lich, an interdisciplinary research center based in Germany, was the largest neuronal network simulation to date.
It used the open-source Neural Simulation Technology (NEST) tool to replicate a network consisting of 1.73 billion nerve cells connected by 10.4 trillion synapses.

While significant in size, the simulated network represented just one per cent of the neuronal network in the human brain. Rather than providing new insight into the organ the project’s main goal was to test the limits of simulation technology and the capabilities of the K computer."

My comment: The astonishing complexity and efficiency of the human brain point to Intelligent Design and Creation. Even one cell is hyper complex: In a single human cell, more than 100,000 different biochemical reactions happen every second. Just take a look at the incredible complexity of metabolic pathways of a human cell to have an idea of how perfectly designed the cellular mechanisms are.



A Few Years Ago Junk-DNA - Today, One of the Most Powerful Regulatory Mechanisms

Long non coding RNA molecules don't support Darwinian ideas of mutations and selection

Excerpt: "An individual’s risk of developing a common disease typically depends on an interaction of genetic and environmental factors. Epigenetic research is uncovering novel ways through which environmental factors such as diet, air pollution, and chemical exposure can affect our genes. DNA methylation and histone modifications are the most commonly studied epigenetic mechanisms. The role of long non-coding RNAs (lncRNAs) in epigenetic processes has been more recently highlighted. LncRNAs are defined as transcribed RNA molecules greater than 200 nucleotides in length with little or no protein-coding capability. While few functional lncRNAs have been well characterized to date, they have been demonstrated to control gene regulation at every level, including transcriptional gene silencing via regulation of the chromatin structure and DNA methylation.
  • LncRNAs can bind to DNA, RNA, and proteins and act in diverse ways within the cell. LncRNAs regulate gene expression by multiple mechanisms. They can guide chromatin remodeling complexes to the correct chromosomal locations controlling the balance between transcriptionally active euchromatin and silent heterochromatin both locally and globally (a).
  • Furthermore, lncRNAs can inhibit or facilitate the recruitment of RNA pol II, transcription factors, and/or cofactors to gene promoters, thereby controlling transcription of target genes (b).
  • They can regulate alternative splicing of pre-mRNAs and thereby contribute to the transcriptome complexity (c).
  • Moreover, they can affect the stability and translation of mRNA by base pairing with mRNA molecules (d).
  • LncRNAs can compete for miRNA binding and thereby preventing their function and influencing the expression of miRNA target gene expression (e).
  • They can also be processed into small, single-, or double-stranded RNAs that act as siRNAs and target other RNAs, which subsequently could result in target degradation (f).
  • Their flexible scaffold nature enables lncRNAs to join multiple protein factors that would not interact or functionally cooperate if they only relied on protein–protein interactions (g).
  • The scaffold function is also important for protein activity and localization as well as subcellular structures (h, i).
(Adapted from: Gutschner T, Diederichs S: The hallmarks of cancer: a long non-coding RNA point of view. RNA Biol. 2012 Jun;9(6):703–19)"

Here's an example of a long non coding RNA molecule. Look at its structure.


"These lncRNAs can be processed by several mechanisms, including ribonuclease P (RNase P) cleavage to generate mature 3′ ends, capping by small nucleolar RNA (snoRNA)–protein (snoRNP) complexes at their ends, or the formation of circular structures."

My comment: LncRNAs have several crucial roles in regulating cellular processes. Mutations in these complex structures are associated with severe diseases, such as cancer. The number of human lncRNAs in 2016 was 167,150 according to NONCODE 2016. The number of protein coding genes in human DNA is only ~19,600. Different proteins in a human body however, is up to one million.

Some lncRNAs undergo alternative splicing. Most of them regulate alternative pre-mRNA splicing. Some lncRNAs act as precursors for certain short RNA molecules, such as microRNAs.

DNA methylation is mostly regulated by lncRNAs or shorter RNA molecules derived from lncRNAs. Epigenetic markers on histones are established by maternal and paternal lncRNAs. Those markers strongly regulate skull and skeletal morphogenesis and other phenotype associated traits within organisms.

For evolutionists the significance of lncRNAs is a bad news: They are poorly conserved. The similarity between human/chimp lncRNA transcripts is only 29.8%. Human/pig lncRNA transcripts are much more similar, about 57%.

Random mutations or selection have no role in biodiversity. Everything points to Design and Creation. Don't get misled.


Honeybees become workers or queens depending on the plant microRNAs in their diet

Plant microRNAs strongly affect gene expression


Excerpt: "Bee larvae develop into workers, in part, because their diet of pollen and honey, called beebread, is rich in plant regulatory molecules called microRNAs, which delay development and keep their ovaries inactive. Xi Chen of Nanjing University in China and colleagues, report these August 31, 2017 in PLOS Genetics.

Researchers have long known that diet plays an important role in the complex process that determines whether a honeybee larva will become a worker or a queen. While the workers primarily consume beebread, the queens feast on royal jelly secreted by the glands of nurse bees. Beebread contains much higher levels of plant microRNAs than royal jelly, so researchers decided to investigate if these molecules, which regulate gene expression in plants, could also impact honeybee caste development. They found that honeybees raised in the lab on simulated beebread supplemented with plant microRNAs developed more slowly and had a smaller body and smaller ovaries than larvae raised without the supplements. The plant microRNAs also had a similar effect on fruit fly larvae, even though fruit flies are not social insects. Further experiments showed that one of the most common plant microRNAs in beebread targets the TOR gene in honeybees, which helps determine caste.

The study shows that there is more to the story of honeybee caste formation than the traditional focus on royal jelly and identifies a previously unknown function of plant microRNAs in fine-tuning larval development."

My comment: This is an epigenetic mechanism by which an organism's gene expression is regulated by external dietary microRNAs. Plant miRNAs also act as enhancers during a process called alternative splicing. That makes it possible for a cell to produce thousands of different protein isoforms by using only one DNA strand or a combination of several DNA strands as an information library. This library is then read, copied and modified by several complex mechanisms for producing the required protein by the cell.

MicroRNAs and other non-coding RNAs from diet play a significant role in organisms' gene expression and other mechanisms involved in ecological adaptation. This is why GMO food might be surprisingly harmful for humans.

Infants are able to digest lactose in breast milk due to microRNAs originated from mammary glands. This means that miRNAs override other regulatory factors regarding lactase production.

MicroRNAs derived from diet tell us about designed regulatory factors that refute the claims about random mutations and selection. There is no such thing as mutation driven evolution. Don't get lost.