Ancient Jellies, Modern Tricks: How Sea Blobs Beat Us to DNA Mastery

     Scientists recently discovered that even super simple sea creatures called comb jellies have a surprisingly advanced way of controlling their genes. This method, known as distal gene regulation, lets parts of DNA that are far apart loop around and interact, like sending messages across long distances. These loops help control which genes turn on or off, and when. What’s really surprising is that comb jellies don’t use the same proteins humans and other animals use for this process—they’ve got their own unique way of doing it. This means that this complex gene control system evolved way earlier than scientists thought—like over 650 million years ago.

    This discovery is a huge deal because it shows that the ability to tightly control gene activity isn’t just something that showed up in more modern or complex animals. It was already happening way back in early animals, helping them grow different types of cells and body structures. Understanding how these ancient systems work could even help us learn more about our own DNA and how it affects health, development, and disease today.

MIT Biologists Found a New Layer of Gene Regulation in RNA Splicing

A recent study, published in the MIT News, discusses how scientists have uncovered a new way RNA splicing is regulated, making gene expression more complex than before. RNA splicing is an important process where non-coding sections (introns) are removed from messenger RNA, allowing genes to create proteins. Scientists previously believed that splicesome, a RNA-protein complex, determined the splicing sites, but this study found that a family of proteins called Luc7 also play a major role. These proteins help decide which introns get spliced out, affecting almost half of all human genes. The researchers also found this process in plants, indicating it evolved early in life's history.

             This discovery could offer insights into diseases like acute myeloid leukmeia (AML), where faulty splicing is linked to cancer. It could also be helpful for targeted treatments like small-molecule drugs that stabilize RNA splicing at specific sites. Undertsanding how genes are expressed at such fine level is important in improving treatments in genetic disorders and cancer research.

An “oracle” for predicting the evolution of gene regulation

Researchers build a mathematical framework for examining the genome and detecting natural selection signs in order to comprehend non-coding DNA's evolutionary past and future. Researchers have been working on mathematical maps that allow them to look at an organism's genome, forecast which genes will be expressed, and estimate how that expression will alter the organism's observable features in order to better comprehend the consequences of such changes. These maps, known as fitness landscapes, were first proposed almost a century ago to better understand how genetic makeup effects one common indicator of organismal fitness: reproductive success. Fitness landscapes in the beginning were frequently relatively simple, focused on a small number of mutations. Researchers still require extra tools to classify and visualize such complicated data, despite the availability of much larger datasets. This capability would not only assist researchers better understand how particular genes have developed through time, but it would also aid in predicting future sequence and expression changes.

A group of scientists developed a framework for studying the fitness landscapes of regulatory DNA in a new study published in Nature on March 9th. They constructed a neural network model that, when trained on hundreds of millions of experimental measurements, was capable of predicting how alterations to these non-coding regions in yeast affected gene expression. They also developed a novel two-dimensional representation of landscapes, making it easier to comprehend the history and predict future development of non-coding sequences in organisms other than yeast, as well as construct specific gene expression patterns for gene treatments and industrial uses.

Many scientists have simply trained their models on known mutations (or modest variants thereof) found in nature prior to this work. However, Aviv Regev, an MIT biology professor, and her colleagues intended to take it a step further by developing their own unbiased models capable of predicting an organism's fitness and gene expression based on any possible DNA sequence, including sequences they'd never seen before. Researchers would be able to utilize such models to manipulate cells for medicinal objectives, such as novel cancer and autoimmune disease treatments.

McElvery , Raleigh. “An ‘Oracle’ for Predicting the Evolution of Gene Regulation.” MIT News | Massachusetts Institute of Technology, https://news.mit.edu/2022/oracle-predicting-evolution-gene-regulation-0311. 

McElvery, Raleigh. “A DNA ‘Oracle’ for Predicting the Future Evolution of Gene Regulation.” SciTechDaily, 13 Mar. 2022, https://scitechdaily.com/a-dna-oracle-for-predicting-the-future-evolution-of-gene-regulation/.

Stanley Qi's Alteration of CRISPR is Leading to A Revolution in Genetic Engineering

Stanley Qi is a bioengineer who attended Stanford University and worked on the CRISPR enzyme for most of his graduate years. CRISPR is composed of RNA and guides the DNA cutting enzyme known as Cas9. What Qi did was make Cas9 unable to cut DNA, making it dead (dCas9). Attaching enzymes or other structures allowed scientists to use dCas9 as a gene regulator. Qi hopes to use this invention to cure genetic diseases. Qi has also developed versions of the Cas9 gene that can move around large chunks of the DNA genome. He says this can be used particularly in studying cancers. It can also be used to study how stem cells mature.

I think this is an important discovery in bioengineering because its applications can be limitless. Right now, scientists are figuring out practical uses for this technology. They say that it can be used to cure genetic diseases and learn more about cancer and stem cells. I feel this tech is a cornerstone in human development. There are so many people with genetic diseases that are incurable. With this technology, those people might finally get a cure. In addition, with extensive cancer understanding, the survival rate of cancers might skyrocket or we might even find a cure. The possibilities really are endless.
https://www.sciencenews.org/article/stanley-qi-sn-10-scientists-to-watch
https://www.yourgenome.org/facts/what-is-crispr-cas9

Breakthrough in Gene Regulation

"Rendering of DNA"

In an article published by Science Daily, structures that resemble a microscopic footballs were discovered to play a crucial role in gene regulation. Transcription factors are not in fact single molecules, however are around 7-10 molecules in size, and work together to express certain genes. The discovery was made at the University of York utilizing super-resolution microscopy, and researchers watched the transcription happen in real time. Professor Mark Leake, who led the project, was quoted saying "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." Gene regulation, and the process of turning genes on and off is crucial to life and health. And although currently the research is being done in yeast cells, it will soon be applied to humans and advancing knowledge in medicine and beyond.

I feel this is an incredible breakthrough in how genes are regulated, and its exciting to know this could be the next big thing in health and medicine.

How closely are we related to Spongebob?

https://www.sciencedaily.com/releases/2017/04/170411104532.htm



Scientists have revealed that gene regulation by histones is one of the major effects of evolutionary diversity in organisms ranging from the sponge to humans. The regulation of genes is controlled by the histones that wrap the DNA inside the nucleus. These histones determine whether or not a gene is going to be turned on or off. At the University of Queensland in Australia, a study consisted of Great Barrier Reef sponges and genetic testing was preformed on the histones to see if the genetic marks are the same as in more complex organisms. The common ancestor for the sponge and human is long extinct, but this connection determines that this genetic component is important for evolution and diversity amongst simple to complex organisms.
In my opinion, this study is important to understanding evolutionary drives in ecosystems. Finding a common link in gene expression between two very different organisms is a large step for evolutionary science.

Gene Regulation of Humans and Sponges

According to new research at the University of Queensland, humans and sponges have a lot in common. The study found that sponges gene regulation is as complex as humans. Gene regulation is the process that refers to when and how genes are activated. Histones are proteins that are packaged within the genetic material and help to determine whether a gene is turned off or on. The discovery of histones in Amphimdeon queenslandica, or sponges, shows that this mechanism was “present at the evolutionary dawn of multicellular animals and across animal species’ (Science Daily, 2017). 

Original Science Daily Article

Additional Nature.com Information

Humans and sponges share gene regulation

Recent research has shown that complex organisms such as humans have more in common genetically with a very simple organism, sponges.  This similarity mainly lies in gene regulation, or how and when a certain gene is activated.  The ability of organisms to turn certain genes on and off was thought to be reserved for higher life forms, however even an organism as simple as a sponge posses this ability.  Scientists used to believe that the complexities of different animals was dictated by the number of genes they had, but they've recently discovered most animals have a similar number of genes.  This lead them to believe that gene regulation is actually what has driven evolution and lead to such a wide animal diversity.  Being that the sponge is one of the oldest multicellular organisms it can be inferred that the gene regulation has at least been present for 700 million years, or the time that the common ancestor of sponges and people was present.  This shows a key connection between gene regulation and evolutionary diversity.  

Article  

Scientific Study

What Turns Genes On and Off?

     A team of researchers from Perelman School
of Medicine at University of Pennsylvania have
shed light on how structure of regulatory sequences in DNA is packaged in a cell. The research gives a better understanding of how gene sequences, contribute to gene activity. Enhancers are what influences genes in each cell to be turned on or off. The ultimate purpose of this is to dictate the quality of an encoded protein that is made in response to a physiological change. The following link gives further insight to gene expression and how they can be turned on and off. One reason this research is so important is that many studies have shown errors in enhancers lead to disease or cancer.

      Nucleosomes are a protein that DNA winds around in every cell, and in the past it was believed that when nucleosomes are present the surrounding genes are turned off; therefore not playing a role at enhancer sites. This study provides data to dispute this recently believed theory, and nucleosomes are present at enhancer sites.

     The team of researchers found that certain stretches of DNA were bound to nucleosomes and could be modified to have genes turned on. They removed linker histones from DNA, and allowed enhancers to activate that a single gene which caused the cell to function normally. The team believes this is very promising, because with these techniques cancers and disease can be fought. Also it can be useful in embryo therapy.

      I agree that this study shows very promising results. If scientist can learn to completely turn genes on or off it will cause medical break throughs. It will gives doctors a new angle on fighting disease and forms of cancer. These advancements can also help correct errors in developing embryos or fetuses.

The Truth About Telomeres

          Telomeres are located at the ends of a chromosome, their only job is to protect genetic material on the chromosomes from degradation. Or so we thought. Until recently, there was no strong evidence that telomeres played any other role in genetics besides providing a buffer zone. Researchers Jerry W. Shay and Woodring Wright of the University of Texas Southwestern Medical Center in Dallas have uncovered that when telomeres come in contact with other genes (via nuclear folding) they actually alter how the genes are expressed. Furthermore, as telomeres shorten due to aging, the patterns of chromosome looping and gene expression change!
          Telomeres interact with other genes through intricate looping patterns. As telomere length was manipulated by the researchers, the looping patterns reconfigured and changed drastically. The specific mechanism by which this occurs remains fuzzy, to say the least. It is possible that the telomere shortening can regulate gene expression throughout the aging process for individual cells and the organism as a whole. In the article from The-Scientist.com Dr. Shay suggests that, "cells could alter gene expression to slow cell division in ailing cells even before telomeres become critically shortened".
          These new findings will hopefully open the door to more research about the genetic role telomeres play. Also, one could speculate that manipulation of telomere length could eventually lead to a cure for cancer, by stopping cell division of malignant cells. Or that the telomeres trigger gene expression in healthy cells such as during developmental stages in humans. The possibilities remain endless at this point.

Mice, Humans, and the ENCODE Project

The purpose of this article was to depict the similarities and differences between the human and mouse genomes, and it intended to illuminate the fact that mice may be used to study human biology only to an extent. Researchers have determined that the ways in which humans and mice regulate their genes has been around for a long time; in other words, the gene regulation is evolutionary. The ENCODE project (the Encyclopedia of DNA Elements) is currently keeping track of the similarities between the two genomes, such as which genes are activated at what time and the DNA sequences of each. The ENCODE project has proven to be an effective database for genetic biologists nationwide, allowing professionals to use the mouse genome to assist in treatments for diseases.

However, the genome of mice can't be used to aid in the treatment in human disease in all cases. Two examples of systems that can't be compared between the two genomes is the immune system and response to stress. Environmental factors may have contributed to the differences between the mouse and human genomes. However, the ways in which genes are regulated are extremely similar; gene transcription and chromatin modification are two examples of gene regulation. Despite the similarities in these processes, they differed from one type of cell to the next. In one project, an author of Nature found several statistics that demonstrate the difference and similarities between the genomes. For example, after studying over one million locations of DNase 1, he found that approximately 35% of the information was the same in mice and humans.

Article: http://www.sciencedaily.com/releases/2014/11/141119132703.htm
Supporting Article: https://www.broadinstitute.org/scientific-community/science/projects/mammals-models/mouse/mouse-genome-project

Analysis of Stickleback Genome Sequence Catches Evolution in Action

In HHMI, David Kingsley and his team at Stanford School of Medicine have recently published their investigations on the genome sequence of stickleback fish and how both genome sequence as well as gene expression change over time as the species adapts to environmental changes.

Marine sticklebacks are normally found in salt water, but as glaciers melted during the last ice age 10,000 to 20,000 years ago, many sticklebacks found themselves in fresh water.  Such dramatic environmental changes became settings for evolutionary changes, and fresh-water sticklebacks were naturally selected to survive to their new conditions in ways that make sense physiologically.  For instance, their natural armor became softer to help escape predators and their osmoregulation adapted to the fresh-water environment.

As scientists sequence the genome of both fresh-water and marine-water sticklebacks, they have found that 147 'reused' regions of the fish's genome are responsible for the variations found.  Intriguingly, these genes not only account for phenotypic variations [such as softer armor] but also subtle genetic changes in cell metabolics, developmental signaling, and behavioral interactions between animals.  These changes, such as the ones found in the WNT family that helps stickleback's osmoregulation in fresh water, must work in concert in order to produce functional changes that increase survival.

The study of evolutionary changes through genome sequencing also have allowed scientists to make determinations on what changes are genomic mutations and what changes are gene regulation and how the two are related.

[caption id="attachment_4269" align="aligncenter" width="353" caption="The Stickleback."][/caption]

Researchers Find an Epigenetic Culprit of Memory Decline

In HHMI, Dr. Li-Huei Tsai and her team have recently published a mouse model study suggesting that Alzheimer’s disease has epigenetic origins:  her team's studies conclude that a single overactive enzyme is responsible for disabling the expression of other proteins required for neuron functionality.

The primarily culprit seems to be protein HDAC2, an enzyme which belongs to the histone deacetylase family.  A well-studied form of gene regulation is histone acetylation, wherein histones which are enrapt with DNA strands are acetylated.  Aceytlation of the lysine groups on histone tails neutralizes their positive charges, causing a relaxation in binding of the histones to their nucleosome partners.  As a result, transcription factors have an easier access to genes in acetylated regions.  An overactive histone deacetylase such as HDAC2, which deacetylates regions of DNA-histone complex,can thus dramatically reduce the expression of  related key genes necessary for the functionality of any biological processes, in this case neuron functionality.

The study suggests that inhibition of HDAC2 in mouse models resulted in control and experimental groups performing uniformly better in cognitive tests as opposed to their uninhibited HDAC2 counterparts.  Also, post-mortem autopsies of mouse models known to have degenerative disease states have elevated levels of HDAC2.  However, the scientists noted that although inhibition of HDAC2 restored neuron functionality, the rate of neuron cell death remained higher in mutants than in wild-type.  Dr. Tsai suggests that inhibition of HDAC2 'wakes up' malfunctioning neurons that would otherwise be operational; HDAc2 regulation, however, seems for now to be unlinked to increased neuron cell death.

Histopathologic image of senile plaques seen in the cerebral cortex of a person with Alzheimer's disease of presenile onset. Silver impregnation.