In the Genetics of Congenital Heart Disease, Noncoding DNA Fills in Some Blanks

Nancy Fliesler, from the Boston’s Children Hospital, talks about how for a couple decades now, researchers have been trying to find out what are the genetic causes for congenital heart disease (CHD). Some causes include chromosomal abnormalities, genetic variants affecting protein-coding genes, and environmental factors, but this only accounts for about 45 percent of cases of CHD. There has been evidence that noncoding DNA does contribute to CHD. It’s difficult to find out which noncoding variants are involved in heart disease, and which are not. Statistical filters were applied to separate the noncoding variants that were not contributing to CHD. 7,000 variants in noncoding DNA regions were left after the separation. 403 affected the activity of transcription enhancers out of the 7,000 variants they tested. 

They then had to introduce 10 of the noncoding variants into normal human stem cells at a certain location on the genome. Four out of the ten variants altered the expression of neighboring genes when the stem cells formed into cardiomyocytes. The research conducted suggest that hundreds more noncoding variants contribute to CHD which could explain cases that are negative by exome sequencing. Future findings could eventually be used to classify patients’ risks, predict outcomes of surgery, or change the course of structural heart disease during pregnancy or after birth. This is important research as we didn’t know for sure what was causing CHD. To know now that there is a noncoding DNA that is the culprit for this disease is revolutionary. 

Main Article: https://answers.childrenshospital.org/congenital-heart-disease-noncoding-dna/

2nd link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892081/ 

Unraveling Chromatin in Gene Expression

DNA is an incredibly long molecule, with a single cell containing anywhere from two to three meters of DNA in its nucleus. In order to keep this delicate and immense molecule organized and protected, the strands are wrapped around specialized proteins and referred to as chromatin. However, when a gene needs to be expressed, this requires the chromatin matrix to be unraveled and the necessary gene to be exposed. The mechanism for how this occurs is largely unknown, but Beat Fierz's lab believes they have uncovered the first step.

Fierz's lab conducted a study on these "pioneer transcription factors" using yeast as a model organism. In order to study a specific transcription factor Rap1, the team sought to replicate one of the architectural genes within yeast using single-molecule fluorescence as a marker. Rap1 serves to activate a machine within the chromatin and expose relevant DNA so necessary proteins can access the DNA.

This research is interesting because the mechanism for this process is almost entirely unknown to scientists at this moment, and the more we understand about this, the better we will understand gene expression. Additionally, as we learn more about this process, we might be able to identify different illnesses caused by malfunctions in chromatin unwinding, and maybe even finding cures or treatments for them.

Article: https://www.sciencedaily.com/releases/2019/11/191121121736.htm
Related Link (Understanding Gene Expression): https://www.news-medical.net/life-sciences/A-Guide-to-Understanding-Gene-Expression.aspx

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.

Transcription Promoter Shape and Gene Expression

         

          Recent research published in the Journal Nature Genetics looked into the effects of promoter shape on promoter evolution and expression noise in animals. As covered in class, a promoter is a portion of DNA at which the process of transcription is initiated. Promoters can fall into two categories, broad or narrow. These categories are what is referred to as the promoter "shape". The published findings indicated that promoter shape not only varies across species but also within individual populations. The model organism used in the study was our old friend Drosophila.
          The function of differing promoter shape is not fully understood but the researchers were able to show that shape did not directly relate to transcription levels. Results also indicated that expression noise may play a role in the evolution of promoters. I found a short article here that gives a quick overview of gene expression noise for those interested. Overall this research is important in broadening our understanding of the complex interactions that lead to gene expression at a cellular level.

Link Between DNA Transcription, Disease-Causing Expansions

     Scientists have known that long nucleotide base repeats in the human genome have led to heritable human diseases such as Huntington’s disease. Huntington’s disease is a neurodegenerative disease that affects muscle coordination and leads to a deterioration of cognitive thought. There are many nucleotide base repeats that are stable, but their lengthening over time leads to genome instability and changes in gene expression which can cause these diseases. Up until now, it was thought that the lengthening of these nucleotide base repeats was caused during DNA replication or when DNA repair machinery was active in the cell. However, it was found that the lengthening of these base pair repeats also occurs during transcription, which is the process of forming RNA from a DNA template within a cell.

                    

In a study performed by a research team led by Sergei Mirkin, the White Family Professor of Biology at Tufts' School of Arts and Sciences, the correlation between transcription and the expansion of base pair repeats was observed in yeast. The team used genetic systems to track the lengthening of nucleotide base pair repeats during DNA replication, DNA repair, and transcription. These genetic systems were also used to track the number of expansions in transcribed and non-transcribed parts of reporter genes. It was found that both transcribed and non-transcribed fragments of the reporter genes showed expansion, but the transcribed form of the reporter genes was ten times more likely to undergo the expansion process. This is because in a transcriptionally active state, the transcribed DNA segment has significantly less nucleosome density which leaves more room for repeat expansions of nucleotide base pairs.

                                      
     I find this article interesting because it relates the expansion of nucleotide base pairs to heritable diseases such as Huntington’s. By learning more about what causes these diseases, more efficient methods of treatment or cures can be discovered and implemented.

Source: Link Between DNA Transcription, Disease-Causing Expansions

Plants Return to Earth after Growing in Space

     More than one thousand plants were put into deep freeze and sent to the International Space Station in order to determine the effect of microgravity on plant growth. As the plants are thawed, their RNA will be sampled using an instrument that will determine the activity of their approximately 30,000 genes. Gravity itself is a force that strongly affects biology, as humans who spend a prolonged period of time in space show decreased bone mass as it is not required to support weight. Similarly, plants that are grown in low-gravity environments grow taller and thinner, and tend to have less structural support.

     Genes produce RNA which then code for separate proteins in the genetic process called transcription. By observing the genetic expression of plants grown in microgravity versus an identical group grown on Earth, the influence of microgravity on plant genes can be determined. It has been shown that plants grown with a lack of physical adversity, such as rain or wind, tend to be less strong and are more susceptible to diseases and pests. Plants grown in space tend to be more vulnerable to diseases due to the same mechanism. Therefore, by determining how to grow plants in space that are resistant to disease, it will be easier to provide food and oxygen for astronauts in the near future.

     I find this article interesting because it directly relates genetic expression to physical adversity. As scientists are able to determine how to grow plants that are less susceptible to disease, it will become more efficient to send astronauts to the International Space Station. In addition, astronauts will be able to go on longer trips if they can produce their own food without worry, meaning that humans will be able to explore more of space after this experiment is completed.

Source: Plants Return to Earth after Growing in Space

     

Could be more to know about the world of Epigenetics than previously assumed...

As time pushes onward, humans are constantly obtaining more information about how the body works and how our traits are passed from generation to generation. This article gives insight to the world of Epigenetics, which scientists have previously believed to be set in stone. However, as researchers backtrack and take a closer look, epigentics is not as simple as we assumed. This article mentions how we have viewed the DNA sequence as an independent of the epigenetic mechanisms (that which are responsible for controlling the gene expressions and are heritable). Further reading of this article will allow the readers to be able to see just how complex the transcription of the DNA can be. Some of the transcription ways are straightforward, but others occur at different rates or times which can all effect the output of the process. I feel that is is important that researchers keep investigating what controls our traits, that way we can learn how to better ourselves and the future generations to come. 

Source: http://www.sciencemag.org/content/342/6159/705.full

Below is a link to another article, also giving details about epigentics: 

http://www.nature.com/scitable/topicpage/epigenetic-influences-and-disease-895

Mobile DNA Elements Can Disrupt Gene Expression and Cause Biological Variation, Study Shows

According to an article on the website of Science Daily,  a group of researchers at the Ohio State University Comprehensive Cancer Center found that transposons are can affect gene expression even if they are thousands of base pairs away from premature stop site in the genomic DNA. Another factor that determined whether or not the transposons affected the expression of gene was gender of the parent that the transposon was inherited from.

Transposons  are movable pieces of DNA, also called “jumping genes” as they can move from one location to another on a chromosome, but unlike viruses they can’t move from one cell to another. Transposons makeup half of the genomic DNA in humans and mice as they have accumulated in the genome over time.



The transposons studied in this research study were that of diverse mouse strains called endogenous retroviruses (ERVs). They found that ERVs disrupted the gene expression by halting gene transcription. If the gene containing an ERV came from the father it produced an incomplete form of mRNA but if it came from the mother a full length mRNA was produced from the gene.

According to an assistant professor of molecular virology, immunology and medical genetics Dr. David E Symer,  this an unusual example of DNA imprinting.They are in the process of determining how the transposon is able to trigger or halt the expression of the gene and also how the transposons affect the gene expression differently based on the gender of the parent that it came from. Dr. Symer says these finding are important in understanding mechanisms of natural variation and human biology also cancer and other diseases.

Observing Transcription

Researchers at  Albert Einstein College of Medicine of Yeshiva University were able to watch, in real time, the process of gene transcription. They used florescent  proteins to track the mRNA activity by inserting DNA  sequences into a gene in live yeast cells. RNA made from these sequences bound a modified green fluorescent protein; expression of the entire gene resulted in mRNA molecules that were visible with fluorescent light. By monoriting the activity of RNA polymerase scientists were able to directly observe and measure the key steps involved in transcription: initiation, elongation, and termination.  By observing how transcription works in the cells of yeast, we are better able to determine steps of the same processes in humans. For instance, one element researches saw was that initiation was a random event. "By contrast, once initiation occurs, RNA polymerase recruits individual nucleotides for the growing mRNA molecule in an efficient and predictable manner" said Dr. Singer.