Author: smccl013

smccl013

The Great Research Project

Insight on Cell Senescence:

             Cell senescence is a permanent, stable cell cycle arrest, where cells that have reached their division limit or have undergone stress, then exit the cell cycle and enter senesscence1. This arrest state halts the division of the cell; however, the cell still maintains metabolic activities and secretes substances into the environment1.  Senescent cells are associated with both protective and deleterious effects2. A category important to mention is replicative senescence. Under replicative senescence, the cells have only a short telomere left, typically uncapped1. The shortened telomere leads to DNA damage responses and triggers senescence2. Accumulated findings support stress is the main way cells enter this phase instead of apoptosis1. Majority of cells can reach this phase, and it can be understood as similar to the G0 phase of the cell cycle3. Don’t be misled though, the G0 phase is a resting state from the cell cycle and will return to division, often referred to as Quiescent 3. Cell senescence is the irreversible phase of G03.

            The irreversibility of cell senescence is where concerns lie. While senescence has the ability to avoid malignant transformation of damaged cells, the onset of the state is known to contribute to pathologies like cancer, aging tissue, and inflammatory disease2. The contribution to the pathologies lies in the secreted substances1,2. These are known as pro-inflammatory senescence-associated secretory phenotype (SASP) that communicate with the surrounding cells and immune system2.  SASP is responsible for both promoting and inhibiting tumor growth2. The SASP’s ability to attract immune cells to senescence cells aids in their death, acting as a tumor suppression and preventation2. However, SASP has also been found to induce tumor progression by releasing factors that stimulate angiogenesis, extracellular matrix remodeling, and epithelial-mesenchymal transition (EMT)2. Further, chronic inflammation triggered by senescence can lead to systemic immunosuppression, possibly contributing to the development of cancer2. This persistent inflammatory state not only affects immune function but may also accelerate tissue damage and aging-related degeneration as it communicates to the other cells2. From this knowledge, the complexity of cell senescence is shown along with the uncertainties it holds.

A deeper look into Transcription:

            All processes have to begin somewhere and for normal transcription that is the promoter sequence4. A promoter sequence is the kickstart of the protein coding gene to be transcribed into RNA5. The promoter sequence holds an important power, depending on the length of the sequence on each DNA, the level of control for gene-expression differs4. Combination of promoter lengths and location on DNA, help create the variety and specific purposes of each promoter sequence4. Located just upstream of the coding sequence the increased surface area of longer promoter sequences allows more proteins to bind to the promoter sequence and the range of control can be quite dramatic4. Proteins binding to the promoter sequence is specific to eukaryotes, known as transcription factors and have specific chosen DNA for every binding process.4.

Interestingly, a phenomenon can occur, interfering with the normal transcription process5. From the above paragraph, we have learned that the promoter sequence is the beginning of a normal transcription process due to its specific location on the DNA5. This process is well regulated by the cells, but sometimes a look-alike sequence fools the process5. The phenomenon is called cryptic transcription and occurs when promoter sequence look-alikes exist on other locations within the DNA5. In mammalian studies, the arise of cryptic transcription is found to increase with cell age5.

In this process of another form of transcription can occur6. Cryptic Transcription occurs in senescent cells and normal cells and can have harmful consequences5,6. RNA transcripts are produced from a short sequence that is located with individual genes6. However, how the harmful consequences of this process occurs, has been a question to scientist for years6.  What we do know is Cryptic transcription has been associated with spurious behavior, meaning any at chromatin region (gene sequence), RNA polymerase II can be recruited7.  This area is outside of the normal promoter sequence, and be called the cryptic promoter7.What makes this process cryptic is how the process functions within normal transcription, but creates an error-like expression in the gene when the cryptic promoter recruits the RNA polymerase7. Some studies have found Cryptic transcripts to be chromatin sensitive, allowing for a type of research to highlight the cryptic transcripts in the act, but many are still hard to detect7. A key difference between normal transcription and cryptic transcription is that normal transcription holds a strict process, while cryptic transcription sneaks into the process and changes the coding process unnoticeably until expressed,6,7.

 The Misleading Zombie:

            One could say aging is like becoming a zombie, and in the paper “Spurious intragenic transcription is a feature of mammalian cellular senescence and tissue aging8”, we will delve into the process of mammalian cells becoming a “zombie” with the topics we have just explored.            

            A eukaryotic genome is transcribed into pre-mRNA and is then catalyzed by RNA polymerase8. In typical transcription once this occurs, it is crucial the chromatin structure of the replicated sequence is restored8. If not, then risk for cryptic promoter sequences increases which is known to age cells due to altering normal nucleosome arrangment8.  Senescence cells attempt to prevent this damage by ceasing to replicate so they secrete soluble factors to increase immunity, but high exposure of the secretion can cause aging or damage in the still replicating, young cells8. Senescence will no longer undergo normal transcription due to risk damage or age, while normal cells carry out transcription and under senescence secretion may have a high chance of a cryptic promoter opening up and altering the RNA8.  Figure g shows proliferating cells to emit a strong signal, while senescent cells barely emitted a signal8.

The researchers previous work in yeast and worms, results showed prevention of age-related intragenic cryptic transcription8. A gene body trimethylation mark on lysine 36 of histone H3 (H3K36me3) showed increased transcriptional stability, while in mice embryonic stem cells, DNA in cooperation with H3K36 methylation resulted in prevention of cryptic transcription8. In this, It was found that younger genes have a strict regulation to ensure transcription runs smoothly8.

References

  • 1 Fridlyanskaya, I., Alekseenko, L., Nikolsky, N. Senescence as a general cellular response to stress: A mini-review. Experimental Gerontology. 2015; 72: 124-128
  • 2 Cellular Senescence. Cell Signaling Technology,https://www.cellsignal.com/science-resources/overview-of-cellular-senescence
  • 3 Wikipedia contributors. G0 phase 2024;https://en.wikipedia.org/wiki/G0_phase
  • 4 OpenStaxCollege. Biology- Eukaryotic Transcription Gene Regulation. 2012; Pressbooks,
  • https://pressbooks-dev.oer.hawaii.edu/biology/chapter/eukaryotic-transcription-gene-regulation/
  • 5 Baylor College of Medicine. Cryptic transcription, a novel phenomenon in mammalian stem  cells, linked to aging. 2021; ScienceDaily, https://www.sciencedaily.com/releases/2021/08/210802160654.htm.
  • 6 Nahas, K. “cryptic transcription”: How aging cells express fragments of genes, TheScientist, https://www.the-scientist.com/cryptic-transcription-how-aging-cells-express-fragments-of-genes-71056 (Accessed: 22 June 2024).
  • 7 Wei, W., Hennig, B., Wang, J., Zhang, Y., Piazza,I. et al. (2019) Chromatin-sensitive cryptic promoters putatively drive expression of alternative protein isoforms in yeast, Genome research. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886497/.
  • 8 Sen, P., Donahue, G., Li, C., Eggervari, G., Yang, N., Lan, Y., Robertson, N., Shah, P.p., Kerkoven, E., Schultz, D.C., et al. (2023). Spurious intragenic transcription is a feature of mammalian cellular senescence and tissue aging. Nat Aging 3, 402-417. 10.1038/s43587-023-00384-

Melanoma In Swordtail fish

Powel et al. look at the genetic factors that lead to melanoma, a skin cancer in swordtail fish caused by incompatible alleles. It focuses on species of Xiphophorus (swordtail fish) that naturally hybridize within their own population, not represented by the parent population. The study shows that the hybrids have conflicting genetic traits (alleles) linked to an increased risk of developing melanoma and exhibit unique pigmentation patterns. The researchers had a goal of studying how these species breed and face reproductive barriers to gain insight on the individual genes that are responsible for the distance in the related species.
The research was completed using controlled breeding experiments and genomic analyses. The study found that the hybrids had incompatible alleles from both parent species. This causes disruptions in the cellular process related to the development of pigment cells, leading to the uncontrolled and dangerous overgrowth of pigment cells, a characteristic of melanoma. Degradation of the fin was found to play a role in lack of survival for the hybrids. The researchers used the Dobzhansky-Muller model as a comparing framework on why distant related species created hybrids with low viability. However, experimental work to support the model is slim.
Due to divergence of related model species, data to back the model has become unclear. Most of the mapped incompatibilities are now species that no longer hybridize. Powell et al. look at breeding of Xiphophorus birchmanni and Xiophophorus malinche. These two species naturally hybridize and have a subset of viable and fertile offspring. However, results found that in some populations, males were developing melanoma before sexual maturity, interfering with continuing the lineage.
Moreover, further research found the phenotype of a dark blotch on the caudal fin is derived from X. birchmanni. This spot is called spotted caudal and allowed Powell et al. to further genetic mapping from the macromelaocyte cells that made up the spotted caudal. Hybrid populations of X. birchmanni exhibited spotting at different and growing phenotypes than the stable phenotype of the parent. Observation in the lab showed the spots growing over a 6-month period in hybrids, which were linked to the overgrowth of the macromelaocyte.
The results highlight the necessity of understanding genetic compatibility and the effects of hybridization in marine biology, as the parent species X. birchmanni has never been recorded to have melanoma. Researchers noted ultraviolet radiation and natural carcinogens cannot be key contributors to the dramatic difference in melanoma rates between the parent and hybrid species.

    In conclusion, the study serves as a compelling example of how natural hybridization can unveil intricate genetic interactions that contribute to disease, reinforcing the importance of genetic diversity in comprehending health of related species breeding and divergence. The authors advocate for continued research to investigate the byproduct of their findings for conservation strategies and the management of hybrid populations. 

Reference
Daniel L. Powell et al., Natural hybridization reveals incompatible alleles that cause melanoma in swordtail fish. Science 368, 731-736. 10.1126/science.aba5216 (2020).

Primary and Review Articles

Primary articles are reports of scientific findings that are original to the knowledgeable publishers. These articles aim to advance fields in science and focus on new data and analysis. The content shares direct scientific knowledge on new discoveries, including an explanation of the procedure and results. The concept is that the discoveries can be replicated by other experts via following the procedures outlined in the primary article. Normally, the discoveries are credited through evaluation by other related experts, identified as peer-reviewed.

Review articles summarize existing scientific literature on specific topics. Their main goal is to bring together published research and provide an overview of a scientific subject. While they might not cover every detail, these articles are helpful learning tools that give useful insights into the current knowledge in the field.

When a researcher intends to submit their work to a scholarly journal, they must follow a process known as peer review. The researcher prepares a paper outlining their procedures and results, while keeping the target publication in mind. After submission, the journal editor evaluates whether the research aligns with the publication’s focus. If deemed suitable, the research paper is then sent to experts in the relevant field for further review. The experts evaluate the research by posing a series of questions aimed at assessing its originality, significance, logic, and methodology. This step is where the term ‘peer’ in ‘peer review’ is founded, as reviewers are expert peers in same field as the submitting researcher.  Next, if the research receives approval from the experts, it is

then returned to the editor, typically with recommendations for revisions. This process is very selective and once research is back to the editor it is still unlikely to be officially approved. After months or even years, if the editor approves the research following revisions, it will be published and officially designated as peer-reviewed.

From the provided articles, the primary article is, “Base editing of hematopoietic stem cells rescues sickle cell disease in mice,” as it details a specific procedure from a first-person perspective, presenting the results, data, and participants. The review article is “Hematopoietic Stem Cell Gene-Addition/Editing Therapy in Sickle Cell Disease” as it discusses multiple advancements in treating sickle cell disease, including citations to credit the information, and it does not provide detailed descriptions for conduction of procedures.

Personal Statement

After receiving an associates of science degree while playing volleyball, my not-too-distant plans were to become an X-ray associate to an MRI technician. I have spent the past 3 years working in a hospital and an outpatient diagnostic imaging facility to prepare for my future, though two years in, realization set in. While waiting to hear about my application status for a radiography program, the reality was, I was not excited about the possibility of being accepted. I reflected on the environment I had experienced and the growth I had obtained working with technicians of all imaging modalities with great fondness and gratitude, but I was missing the signs where my personality and intentions really stood. 

I found myself in a place of raw honesty after not getting accepted by just one rank. While I loved patient care and aimed to be a positive moment in rough times, life slammed me into a place of close reliability to those I aided. I could continue to become an X-ray Technician, even though my heart now empathized and hurt a different way with each case, or I could take time to reevaluate.

Not too long after, the signs that were always there made themselves clear. Part of my personal foundation had always been with aquatic life and the ocean. I grew up raising a variety of fish, from indoor tanks to outdoor ponds, which led to my first marine biology class and educated-interest in marine animals. At the beginning of my teen years, I saved to buy my own saltwater tank. Caring for and learning about the world of marine life, from fish to corals, turned into a seven-year hobby. Not only did I have a history of caring for marine life, I have always had an at-home-feeling of being in the ocean and observing what sea life is in the surroundings. With this realization, I knew I had to look into what a career involving this passion would include.