Chromatin and Epigenetics
Every single cell in our body has 46 chromosomes that if attached together would make a very thin but about 2 m long string of DNA [1]. To be able to fit this DNA into the volume of a human cell nucleus that has average diameter of 10 mm the DNA must be organized in high-order nucleoprotein complex – chromatin [1]. In the chromatin the DNA is wrapped around nucleosomes that consists of two molecules of each core histones – H2A, H2B, H3, and H4. With the help of the fifth linker H1 histone they establish and maintain the chromatin structure and function [2]. The chromatin organization prevents enzymes and proteins like transcriptional factors, replication factors, and repair enzymes to access the DNA. To regulate the access to the DNA the cells are employing different mechanisms, including changes in the histone composition, histone post-translational modifications, nucleosome occupancy and positioning within chromatin and many others [3].
Search in the literature and find examples of specific epigenetic mechanism(s) involved in regulation of your favorite process – expression of particular gene in particular type of cells, regulation of DNA repair in particular context, maintain stemness in pluripotent cells, etc., the possible examples are enormous.
1. Even-Faitelson L, Hassan-Zadeh V, Baghestani Z, Bazett-Jones DP. Coming to terms with chromatin structure. Chromosoma. 2016;125(1):95-110. doi:10.1007/s00412-015-0534-9
2. Fyodorov DV, Zhou BR, Skoultchi AI, Bai Y. Emerging roles of linker histones in regulating chromatin structure and function. Nat Rev Mol Cell Biol. 2018;19(3):192-206. doi:10.1038/nrm.2017.94
3. Lai WKM, Pugh BF. Understanding nucleosome dynamics and their links to gene expression and DNA replication. Nat Rev Mol Cell Biol. 2017;18(9):548-562. doi:10.1038/nrm.2017.47
here’s response 1 from classmate please reply Sabrina Harris
RE: Chromatin and Epigenetics
Epigenetics is the term used to refer to heritable alterations not due to changes in DNA sequence. There are many epigenetic mechanisms that allow for the regulation of the level of accessibility of DNA to other cells in the body. I found the epigenetic mechanisms of the brain extremely interesting. Specific epigenetic mechanisms play a very important regulatory role in neural processes during brain development and the phenotype outcome. It has been proven that epigenetic changes to the genome promote a variety of processes that are important for the development of the brain as well as functionality of the brain. Stress related disordered have a direct relationship to epigenetic disorders. Epigenetic mechanisms play a role in the regulation of gene expression in a “tissue specific and age-dependent manner” (Shinozaki, 2014). In a recent study rats were used to determine that optimal maternal care impacted the expression of the glucocorticoid receptors gene in the hippocampus. Higher levels of expressivity lead to higher reactivity during periods of elevated cortisol levels. Epigenetic mechanisms, including DNA methylation and histone modification were shown to be directly related to the regulation of these genes, and changed in expression. In humans there has also been suggestive evidence supporting the idea that stress can induce epigenetic changes.
Citation
Gudsnuk, Kathryn, and Frances A Champagne. “Epigenetic influence of stress and the social environment.” ILAR journal vol. 53,3-4 (2012): 279-88. doi:10.1093/ilar.53.3-4.279.
Blaze J, Roth TL. Evidence from clinical and animal model studies of the long-term and transgenerational impact of stress on DNA methylation. Semin Cell Dev Biol. 2015 Jul;43:76-84. doi: 10.1016/j.semcdb.2015.04.004. Epub 2015 Apr 23. PMID: 25917771; PMCID: PMC4618788
here’s response 2 think that the research that I am currently working on (the authors listed in the second article) is a great example of epigenetics and differential gene expression.
Autoimmune Inner Ear Disease (AIED), a disease that induces hearing loss, a corticosteroid (dexamethasone) is used to treat the hearing loss. However, only about half of those treated with dexamethasone respond to the drug, restoring some hearing loss. Of the half that respond to dexamethasone, the efficacy is lost over time. The research we are currently doing, asks the question “why do people not respond (or lose effectiveness) to dexamethasone?”
The doctors I am working with have found that IL-1B, a cytokine protein encoded for by the IL-1B gene, is elevated in those non-responders (Pathak). The IL-1B gene subsequently induces MMP-9 protein, so that gene has an uptick in expression as well. These proteins have also been linked to causing inflammation (Dinarello).
This concept connects to what we are currently learning about in class. We know that people who develop AIED, and especially those who don’t respond to dexamethasone treatment, must have the IL-1B and MMP-9 genes acetylated so that it is euchromatin. At this point, the DNA is not very tightly packed, so transcriptional activities to create IL-1B and MMP-9 proteins occur at a high rate. Subsequently, inflammation in the inner ear occurs.
As for people that don’t have AIED, the IL-1B and MMP-9 genes are likely methylated, so that they are not unwound and remain tightly packed with the histones. As a result, these genes are not expressed as greatly, and no inflammation occurs.
Citations
Dinarello, Charles A, Anna Simon, and Jos W M van der Meer. “Treating Inflammation by Blocking Interleukin-1 in a Broad Spectrum of Diseases.” Nature reviews. Drug discovery. U.S. National Library of Medicine, August 2012. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644509/.
Pathak, Shresh, Elliot Goldofsky, Esther X Vivas, Vincent R Bonagura, and Andrea Vambutas. “IL-1? Is Overexpressed and Aberrantly Regulated in Corticosteroid Nonresponders with Autoimmune Inner Ear Disease.” Journal of immunology (Baltimore, Md. : 1950). U.S. National Library of Medicine, February 1, 2011. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031454/.
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