Chapter 14: Gene Regulation and Human Disease

The central role of gene control processes in normal cellular function which has been discussed throughout this book makes it inevitable that abnormalities in such processes will result in disease. In addition to the abnormalities that occur in cancer (see Chapter 13), it has been demonstrated that many human genetic diseases involve the inheritance of mutated genes encoding proteins that regulate gene expression. A number of different diseases have been shown to involve mutations in proteins involved in each of the three fundamental processes that regulate gene expression (see Chapters 4–9), namely the processes of transcription itself, the regulation of chromatin structure which is necessary for transcription to occur, and post-transcriptional processes. These cases will be discussed in Sections 14.1–14.3 of this chapter, respectively. Section 14.4 will describe the manner in which abnormalities in regulatory RNAs are involved in human genetic diseases and Section 14.5 will describe alterations in gene regulatory processes that can occur in human infectious disease. Finally, it is clear that the insights obtained by studies on gene regulation in cancer and other human diseases may lead to the development of effective therapies for manipulating gene expression in these diseases and this is discussed in Section 14.6.

Multiple-choice questions

Questions for Discussion

Trinucleotide repeat expansions (TNREs) are linked to a variety of inherited human diseases. Describe a specific type of TNREs that encode codons for long stretch of an amino acid in its coding sequence. Do you think this TNRE sequence will prevent the RNA polymerase from transcribing it? Also, If an individual has a mild form of a TNRE disorder, what factors should this person consider for future offspring?
Several research studies are underway that involve the use of gene therapies for several diseases. Discuss the advantages and disadvantages of gene therapies and the potential implications on evolution that scientists and society should consider before the approval of gene therapies.
Discuss the paradoxical role of the innate immune system, such as interferon signaling, in antiviral, antitumor, and procancer functions.
Discuss the role of epigenetic processes in neuroinflammation and its effect on neuronal regeneration.
Discuss the role of non-coding RNA in chronic disease such as multiple sclerosis, Alzhiemers, and diabetes.

Lee T.I. & Young R.A. (2013) Transcriptional regulation and its misregulation in disease. Cell 152:1237–1251.
Zaugg, J. B., Sahlén, P., Andersson, R., Alberich-Jorda, M., de Laat, W., Deplancke, B., Ferrer, J., Mandrup, S., Natoli, G., Plewczynski, D., Rada-Iglesias, A., & Spicuglia, S. (2022). Current challenges in understanding the role of enhancers in disease. Nature Structural & Molecular Biology, 29(12), 1148–1158. https://doi.org/10.1038/s41594-022-00896-3

14.2 The epigenome and human disease

Aguilera, P., & López-Contreras, A. J. (2023). ATRX, a guardian of chromatin. Trends in Genetics: TIG, 39(6), 505–519. https://doi.org/10.1016/j.tig.2023.02.009

Baccarelli, A., Dolinoy, D. C., & Walker, C. L. (2023). A precision environmental health approach to prevention of human disease. Nature Communications, 14(1), 2449. https://doi.org/10.1038/s41467-023-37626-2

Dyer, M. A., Qadeer, Z. A., Valle-Garcia, D., & Bernstein, E. (2017). ATRX and DAXX: Mechanisms and Mutations. Cold Spring Harbor Perspectives in Medicine, 7(3), a026567. https://doi.org/10.1101/cshperspect.a026567

Han, V. X., Patel, S., Jones, H. F., & Dale, R. C. (2021). Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. Nature Reviews. Neurology, 17(9), 564–579. https://doi.org/10.1038/s41582-021-00530-8

Oh, E. S., & Petronis, A. (2021). Origins of human disease: The chrono-epigenetic perspective. Nature Reviews. Genetics, 22(8), 533–546. https://doi.org/10.1038/s41576-021-00348-6

Richter, W. F., Nayak, S., Iwasa, J., & Taatjes, D. J. (2022). The Mediator complex as a master regulator of transcription by RNA polymerase II. Nature Reviews Molecular Cell Biology, 23(11), 732–749. https://doi.org/10.1038/s41580-022-00498-3

Schiano, C., Luongo, L., Maione, S., & Napoli, C. (2023). Mediator complex in neurological disease. Life Sciences, 329, 121986. https://doi.org/10.1016/j.lfs.2023.121986

Wu, H., Eckhardt, C. M., & Baccarelli, A. A. (2023). Molecular mechanisms of environmental exposures and human disease. Nature Reviews. Genetics, 24(5), 332–344. https://doi.org/10.1038/s41576-022-00569-3

14.3 Post-transcriptional processes and human disease

Gy, L., & Dm, S. (2020). mTOR at the nexus of nutrition, growth, ageing and disease. Nature Reviews. Molecular Cell Biology, 21(4). https://doi.org/10.1038/s41580-019-0199-y

Hachiya, N., Sochocka, M., Brzecka, A., Shimizu, T., Gąsiorowski, K., Szczechowiak, K., & Leszek, J. (2021). Nuclear Envelope and Nuclear Pore Complexes in Neurodegenerative Diseases—New Perspectives for Therapeutic Interventions. Molecular Neurobiology, 58(3), 983–995. https://doi.org/10.1007/s12035-020-02168-x

Jishi, A., Qi, X., & Miranda, H. C. (2021). Implications of mRNA translation dysregulation for neurological disorders. Seminars in Cell & Developmental Biology, 114, 11–19. https://doi.org/10.1016/j.semcdb.2020.09.005

López-Martínez, A., Soblechero-Martín, P., de-la-Puente-Ovejero, L., Nogales-Gadea, G., & Arechavala-Gomeza, V. (2020). An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I. Genes, 11(9), 1109. https://doi.org/10.3390/genes11091109

Moss, T., LeDoux, M. S., & Crane-Robinson, C. (2023). HMG-boxes, ribosomopathies and neurodegenerative disease. Frontiers in Genetics, 14, 1225832. https://doi.org/10.3389/fgene.2023.1225832

Nishimura, K., Yamazaki, H., Zang, W., & Inoue, D. (2022). Dysregulated minor intron splicing in cancer. Cancer Science, 113(9), 2934–2942. https://doi.org/10.1111/cas.15476

Richter, J. D., & Zhao, X. (2021). The molecular biology of FMRP: New insights into fragile X syndrome. Nature Reviews. Neuroscience, 22(4), 209–222. https://doi.org/10.1038/s41583-021-00432-0

Yang, Y., Guo, L., Chen, L., Gong, B., Jia, D., & Sun, Q. (2023). Nuclear transport proteins: Structure, function, and disease relevance. Signal Transduction and Targeted Therapy, 8(1), 1–29. https://doi.org/10.1038/s41392-023-01649-4

14.4 Regulatory RNAs and human disease

Ariyanfar, S., & Good, D. J. (2022). Analysis of SNHG14: A Long Non-Coding RNA Hosting SNORD116, Whose Loss Contributes to Prader-Willi Syndrome Etiology. Genes, 14(1), 97. https://doi.org/10.3390/genes14010097

DiStefano, J. K., & Gerhard, G. S. (2022). Long Noncoding RNAs and Human Liver Disease. Annual Review of Pathology, 17, 1–21. https://doi.org/10.1146/annurev-pathol-042320-115255

MacDonald, W. A., & Mann, M. R. W. (2020). Long noncoding RNA functionality in imprinted domain regulation. PLOS Genetics, 16(8), e1008930. https://doi.org/10.1371/journal.pgen.1008930

Mangiavacchi, A., Morelli, G., & Orlando, V. (2023). Behind the scenes: How RNA orchestrates the epigenetic regulation of gene expression. Frontiers in Cell and Developmental Biology, 11. https://doi.org/10.3389/fcell.2023.1123975

Nowak, A., Wicik, Z., Wolska, M., Shahzadi, A., Szwed, P., Jarosz-Popek, J., Palatini, J., Postula, M., Czlonkowska, A., Mirowska-Guzel, D., & Eyileten, C. (2022). The role of non-coding RNAs in neuroinflammatory process in multiple sclerosis. Molecular Neurobiology, 59(8), 4651–4668. https://doi.org/10.1007/s12035-022-02854-y

Ramírez, A. E., Gil-Jaramillo, N., Tapias, M. A., González-Giraldo, Y., Pinzón, A., Puentes-Rozo, P. J., Aristizábal-Pachón, A. F., & González, J. (2022). MicroRNA: A Linking between Astrocyte Dysfunction, Mild Cognitive Impairment, and Neurodegenerative Diseases. Life (Basel, Switzerland), 12(9), 1439. https://doi.org/10.3390/life12091439 14.5

14.5 Infectious diseases and cellular gene expression

Beyond Good and Evil: Molecular Mechanisms of Type I and III IFN Functions | The Journal of Immunology | American Association of Immunologists. (n.d.). Retrieved April 8, 2024, from https://journals.aai.org/jimmunol/article/208/2/247/234825

Krischuns, T., Lukarska, M., Naffakh, N., & Cusack, S. (2021). Influenza Virus RNA-Dependent RNA Polymerase and the Host Transcriptional Apparatus. Annual Review of Biochemistry, 90, 321–348. https://doi.org/10.1146/annurev-biochem-072820-100645

Liang, Y., & Wang, L. (2021). Inflamma-MicroRNAs in Alzheimer’s Disease: From Disease Pathogenesis to Therapeutic Potentials. Frontiers in Cellular Neuroscience, 15, 785433. https://doi.org/10.3389/fncel.2021.785433

Mazewski, C., Perez, R. E., Fish, E. N., & Platanias, L. C. (2020). Type I Interferon (IFN)-Regulated Activation of Canonical and Non-Canonical Signaling Pathways. Frontiers in Immunology, 11. https://doi.org/10.3389/fimmu.2020.606456

Shehata, S. I., Watkins, J. M., Burke, J. M., & Parker, R. (2024). Mechanisms and consequences of mRNA destabilization during viral infections. Virology Journal, 21(1), 38. https://doi.org/10.1186/s12985-024-02305-1

14.6 Gene regulation and therapy of human disease

El Marabti, E., & Abdel-Wahab, O. (2021). Therapeutic Modulation of RNA Splicing in Malignant and Non-Malignant Disease. Trends in Molecular Medicine, 27(7), 643–659. https://doi.org/10.1016/j.molmed.2021.04.005

Frontiers | Regulatory Effects of Histone Deacetylase Inhibitors on Myeloid-Derived Suppressor Cells. (n.d.). Retrieved April 8, 2024, from https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.690207/full

Hartmann, D., Smith, J. M., Mazzotti, G., Chowdhry, R., & Booth, M. J. (2020). Controlling gene expression with light: A multidisciplinary endeavour. Biochemical Society Transactions, 48(4), 1645–1659. https://doi.org/10.1042/BST20200014

Le Blévec, E., Muroňová, J., Ray, P. F., & Arnoult, C. (2020). Paternal epigenetics: Mammalian sperm provide much more than DNA at fertilization. Molecular and Cellular Endocrinology, 518, 110964. https://doi.org/10.1016/j.mce.2020.110964

Łoboda, A., & Dulak, J. (2020). Muscle and cardiac therapeutic strategies for Duchenne muscular dystrophy: Past, present, and future. Pharmacological Reports, 72(5), 1227–1263. https://doi.org/10.1007/s43440-020-00134-x

Moia, R., Boggione, P., Mahmoud, A. M., Kodipad, A. A., Adhinaveni, R., Sagiraju, S., Patriarca, A., & Gaidano, G. (2020). Targeting p53 in chronic lymphocytic leukemia. Expert Opinion on Therapeutic Targets, 24(12), 1239–1250. https://doi.org/10.1080/14728222.2020.1832465

Park, J., Lee, K., Kim, K., & Yi, S.-J. (2022). The role of histone modifications: From neurodevelopment to neurodiseases. Signal Transduction and Targeted Therapy, 7(1), 1–23. https://doi.org/10.1038/s41392-022-01078-9

Pavan, A. R., Lopes, J. R., & Dos Santos, J. L. (2022). The state of the art of fetal hemoglobin-inducing agents. Expert Opinion on Drug Discovery, 17(11), 1279–1293. https://doi.org/10.1080/17460441.2022.2141708

Rogalska, M. E., Vivori, C., & Valcárcel, J. (2023). Regulation of pre-mRNA splicing: Roles in physiology and disease, and therapeutic prospects. Nature Reviews Genetics, 24(4), 251–269. https://doi.org/10.1038/s41576-022-00556-8

Shamshirgaran, Y., Liu, J., Sumer, H., Verma, P. J., & Taheri-Ghahfarokhi, A. (2022). Tools for Efficient Genome Editing; ZFN, TALEN, and CRISPR. Methods in Molecular Biology (Clifton, N.J.), 2495, 29–46. https://doi.org/10.1007/978-1-0716-2301-5_2

Wang, Z. A., & Cole, P. A. (2020). The Chemical Biology of Reversible Lysine Post-translational Modifications. Cell Chemical Biology, 27(8), 953–969. https://doi.org/10.1016/j.chembiol.2020.07.002

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Multiple-choice questions
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