Insights into the role of cis-regulatory elements of 5-HT2A gene in gene expression and regulation: an in silico approach

Authors

  • Kiran Kumar Halagur Bhogegowda Former Post-doc NCBS, Bangalore. Wilson Garden, Bangalore-560030, affiliated to Nrupathunga University, Bengaluru, Karnataka-560001, India
  • Sajeeda Niketh Department of Chemistry and Biochemistry, Government Science College (Nrupathunga University), Bengaluru-560001, Karnataka, India
  • Rama Thyloor Department of Biotechnology, Nrupathunga University, Bengaluru-560001, Karnataka, India
  • Rajeev Ramachandra Kolgi Department of Chemistry and Biochemistry, Government Science College (Nrupathunga University), Bengaluru-560001, Karnataka, India

DOI:

https://doi.org/10.25081/rib.2024.v15.9081

Keywords:

Non-canonical DNA/RNA, Cis-gene regulatory elements (CRE elements), Long non-coding RNA (lncRNA), H3K27ac, DNase I hypersensitive sites

Abstract

In multicellular organisms, coherent functioning of the central nervous system (CNS) and cellular diversity are driven by changes in high-fidelity gene expression. Crucial to these processes are cis-gene regulatory elements (CRE elements), which control transcription in response to chemical and physical stimuli. Variations in these components are a major contributor to several diseases in humans that result in particular phenotypic endpoints. The brain’s neuropsychological processes are dependent on G-protein-coupled receptor (GPCR) activation, and various neuropsychiatric disorders are linked to GPCR dysfunction. The 5-HT2A receptor plays a key role in many brain activities due to its neurobiological and signaling characteristics. The distinct topography of the 5HT2A gene locus is outlined in this work, including the functions of CRE and regulatory elements. Further, the role of CRE elements in imprinting and methylation signatures’ was investigated. Our findings indicate that the non-coding antisense RNA transcript (HTR2A-AS1) present in the locus may control the expression levels of the HTR2A transcript. This region’s combinatorial DNA sequences include promoters, enhancers, silencers, and CTCF all of which may play a crucial role in the regulation of gene expression. Moreover, imprinting and epigenetic inheritance may be made possible by the distinct tapestry of chromatin architecture components, including H3K27ac, DNase I hypersensitivity, and CTCF binding regions found in the region. It is also possible that the non-canonical DNA structures and repetitive elements in the promoter region contribute to these functions and genomic stability. Together, the flanking regulatory elements and the gene-specific CRE contribute to the expression of the gene. They might function as plausible indicators for human illnesses.

Downloads

Download data is not yet available.

References

Abdolmaleky, H. M., & Thiagalingam, S. (2011). Can the schizophrenia epigenome provide clues for the molecular basis of pathogenesis?. Epigenomics, 3(6), 679-683. https://doi.org/10.2217/epi.11.94

Abdolmaleky, H. M., Yaqubi, S., Papageorgis, P., Lambert, A. W., Ozturk, S., Sivaraman, V., & Thiagalingam, S. (2011). Epigenetic dysregulation of HTR2A in the brain of patients with schizophrenia and bipolar disorder. Schizophrenia Research, 129(2-3), 183-190. https://doi.org/10.1016/j.schres.2011.04.007

Agrawal, P., & Rao, S. (2021). Super-Enhancers and CTCF in Early Embryonic Cell Fate Decisions. Frontiers in Cell and Developmental Biology, 9, 653669. https://doi.org/10.3389/fcell.2021.653669

Allen, E. K., Randolph, A. G., Bhangale, T., Dogra, P., Ohlson, M., Oshansky, C. M., Zamora, A. E., Shannon, J. P., Finkelstein, D., Dressen, A., DeVincenzo, J., Caniza, M., Youngblood, B., Rosenberger, C. M., & Thomas, P. G. (2017). SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans. Nature Medicine, 23, 975-983. https://doi.org/10.1038/nm.4370

Annamneedi, A., Gora, C., Dudas, A., Leray, X., Bozon, V., Crépieux, P., & Pellissier, L. P. (2023). Towards the convergent therapeutic potential of G protein-coupled receptors in autism spectrum disorders. British Journal of Pharmacology, 1-24. https://doi.org/10.1111/bph.16216

Antequera, F. (2003). Structure, function and evolution of CpG island promoters. Cellular and Molecular Life Sciences CMLS, 601647-1658. https://doi.org/10.1007/s00018-003-3088-6

Azam, S., Haque, M. E., Jakaria, M., Jo, S.-H., Kim, I.-S., & Choi, D.-K. (2020). G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits. Cells, 9(2), 506. https://doi.org/10.3390/cells9020506

Badcock, C., & Crespi, B. (2006). Imbalanced genomic imprinting in brain development: an evolutionary basis for the aetiology of autism. Journal of Evolutionary Biology, 19(4), 1007-1032. https://doi.org/10.1111/j.1420-9101.2006.01091.x

Bansal, M., Kumar, A., & Yella, V. R. (2014). Role of DNA sequence based structural features of promoters in transcription initiation and gene expression. Current Opinion in Structural Biology, 25, 77-85. https://doi.org/10.1016/j.sbi.2014.01.007

Beacon, T. H., Delcuve, G. P., López, C., Nardocci, G., Kovalchuk, I., van Wijnen, A. J., & Davie, J. R. (2021). The dynamic broad epigenetic (H3K4me3, H3K27ac) domain as a mark of essential genes. Clinical Epigenetics, 13, 138. https://doi.org/10.1186/s13148-021-01126-1

Beck, C. R., Garcia-Perez, J. L., Badge, R. M., & Moran, J. V. (2011). LINE-1 elements in structural variation and disease. Annual Review of Genomics and Human Genetics, 12, 187-215. https://doi.org/10.1146/annurev-genom-082509-141802

Bergman, Y., & Cedar, H. (2013). DNA methylation dynamics in health and disease. Nature Structural & Molecular Biology, 20, 274-281. https://doi.org/10.1038/nsmb.2518

Bevilacqua, P. C., Ritchey, L. E., Su, Z., & Assmann, S. M. (2016). Genome-Wide Analysis of RNA Secondary Structure. Annual Review of Genetics, 50, 235-266. https://doi.org/10.1146/annurev-genet-120215-035034

Bird, A. (2002). DNA methylation patterns and epigenetic memory. Genes & Development, 16(1), 6-21. https://doi.org/10.1101/gad.947102

Blaudin de Thé, F. X., Rekaik, H., Peze-Heidsieck, E., Massiani-Beaudoin, O., Joshi, R. L., Fuchs, J., & Prochiantz, A. (2018). Engrailed homeoprotein blocks degeneration in adult dopaminergic neurons through LINE-1 repression. The EMBO Journal, 37(15), e97374. https://doi.org/10.15252/embj.201797374

Boulougouris, V., & Robbins, T. W. (2010). Enhancement of spatial reversal learning by 5-HT2C receptor antagonism is neuroanatomically specific. The Journal of Neuroscience, 30(3), 930-938. https://doi.org/10.1523/JNEUROSCI.4312-09.2010

Bowater, R. P., & Brázda, V. (2022). Impacts of Molecular Structure on Nucleic Acid-Protein Interactions. International Journal of Molecular Sciences, 24(1), 407. https://doi.org/10.3390/ijms24010407

Brandler, W. M., Antaki, D., Gujral, M., Kleiber, M. L., Whitney, J., Maile, M. S., Hong, O., Chapman, T. R., Tan, S., Tandon, P., Pang, T., Tang, S. C., Vaux, K. K., Yang, Y., Harrington, E., Juul, S., Turner, D. J., Thiruvahindrapuram, B., Kaur, G., … Sebat, J. (2018). Paternally inherited cis-regulatory structural variants are associated with autism. Science, 360(6386), 327-331. https://doi.org/10.1126/science.aan2261

Bray, N. J., Buckland, P. R., Owen, M. J., & O'Donovan, M. C. (2003). Cis-acting variation in the expression of a high proportion of genes in human brain. Human Genetics, 113, 149-153. https://doi.org/10.1007/s00439-003-0956-y

Brucato, N., DeLisi, L. E., Fisher, S. E., & Francks, C. (2014). Hypomethylation of the paternally inherited LRRTM1 promoter linked to schizophrenia. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 165(7), 555-563. https://doi.org/10.1002/ajmg.b.32258

Buckland, P. R., D'Souza, U., Maher, N. A., & McGuffin, P. (1997). The effects of antipsychotic drugs on the mRNA levels of serotonin 5HT2A and 5HT2C receptors. Brain research. Molecular Brain Research, 48(1), 45-52. https://doi.org/10.1016/s0169-328x(97)00076-4

Bunzel, R., Blümcke, I., Cichon, S., Normann, S., Schramm, J., Propping, P., & Nöthen, M. M. (1998). Polymorphic imprinting of the serotonin-2A (5-HT2A) receptor gene in human adult brain. Molecular Brain Research, 59(1), 90-92. https://doi.org/10.1016/s0169-328x(98)00146-6

Bylino, O. V., Ibragimov, A. N., & Shidlovskii, Y. V. (2020). Evolution of Regulated Transcription. Cells, 9(7), 1675. https://doi.org/10.3390/cells9071675

Carullo, N. V. N., & Day, J. J. (2019). Genomic Enhancers in Brain Health and Disease. Genes, 10(1), 43. https://doi.org/10.3390/genes10010043

Chatterjee, S., & Ahituv, N. (2017). Gene Regulatory Elements, Major Drivers of Human Disease. Annual Review of Genomics and Human Genetics, 18, 45-63. https://doi.org/10.1146/annurev-genom-091416-035537

Chen, X.-F., Zhu, D.-L., Yang, M., Hu, W.-X., Duan, Y.-Y., Lu, B.-J., Rong, Y., Dong, S.-S., Hao, R.-H., Chen, J.-B., Chen, Y.-X., Yao, S., Thynn, H. N., Guo, Y., & Yang, T.-L. (2018). An Osteoporosis Risk SNP at 1p36.12 Acts as an Allele-Specific Enhancer to Modulate LINC00339 Expression via Long-Range Loop Formation. American Journal of Human Genetics, 102(5), 776-793. https://doi.org/10.1016/j.ajhg.2018.03.001

Cordaux, R., & Batzer, M. A. (2009). The impact of retrotransposons on human genome evolution. Nature Reviews Genetics, 10(10), 691-703. https://doi.org/10.1038/nrg2640

Cuddapah, S., Jothi, R., Schones, D. E., Roh, T. Y., Cui, K., & Zhao, K. (2009). Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. Genome Research, 19(1), 24-32. https://doi.org/10.1101/gr.082800.108

Das, R., Anderson, N., Koran, M. I., Weidman, J. R., Mikkelsen, T. S., Kamal, M., Murphy, S. K., Linblad-Toh, K., Greally, J. M., & Jirtle, R. L. (2012). Convergent and divergent evolution of genomic imprinting in the marsupial Monodelphis domestica. BMC Genomics, 13, 394. https://doi.org/10.1186/1471-2164-13-394

De Luca, V., Viggiano, E., Dhoot, R., Kennedy, J. L., & Wong, A. H. (2009). Methylation and QTDT analysis of the 5-HT2A receptor 102C allele: analysis of suicidality in major psychosis. Journal of Psychiatric Research, 43(5), 532-537. https://doi.org/10.1016/j.jpsychires.2008.07.007

de Vos, C. M. H., Mason, N. L., & Kuypers, K. P. C. (2021). Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. Frontiers in Psychiatry, 12, 724606. https://doi.org/10.3389/fpsyt.2021.724606

Debaugny, R. E., & Skok, J. A. (2020). CTCF and CTCFL in cancer. Current Opinion in Genetics & Development, 61, 44-52. https://doi.org/10.1016/j.gde.2020.02.021

Dehingia, B., Milewska, M., Janowski, M., & Pękowska, A. (2022). CTCF shapes chromatin structure and gene expression in health and disease. EMBO Reports, 23(9), e55146. https://doi.org/10.15252/embr.202255146

Dorsam, R. T., & Gutkind, J. S. (2007). G-protein-coupled receptors and cancer. Nature Reviews Cancer, 7(2), 79-94. https://doi.org/10.1038/nrc2069

Douglas, A. T., & Hill, R. D. (2014). Variation in vertebrate cis-regulatory elements in evolution and disease. Transcription, 5(3), e28848. https://doi.org/10.4161/trns.28848

Duardo, R. C., Guerra, F., Pepe, S., & Capranico, G. (2023). Non-B DNA structures as a booster of genome instability. Biochimie, 214(Part A), 176-192. https://doi.org/10.1016/j.biochi.2023.07.002

Falkenberg, V. R., Gurbaxani, B. M., Unger, E. R., & Rajeevan, M. S. (2011). Functional genomics of serotonin receptor 2A (HTR2A): interaction of polymorphism, methylation, expression and disease association. Neuromolecular Medicine, 13, 66-76. https://doi.org/10.1007/s12017-010-8138-2

Ferry, R. C., & Molinoff, P. B. (1996). Regulation of 5-HT2A receptor mRNA in P11 cells. Behavioural Brain Research, 73(1-2), 187-191. https://doi.org/10.1016/0166-4328(96)00094-0

Fukuda, Y., Koga, M., Arai, M., Noguchi, E., Ohtsuki, T., Horiuchi, Y., Ishiguro, H., Niizato, K., Iritani, S., Itokawa, M., & Arinami, T. (2006). Monoallelic and unequal allelic expression of the HTR2A gene in human brain and peripheral lymphocytes. Biological Psychiatry, 60(12), 1331-1335. https://doi.org/10.1016/j.biopsych.2006.06.024

Fullard, J. F., Halene, T. B., Giambartolomei, C., Haroutunian, V., Akbarian, S., & Roussos, P. (2016). Understanding the genetic liability to schizophrenia through the neuroepigenome. Schizophrenia Research, 177(1-3), 115-124. https://doi.org/10.1016/j.schres.2016.01.039

Gelber, E. I., Kroeze, W. K., Willins, D. L., Gray, J. A., Sinar, C. A., Hyde, E. G., Gurevich, V., Benovic, J., & Roth, B. L. (1999). Structure and function of the third intracellular loop of the 5-hydroxytryptamine2A receptor: the third intracellular loop is alpha-helical and binds purified arrestins. Journal of Neurochemistry, 72(5), 2206-2214. https://doi.org/10.1046/j.1471-4159.1999.0722206.x

Ghadirivasfi, M., Nohesara, S., Ahmadkhaniha, H. R., Eskandari, M. R., Mostafavi, S., Thiagalingam, S., & Abdolmaleky, H. M. (2011). Hypomethylation of the serotonin receptor type-2A Gene (HTR2A) at T102C polymorphic site in DNA derived from the saliva of patients with schizophrenia and bipolar disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 156(5), 536-545. https://doi.org/10.1002/ajmg.b.31192

Gibbons, M. D., Fang, Y., Spicola, A. P., Linzer, N., Jones, S. M., Johnson, B. R., Li, L., Xie, M., & Bungert, J. (2022). Enhancer-Mediated Formation of Nuclear Transcription Initiation Domains. International Journal of Molecular Sciences, 23(16), 9290. https://doi.org/10.3390/ijms23169290

Hennessey, R. C., & Brown, K. M. (2021). Cancer regulatory variation. Current Opinion in Genetics & Development, 66, 41-49. https://doi.org/10.1016/j.gde.2020.11.010

Horner, K. A., Gilbert, Y. E., & Noble, E. S. (2011). Differential regulation of 5-HT2A receptor mRNA expression following withdrawal from a chronic escalating dose regimen of D-amphetamine. Brain Research, 1390, 10-20. https://doi.org/10.1016/j.brainres.2011.03.033

Huang, Y., Todd, N., & Thathiah, A. (2017). The role of GPCRs in neurodegenerative diseases: avenues for therapeutic intervention. Current Opinion in Pharmacology, 32, 96-110. https://doi.org/10.1016/j.coph.2017.02.001

Inserra, A., De Gregorio, D., & Gobbi, G. (2021). Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms. Pharmacological Reviews, 73(1), 202-277. https://doi.org/10.1124/pharmrev.120.000056

Javierre, B. M., Burren, O. S., Wilder, S. P., Kreuzhuber, R., Hill, S. M., Sewitz, S., Cairns, J., Wingett, S. W., Várnai, C., Thiecke, M. J., Burden, F., Farrow, S., Cutler, A. J., Rehnström, K., Downes, K., Grassi, L., Kostadima, M., Freire-Pritchett, P., Wang, F., … Fraser, P. (2016). Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters. Cell, 167(5), 1369-1384.e19. https://doi.org/10.1016/j.cell.2016.09.037

Kaidery, N. A., Tarannum, S., & Thomas, B. (2013). Epigenetic landscape of Parkinson's disease: emerging role in disease mechanisms and therapeutic modalities. Neurotherapeutics, 10(4), 698-708. https://doi.org/10.1007/s13311-013-0211-8

Kato, M. V., Shimizu, T., Nagayoshi, M., Kaneko, A., Sasaki, M. S., & Ikawa, Y. (1996). Genomic imprinting of the human serotonin-receptor (HTR2) gene involved in development of retinoblastoma. American Journal of Human Genetics, 59(5), 1084-1090.

Kazazian, H. H., Jr, & Moran, J. V. (2017). Mobile DNA in Health and Disease. The New England Journal of Medicine, 377(4), 361-370. https://doi.org/10.1056/NEJMra1510092

Khetan, S., Kursawe, R., Youn, A., Lawlor, N., Jillette, A., Marquez, E. J., Ucar, D., & Stitzel, M. L. (2018). Type 2 Diabetes-Associated Genetic Variants Regulate Chromatin Accessibility in Human Islets. Diabetes, 67(11), 2466–2477. https://doi.org/10.2337/db18-0393

Kovtun, I. V., & McMurray, C. T. (2008). Features of trinucleotide repeat instability in vivo. Cell Research, 18(1), 198-213. https://doi.org/10.1038/cr.2008.5

Kroeze, W. K., & Roth, B. L. (1998). The molecular biology of serotonin receptors: therapeutic implications for the interface of mood and psychosis. Biological Psychiatry, 44(11), 1128-1142. https://doi.org/10.1016/s0006-3223(98)00132-2

Land, M. A., Ramesh, D., Miller, A. L., Pyles, R. B., Cunningham, K. A., Moeller, F. G., & Anastasio, N. C. (2020). Methylation Patterns of the HTR2A Associate With Relapse-Related Behaviors in Cocaine-Dependent Participants. Frontiers in Psychiatry, 11, 532. https://doi.org/10.3389/fpsyt.2020.00532

Lesseur, C., Paquette, A. G., & Marsit, C. J. (2014). Epigenetic Regulation of Infant Neurobehavioral Outcomes. Medical Epigenetics, 2(2), 71-79. https://doi.org/10.1159/000361026

Liao, X., Zhu, W., Zhou, J., Li, H., Xu, X., Zhang, B., & Gao, X. (2023). Repetitive DNA sequence detection and its role in the human genome. Communications Biology, 6, 954. https://doi.org/10.1038/s42003-023-05322-y

Lieberman-Aiden, E., van Berkum, N. L., Williams, L., Imakaev, M., Ragoczy, T., Telling, A., Amit, I., Lajoie, B. R., Sabo, P. J., Dorschner, M. O., Sandstrom, R., Bernstein, B., Bender, M. A., Groudine, M., Gnirke, A., Stamatoyannopoulos, J., Mirny, L. A., Lander, E. S., & Dekker, J. (2009). Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science, 326(5950), 289-293. https://doi.org/10.1126/science.1181369

Lobanenkov, V. V., & Zentner, G. E. (2018). Discovering a binary CTCF code with a little help from BORIS. Nucleus, 9(1), 33-41. https://doi.org/10.1080/19491034.2017.1394536

Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., Burbach, K. F., Zarandi, S. S., Sood, A., Paddy, M. R., Duim, W. C., Dennis, M. Y., McAllister, A. K., Ori-McKenney, K. M., Gray, J. A., & Olson, D. E. (2018). Psychedelics Promote Structural and Functional Neural Plasticity. Cell Reports, 23(11), 3170-3182. https://doi.org/10.1016/j.celrep.2018.05.022

Meltzer, H. Y. (1999). The role of serotonin in antipsychotic drug action. Neuropsychopharmacology, 21(Suppl 1), 106-115. https://doi.org/10.1016/S0893-133X(99)00046-9

Mengod, G., Palacios, J. M., & Cortés, R. (2015). Cartography of 5-HT1A and 5-HT2A Receptor Subtypes in Prefrontal Cortex and Its Projections. ACS Chemical Neuroscience, 6(7), 1089-1098. https://doi.org/10.1021/acschemneuro.5b00023

Metzler, R., & Ambjörnsson, T. (2005). Dynamic approach to DNA breathing. Journal of Biological Physics, 31, 339-350. https://doi.org/10.1007/s10867-005-2410-y

Monk, D., Mackay, D. J. G., Eggermann, T., Maher, E. R., & Riccio, A. (2019). Genomic imprinting disorders: lessons on how genome, epigenome and environment interact. Nature Reviews Genetics, 20, 235-248. https://doi.org/10.1038/s41576-018-0092-0

Nakao, K., Singh, M., Sapkota, K., Fitzgerald, A., Hablitz, J. J., & Nakazawa, K. (2022). 5-HT2A receptor dysregulation in a schizophrenia relevant mouse model of NMDA receptor hypofunction. Translational Psychiatry, 12(1), 168. https://doi.org/10.1038/s41398-022-01930-0

Nestler, E. J., & Lüscher, C. (2019). The Molecular Basis of Drug Addiction: Linking Epigenetic to Synaptic and Circuit Mechanisms. Neuron, 102(1), 48-59. https://doi.org/10.1016/j.neuron.2019.01.016

Nguyen, T. A., Jones, R. D., Snavely, A. R., Pfenning, A. R., Kirchner, R., Hemberg, M., & Gray, J. M. (2016). High-throughput functional comparison of promoter and enhancer activities. Genome Research, 26(8), 1023-1033. https://doi.org/10.1101/gr.204834.116

Nichols, D. E., Johnson, M. W., & Nichols, C. D. (2017). Psychedelics as Medicines: An Emerging New Paradigm. Clinical Pharmacology and Therapeutics, 101(2), 209-219. https://doi.org/10.1002/cpt.557

Ogata, T., & Kagami, M. (2016). Kagami-Ogata syndrome: a clinically recognizable upd(14)pat and related disorder affecting the chromosome 14q32.2 imprinted region. Journal of Human Genetics, 61, 87-94. https://doi.org/10.1038/jhg.2015.113

Paquette, A. G., Lesseur, C., Armstrong, D. A., Koestler, D. C., Appleton, A. A., Lester, B. M., & Marsit, C. J. (2013). Placental HTR2A methylation is associated with infant neurobehavioral outcomes. Epigenetics, 8(8), 796-801. https://doi.org/10.4161/epi.25358

Phillips, J. E., & Corces, V. G. (2009). CTCF: master weaver of the genome. Cell, 137(7), 1194-1211. https://doi.org/10.1016/j.cell.2009.06.001

Poggi, L., & Richard, G. F. (2020). Alternative DNA Structures In Vivo: Molecular Evidence and Remaining Questions. Microbiology and Molecular Biology Reviews, 85(1), e00110-e00120. https://doi.org/10.1128/MMBR.00110-20

Raote, I., Bhattacharya, A., & Panicker, M. M. (2007). Serotonin 2A (5-HT2A). Serotonin 2A (5-HT2A) Receptor Function: Ligand-Dependent Mechanisms and Pathways. In A. Chattopadhyay (Eds.), Serotonin Receptors in Neurobiology (pp. 109-124) Boca Raton, US: CRC Press.

Ray-Jones, H., & Spivakov, M. (2021). Transcriptional enhancers and their communication with gene promoters. Cellular and Molecular Life Sciences, 78, 6453-6485. https://doi.org/10.1007/s00018-021-03903-w

Reinius, B., & Sandberg, R. (2015). Random monoallelic expression of autosomal genes: stochastic transcription and allele-level regulation. Nature Reviews Genetics, 16, 653-664. https://doi.org/10.1038/nrg3888

Riethoven, J. J. (2010). Regulatory regions in DNA: promoters, enhancers, silencers, and insulators. In I. Ladunga (Eds.), Computational Biology of Transcription Factor Binding. Methods in Molecular Biology (Vol. 674, pp. 33-42) New Jersey, US: Humana Press. https://doi.org/10.1007/978-1-60761-854-6_3

Rosenfeld, C. S. (2020). Placental serotonin signaling, pregnancy outcomes, and regulation of fetal brain development†. Biology of Reproduction, 102(3), 532-538. https://doi.org/10.1093/biolre/ioz204

Ruble, C. L., Smith, R. M., Calley, J., Munsie, L., Airey, D. C., Gao, Y., Shin, J. H., Hyde, T. M., Straub, R. E., Weinberger, D. R., & Nisenbaum, L. K. (2016). Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons. BMC Genetics, 17, 16. https://doi.org/10.1186/s12863-015-0325-6

Rueckert, E. H., Barker, D., Ruderfer, D., Bergen, S. E., O'Dushlaine, C., Luce, C. J., Sheridan, S. D., Theriault, K. M., Chambert, K., Moran, J., Purcell, S. M., Madison, J. M., Haggarty, S. J., & Sklar, P. (2013). Cis-acting regulation of brain-specific ANK3 gene expression by a genetic variant associated with bipolar disorder. Molecular Psychiatry, 18, 922-929. https://doi.org/10.1038/mp.2012.104

Saeliw, T., Kanlayaprasit, S., Thongkorn, S., Songsritaya, K., Sanannam, B., Sae-Lee, C., Jindatip, D., Hu, V. W., & Sarachana, T. (2023). Epigenetic Gene-Regulatory Loci in Alu Elements Associated with Autism Susceptibility in the Prefrontal Cortex of ASD. International Journal of Molecular Sciences, 24(8), 7518. https://doi.org/10.3390/ijms24087518

Saleh, A., Macia, A., & Muotri, A. R. (2019). Transposable Elements, Inflammation, and Neurological Disease. Frontiers in Neurology, 10, 894. https://doi.org/10.3389/fneur.2019.00894

Schoenfelder, S., Clay, I., & Fraser, P. (2010). The transcriptional interactome: gene expression in 3D. Current Opinion in Genetics & Development, 20(2), 127-133. https://doi.org/10.1016/j.gde.2010.02.002

Singal, R., & Ginder, G. D. (1999). DNA methylation. Blood, 93(12), 4059-4070.

Song, M., Yang, X., Ren, X., Maliskova, L., Li, B., Jones, I. R., Wang, C., Jacob, F., Wu, K., Traglia, M., Tam, T. W., Jamieson, K., Lu, S.-Y., Ming, G.-L., Li, Y., Yao, J., Weiss, L. A., Dixon, J. R., Judge, L. M., … Shen, Y. (2019). Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes. Nature Genetics, 51(8), 1252-1262. https://doi.org/10.1038/s41588-019-0472-1

Soriano, V. L., Dueñas Rey, A., Mukherjee, R., Genomics England Research Consortium, Coppieters, F., Bauwens, M., Willaert, A., & De Baere, E. (2024). Multi-omics analysis in human retina uncovers ultraconserved cis-regulatory elements at rare eye disease loci. Nature Communications, 15, 1600. https://doi.org/10.1038/s41467-024-45381-1

Srinivasan, C., Phan, B. N., Lawler, A. J., Ramamurthy, E., Kleyman, M., Brown, A. R., Kaplow, I. M., Wirthlin, M. E., & Pfenning, A. R. (2021). Addiction-associated genetic variants implicate brain cell type- and region-specific Cis-regulatory elements in addiction neurobiology. The Journal of Neuroscience, 41(43), 9008-9030. https://doi.org/10.1523/JNEUROSCI.2534-20.2021

Statello, L., Guo, C. J., Chen, L. L., & Huarte, M. (2021). Gene regulation by long non-coding RNAs and its biological functions. Nature Reviews Molecular Cell Biology, 22, 96-118. https://doi.org/10.1038/s41580-020-00315-9

Stefanucci, L., & Frontini, M. (2022). Non-coding genetic variation in regulatory elements determines thrombosis and hemostasis phenotypes. Journal of Thrombosis and Haemostasis, 20(8), 1759-1765. https://doi.org/10.1111/jth.15754

Strokes, N., & Piao, X. (2010). Adhesion-GPCRs in the CNS. Advances in Experimental Medicine and Biology, 706, 87-97. https://doi.org/10.1007/978-1-4419-7913-1_7

Toth, M. (1996). Transcriptional regulation of the 5-HT2A receptor. Behavioural Brain Research, 73(1-2), 183-186. https://doi.org/10.1016/0166-4328(96)00093-9

Villar, D., Berthelot, C., Aldridge, S., Rayner, T. F., Lukk, M., Pignatelli, M., Park, T. J., Deaville, R., Erichsen, J. T., Jasinska, A. J., Turner, J. M., Bertelsen, M. F., Murchison, E. P., Flicek, P., & Odom, D. T. (2015). Enhancer evolution across 20 mammalian species. Cell, 160(3), 554-566. https://doi.org/10.1016/j.cell.2015.01.006

Wadkins, R. M. (2000). Targeting DNA secondary structures. Current Medicinal Chemistry, 7(1), 1-15. https://doi.org/10.2174/0929867003375461

Werner, A., Carlile, M., & Swan, D. (2009). What do natural antisense transcripts regulate?. RNA Biology, 6(1), 43-48. https://doi.org/10.4161/rna.6.1.7568

Wockner, L. F., Noble, E. P., Lawford, B. R., Young, R. M., Morris, C. P., Whitehall, V. L., & Voisey, J. (2014). Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients. Translational Psychiatry, 4, e339. https://doi.org/10.1038/tp.2013.111

Wohlpart, K. L., & Molinoff, P. B. (1998). Regulation of levels of 5-HT2A receptor mRNA. Annals of the New York Academy of Sciences, 861(1), 128-135. https://doi.org/10.1111/j.1749-6632.1998.tb10183.x

Wojtas, A., & Gołembiowska, K. (2024). Molecular and Medical Aspects of Psychedelics. International Journal of Molecular Sciences, 25(1), 241. https://doi.org/10.3390/ijms25010241

Yadav, P., Pandey, A., Kakani, P., Mutnuru, S. A., Samaiya, A., Mishra, J., & Shukla, S. (2023). Hypoxia-induced loss of SRSF2-dependent DNA methylation promotes CTCF-mediated alternative splicing of VEGFA in breast cancer. iScience, 26(6), 106804. https://doi.org/10.1016/j.isci.2023.106804

Yin, L., Yu, Y., Han, F., & Wang, Q. (2024). Unveiling serotonergic dysfunction of obsessive-compulsive disorder on prefrontal network dynamics: a computational perspective. Cerebral Cortex, 34(6), bhae258. https://doi.org/10.1093/cercor/bhae258

Zhang, X., & Kim, K. M. (2017). Multifactorial Regulation of G Protein-Coupled Receptor Endocytosis. Biomolecules & Therapeutics, 25(1), 26-43. https://doi.org/10.4062/biomolther.2016.186

Zhao, J., Bacolla, A., Wang, G., & Vasquez, K. M. (2010). Non-B DNA structure-induced genetic instability and evolution. Cellular and Molecular Life Sciences, 67(1), 43-62. https://doi.org/10.1007/s00018-009-0131-2

Zhao, J., Qian, X., Yeung, P. Y., Zhang, Q. C., & Kwok, C. K. (2019). Mapping In Vivo RNA Structures and Interactions. Trends in Biochemical Sciences, 44(6), 555-556. https://doi.org/10.1016/j.tibs.2019.01.012

Zhong, W., Liu, W., Chen, J., Sun, Q., Hu, M., & Li, Y. (2022). Understanding the function of regulatory DNA interactions in the interpretation of non-coding GWAS variants. Frontiers in Cell and Developmental Biology, 10, 957292. https://doi.org/10.3389/fcell.2022.957292

Zhu, Q. S., Chen, K., & Shih, J. C. (1995). Characterization of the human 5-HT2A receptor gene promoter. The Journal of Neuroscience, 15(7), 4885-4895. https://doi.org/10.1523/JNEUROSCI.15-07-04885.1995

Zhu, X., Ma, S., & Wong, W. H. (2024). Genetic effects of sequence-conserved enhancer-like elements on human complex traits. Genome Biology, 25, 1. https://doi.org/10.1186/s13059-023-03142-1

Published

29-08-2024

How to Cite

Bhogegowda, K. K. H., Niketh, S., Thyloor, R., & Kolgi, R. R. (2024). Insights into the role of cis-regulatory elements of 5-HT2A gene in gene expression and regulation: an in silico approach. Research in Biotechnology, 15, 1–14. https://doi.org/10.25081/rib.2024.v15.9081

Issue

Section

Articles