Filling the gap: Beyond molecules ... what clinicians ignore
Published
Apr 10, 2019
Almetrics
Dimensions
Google Scholar
##plugins.themes.bootstrap3.article.details##
Abstract
To narrow the gap between the bench and the clinic, healthcare personnel should have a basic understanding of molecular mechanisms ruling cell identity, since it establishes the key differences between health and disease states. The objective of this work is to explain in a simple way, the transcription of codified information in DNA into its intermediary mRNA, through differential gene expression. The importance of this process relies in that even though all cells in an organism have the same genome, they can attain distinct functions through activation of selected genes, whether under physiological or pathological conditions. The process of differential gene expression begins with epigenetic events, where through histone modifications the transcription machinery has access to DNA. Thus, the DNA sequence can be read in multiple ways to obtain a variety of proteins necessary for the organism. Therefore, from the aforementioned, this article seeks to facilitate critical understanding of advancements that have been emerging in this field. In the last decades great progress has been attained regarding understanding and conformation of the human genome. Thanks to these advancements, research has focued on determining differential gene expression clinical applications, such as shedding light on the pathological processes of disease, diagnostic tool improvement and possible treatments.
Keywords
Epigenomics, Gene Expression, Transcription factors, Methylation, AcetylationEpigenómica, Expresión Génica, Factores de Transcripción, Metilación, Acetilación
References
1. Venter, J.C., et al., The sequence of the human genome. Science, 2001. 291(5507): p. 1304-51.
2. Lander, E.S., et al., Initial sequencing and analysis of the human genome. Nature, 2001. 409(6822): p. 860-921.
3. Birney, E., et al., Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature, 2007. 447(7146): p. 799-816.
4. Berger, S.L., et al., An operational definition of epigenetics. Genes Dev, 2009. 23(7): p. 781-3.
5. Catalanotto, C., C. Cogoni, and G. Zardo, MicroRNA in Control of Gene Expression: An Overview of Nuclear Functions. Int J Mol Sci, 2016. 17(10).
6. Raghavan, S. and J.L. Vassy, Do physicians think genomic medicine will be useful for patient care? Per Med, 2014. 11(4): p. 424-433.
7. in Understanding Genetics: A New York, Mid-Atlantic Guide for Patients and Health Professionals2009: Washington (DC).
8. Ivanov, M., I. Barragan, and M. Ingelman-Sundberg, Epigenetic mechanisms of importance for drug treatment. Trends Pharmacol Sci, 2014. 35(8): p. 384-96.
9. Avard, D. and B.M. Knoppers, Genomic medicine: considerations for health professionals and the public. Genome Med, 2009. 1(2): p. 25.
10. Bianconi, E., et al., An estimation of the number of cells in the human body. Ann Hum Biol, 2013. 40(6): p. 463-71.
11. Ezkurdia, I., et al., Multiple evidence strands suggest that there may be as few as 19,000 human protein-coding genes. Hum Mol Genet, 2014. 23(22): p. 5866-78.
12. Gilbert, S., General principles of differentiation and morphogenesis, in Inborn Errors of Development: The Molecular Basis of Clinical Disorders of Morphogenesis, R.P.E. Charles J. Epstein, Anthony Joseph Wynshaw-Boris, Editor 2004, Oxford University Press: New York, NY USA. p. 10 - 24.
13. Mazzarello, P., A unifying concept: the history of cell theory. Nat Cell Biol, 1999. 1(1): p. E13-5.
14. Niakan, K.K., et al., Human pre-implantation embryo development. Development, 2012. 139(5): p. 829-41.
15. Braude, P., V. Bolton, and S. Moore, Human gene expression first occurs between the four- and eight-cell stages of preimplantation development. Nature, 1988. 332(6163): p. 459-61.
16. Plusa, B., et al., Distinct sequential cell behaviours direct primitive endoderm formation in the mouse blastocyst. Development, 2008. 135(18): p. 3081-91.
17. Bird, A., Perceptions of epigenetics. Nature, 2007. 447(7143): p. 396-8.
18. Wang, Y., H. Liu, and Z. Sun, Lamarck rises from his grave: parental environment-induced epigenetic inheritance in model organisms and humans. Biol Rev Camb Philos Soc, 2017. 92(4): p. 2084-2111.
19. Kornberg, R.D. and J.O. Thomas, Chromatin structure; oligomers of the histones. Science, 1974. 184(4139): p. 865-8.
20. Luger, K. and J.C. Hansen, Nucleosome and chromatin fiber dynamics. Curr Opin Struct Biol, 2005. 15(2): p. 188-96.
21. Laybourn, P.J. and J.T. Kadonaga, Role of nucleosomal cores and histone H1 in regulation of transcription by RNA polymerase II. Science, 1991. 254(5029): p. 238-45.
22. Allfrey, V.G., R. Faulkner, and A.E. Mirsky, Acetylation and Methylation of Histones and Their Possible Role in the Regulation of Rna Synthesis. Proc Natl Acad Sci U S A, 1964. 51: p. 786-94.
23. Marmorstein, R. and R.C. Trievel, Histone modifying enzymes: structures, mechanisms, and specificities. Biochim Biophys Acta, 2009. 1789(1): p. 58-68.
24. Bannister, A.J. and T. Kouzarides, The CBP co-activator is a histone acetyltransferase. Nature, 1996. 384(6610): p. 641-3.
25. Hassig, C.A. and S.L. Schreiber, Nuclear histone acetylases and deacetylases and transcriptional regulation: HATs off to HDACs. Curr Opin Chem Biol, 1997. 1(3): p. 300-8.
26. Strahl, B.D. and C.D. Allis, The language of covalent histone modifications. Nature, 2000. 403(6765): p. 41-5.
27. Kingston, R.E., A snapshot of a dynamic nuclear building block. Nat Struct Biol, 1997. 4(10): p. 763-6.
28. Rose, N.R. and R.J. Klose, Understanding the relationship between DNA methylation and histone lysine methylation. Biochim Biophys Acta, 2014. 1839(12): p. 1362-72.
29. Cloos, P.A., et al., Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev, 2008. 22(9): p. 1115-40.
30. Klose, R.J. and A.P. Bird, Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci, 2006. 31(2): p. 89-97.
31. Antequera, F. and A. Bird, CpG Islands: A Historical Perspective. Methods Mol Biol, 2018. 1766: p. 3-13.
32. Moore, L.D., T. Le, and G. Fan, DNA methylation and its basic function. Neuropsychopharmacology, 2013. 38(1): p. 23-38.
33. Saxonov, S., P. Berg, and D.L. Brutlag, A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc Natl Acad Sci U S A, 2006. 103(5): p. 1412-7.
34. Zhu, J., et al., On the nature of human housekeeping genes. Trends Genet, 2008. 24(10): p. 481-4.
35. Larsen, F., et al., CpG islands as gene markers in the human genome. Genomics, 1992. 13(4): p. 1095-107.
36. Baubec, T., et al., Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature, 2015. 520(7546): p. 243-7.
37. Alberts B, J.A., Lewis J, Raff M, Roberts K, Walter P, How cells read the genome: from DNA to RNA, in Molecular Biology of the cell2008, Garland Science, Taylor and Francis Group: New York, NY USA. p. 329 - 366.
38. Sonenberg, N. and A.G. Hinnebusch, Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell, 2009. 136(4): p. 731-45.
39. Gilbert, S. and M. Barresi, Defining differential gene expression, in Developmental Biology2016, Sinauer: Sunderland, MA USA. p. 45 - 46.
40. Hahn, S., Structure and mechanism of the RNA polymerase II transcription machinery. Nat Struct Mol Biol, 2004. 11(5): p. 394-403.
41. Hampsey, M., Molecular genetics of the RNA polymerase II general transcriptional machinery. Microbiol Mol Biol Rev, 1998. 62(2): p. 465-503.
42. Tan, N.Y. and L.M. Khachigian, Sp1 phosphorylation and its regulation of gene transcription. Mol Cell Biol, 2009. 29(10): p. 2483-8.
43. Yang, C., et al., Prevalence of the initiator over the TATA box in human and yeast genes and identification of DNA motifs enriched in human TATA-less core promoters. Gene, 2007. 389(1): p. 52-65.
44. Latchman, D.S., Transcription factors: an overview. Int J Exp Pathol, 1993. 74(5): p. 417-22.
45. Phillips, T.H., L., Transcription factors and transcriptional control in eukaryotic cells., in Nature Education 1(1):119, Scitable, Editor 2014, Nature education.
46. SF, G. and M. Barresi, Anatomy of the gene, in Developmental biology2016, Sinauer Associates, Inc: Sunderland, MA. p. 52 - 61.
47. Ong, C.T. and V.G. Corces, Enhancer function: new insights into the regulation of tissue-specific gene expression. Nat Rev Genet, 2011. 12(4): p. 283-93.
48. TW, S., Introduction to molecular regulation and signaling, in Langman’s medical embryology, T. C, Editor 2012, Lippincott Williams & Wilkins: Baltimore. p. 3-9.
49. Shatkin, A.J., Capping of eucaryotic mRNAs. Cell, 1976. 9(4 PT 2): p. 645-53.
50. Gilbert, W., Why genes in pieces? Nature, 1978. 271(5645): p. 501.
51. Graveley, B.R., Alternative splicing: increasing diversity in the proteomic world. Trends Genet, 2001. 17(2): p. 100-7.
52. Wahl, M.C., C.L. Will, and R. Luhrmann, The spliceosome: design principles of a dynamic RNP machine. Cell, 2009. 136(4): p. 701-18.
53. Black, D.L., Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem, 2003. 72: p. 291-336.
54. Chen, M. and J.L. Manley, Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat Rev Mol Cell Biol, 2009. 10(11): p. 741-54.
55. House, A.E. and K.W. Lynch, An exonic splicing silencer represses spliceosome assembly after ATP-dependent exon recognition. Nat Struct Mol Biol, 2006. 13(10): p. 937-44.
56. Sharma, S., et al., Polypyrimidine tract binding protein controls the transition from exon definition to an intron defined spliceosome. Nat Struct Mol Biol, 2008. 15(2): p. 183-91.
57. Batsche, E., M. Yaniv, and C. Muchardt, The human SWI/SNF subunit Brm is a regulator of alternative splicing. Nat Struct Mol Biol, 2006. 13(1): p. 22-9.
58. Sandell, L.J., A.M. Nalin, and R.A. Reife, Alternative splice form of type II procollagen mRNA (IIA) is predominant in skeletal precursors and non-cartilaginous tissues during early mouse development. Dev Dyn, 1994. 199(2): p. 129-40.
59. Ryan, M.C. and L.J. Sandell, Differential expression of a cysteine-rich domain in the amino-terminal propeptide of type II (cartilage) procollagen by alternative splicing of mRNA. J Biol Chem, 1990. 265(18): p. 10334-9.
60. Nonaka, D., et al., Diagnostic utility of thyroid transcription factors Pax8 and TTF-2 (FoxE1) in thyroid epithelial neoplasms. Mod Pathol, 2008. 21(2): p. 192-200.
61. Miettinen, M., et al., Microphthalmia transcription factor in the immunohistochemical diagnosis of metastatic melanoma: comparison with four other melanoma markers. Am J Surg Pathol, 2001. 25(2): p. 205-11.
62. Malouf, G.G., et al., Transcription factor E3 and transcription factor EB renal cell carcinomas: clinical features, biological behavior and prognostic factors. J Urol, 2011. 185(1): p. 24-9.
63. Agoff, S.N., et al., Thyroid transcription factor-1 is expressed in extrapulmonary small cell carcinomas but not in other extrapulmonary neuroendocrine tumors. Mod Pathol, 2000. 13(3): p. 238-42.
64. Takahashi, K. and S. Yamanaka, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 2006. 126(4): p. 663-76.
65. Vierbuchen, T., et al., Direct conversion of fibroblasts to functional neurons by defined factors. Nature, 2010. 463(7284): p. 1035-41.
66. Capetian, P., et al., Plasmid-Based Generation of Induced Neural Stem Cells from Adult Human Fibroblasts. Front Cell Neurosci, 2016. 10: p. 245.
67. Shen, T., et al., Clinical applications of next generation sequencing in cancer: from panels, to exomes, to genomes. Front Genet, 2015. 6: p. 215.
68. Soto, J., et al., The impact of next-generation sequencing on the DNA methylation-based translational cancer research. Transl Res, 2016. 169: p. 1-18 e1.
69. Kamps, R., et al., Next-Generation Sequencing in Oncology: Genetic Diagnosis, Risk Prediction and Cancer Classification. Int J Mol Sci, 2017. 18(2).
70. Baylin, S.B., et al., Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet, 2001. 10(7): p. 687-92.
71. Kvaratskhelia, E., T. Tkemaladze, and E. Abzianidze, Expression pattern of DNA-methyltransferases and its health implication (short review). Georgian Med News, 2014(228): p. 76-81.
72. Yi, J.M. and T.O. Kim, Epigenetic alterations in inflammatory bowel disease and cancer. Intest Res, 2015. 13(2): p. 112-21.
73. Merlo, A., et al., 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med, 1995. 1(7): p. 686-92.
74. Baylin, S.B. and J.G. Herman, DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet, 2000. 16(4): p. 168-74.
75. Teng, Y., et al., DNMT1 ablation suppresses tumorigenesis by inhibiting the self-renewal of esophageal cancer stem cells. Oncotarget, 2018. 9(27): p. 18896-18907.
76. Kareta, M.S., et al., Reconstitution and mechanism of the stimulation of de novo methylation by human DNMT3L. J Biol Chem, 2006. 281(36): p. 25893-902.
77. Shallis, R.M. and A.M. Zeidan, More is less, less is more, or does it really matter? The curious case of impact of azacitidine administration schedules on outcomes in patients with myelodysplastic syndromes. BMC Hematol, 2018. 18: p. 4.
78. Buchheit, T., T. Van de Ven, and A. Shaw, Epigenetics and the transition from acute to chronic pain. Pain Med, 2012. 13(11): p. 1474-90.
79. Doehring, A., G. Geisslinger, and J. Lotsch, Epigenetics in pain and analgesia: an imminent research field. Eur J Pain, 2011. 15(1): p. 11-6.
80. Sarnico, I., et al., NF-kappaB and epigenetic mechanisms as integrative regulators of brain resilience to anoxic stress. Brain Res, 2012. 1476: p. 203-10.
81. Geranton, S.M., Targeting epigenetic mechanisms for pain relief. Curr Opin Pharmacol, 2012. 12(1): p. 35-41.
82. Aspeslagh, S., et al., Epigenetic modifiers as new immunomodulatory therapies in solid tumours. Ann Oncol, 2018. 29(4): p. 812-824.
83. Qi, Y., et al., HEDD: the human epigenetic drug database. Database (Oxford), 2016. 2016.
84. S, G., General principles of differentiation and morphogenesis, in The Molecular Basis of Clinical Disorders of Morphogenesis, A.J. Charles JE, Editor 2004, Oxford University Press: New York. p. 10-24.
85. Cox, D.B., R.J. Platt, and F. Zhang, Therapeutic genome editing: prospects and challenges. Nat Med, 2015. 21(2): p. 121-31.
2. Lander, E.S., et al., Initial sequencing and analysis of the human genome. Nature, 2001. 409(6822): p. 860-921.
3. Birney, E., et al., Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature, 2007. 447(7146): p. 799-816.
4. Berger, S.L., et al., An operational definition of epigenetics. Genes Dev, 2009. 23(7): p. 781-3.
5. Catalanotto, C., C. Cogoni, and G. Zardo, MicroRNA in Control of Gene Expression: An Overview of Nuclear Functions. Int J Mol Sci, 2016. 17(10).
6. Raghavan, S. and J.L. Vassy, Do physicians think genomic medicine will be useful for patient care? Per Med, 2014. 11(4): p. 424-433.
7. in Understanding Genetics: A New York, Mid-Atlantic Guide for Patients and Health Professionals2009: Washington (DC).
8. Ivanov, M., I. Barragan, and M. Ingelman-Sundberg, Epigenetic mechanisms of importance for drug treatment. Trends Pharmacol Sci, 2014. 35(8): p. 384-96.
9. Avard, D. and B.M. Knoppers, Genomic medicine: considerations for health professionals and the public. Genome Med, 2009. 1(2): p. 25.
10. Bianconi, E., et al., An estimation of the number of cells in the human body. Ann Hum Biol, 2013. 40(6): p. 463-71.
11. Ezkurdia, I., et al., Multiple evidence strands suggest that there may be as few as 19,000 human protein-coding genes. Hum Mol Genet, 2014. 23(22): p. 5866-78.
12. Gilbert, S., General principles of differentiation and morphogenesis, in Inborn Errors of Development: The Molecular Basis of Clinical Disorders of Morphogenesis, R.P.E. Charles J. Epstein, Anthony Joseph Wynshaw-Boris, Editor 2004, Oxford University Press: New York, NY USA. p. 10 - 24.
13. Mazzarello, P., A unifying concept: the history of cell theory. Nat Cell Biol, 1999. 1(1): p. E13-5.
14. Niakan, K.K., et al., Human pre-implantation embryo development. Development, 2012. 139(5): p. 829-41.
15. Braude, P., V. Bolton, and S. Moore, Human gene expression first occurs between the four- and eight-cell stages of preimplantation development. Nature, 1988. 332(6163): p. 459-61.
16. Plusa, B., et al., Distinct sequential cell behaviours direct primitive endoderm formation in the mouse blastocyst. Development, 2008. 135(18): p. 3081-91.
17. Bird, A., Perceptions of epigenetics. Nature, 2007. 447(7143): p. 396-8.
18. Wang, Y., H. Liu, and Z. Sun, Lamarck rises from his grave: parental environment-induced epigenetic inheritance in model organisms and humans. Biol Rev Camb Philos Soc, 2017. 92(4): p. 2084-2111.
19. Kornberg, R.D. and J.O. Thomas, Chromatin structure; oligomers of the histones. Science, 1974. 184(4139): p. 865-8.
20. Luger, K. and J.C. Hansen, Nucleosome and chromatin fiber dynamics. Curr Opin Struct Biol, 2005. 15(2): p. 188-96.
21. Laybourn, P.J. and J.T. Kadonaga, Role of nucleosomal cores and histone H1 in regulation of transcription by RNA polymerase II. Science, 1991. 254(5029): p. 238-45.
22. Allfrey, V.G., R. Faulkner, and A.E. Mirsky, Acetylation and Methylation of Histones and Their Possible Role in the Regulation of Rna Synthesis. Proc Natl Acad Sci U S A, 1964. 51: p. 786-94.
23. Marmorstein, R. and R.C. Trievel, Histone modifying enzymes: structures, mechanisms, and specificities. Biochim Biophys Acta, 2009. 1789(1): p. 58-68.
24. Bannister, A.J. and T. Kouzarides, The CBP co-activator is a histone acetyltransferase. Nature, 1996. 384(6610): p. 641-3.
25. Hassig, C.A. and S.L. Schreiber, Nuclear histone acetylases and deacetylases and transcriptional regulation: HATs off to HDACs. Curr Opin Chem Biol, 1997. 1(3): p. 300-8.
26. Strahl, B.D. and C.D. Allis, The language of covalent histone modifications. Nature, 2000. 403(6765): p. 41-5.
27. Kingston, R.E., A snapshot of a dynamic nuclear building block. Nat Struct Biol, 1997. 4(10): p. 763-6.
28. Rose, N.R. and R.J. Klose, Understanding the relationship between DNA methylation and histone lysine methylation. Biochim Biophys Acta, 2014. 1839(12): p. 1362-72.
29. Cloos, P.A., et al., Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev, 2008. 22(9): p. 1115-40.
30. Klose, R.J. and A.P. Bird, Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci, 2006. 31(2): p. 89-97.
31. Antequera, F. and A. Bird, CpG Islands: A Historical Perspective. Methods Mol Biol, 2018. 1766: p. 3-13.
32. Moore, L.D., T. Le, and G. Fan, DNA methylation and its basic function. Neuropsychopharmacology, 2013. 38(1): p. 23-38.
33. Saxonov, S., P. Berg, and D.L. Brutlag, A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc Natl Acad Sci U S A, 2006. 103(5): p. 1412-7.
34. Zhu, J., et al., On the nature of human housekeeping genes. Trends Genet, 2008. 24(10): p. 481-4.
35. Larsen, F., et al., CpG islands as gene markers in the human genome. Genomics, 1992. 13(4): p. 1095-107.
36. Baubec, T., et al., Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature, 2015. 520(7546): p. 243-7.
37. Alberts B, J.A., Lewis J, Raff M, Roberts K, Walter P, How cells read the genome: from DNA to RNA, in Molecular Biology of the cell2008, Garland Science, Taylor and Francis Group: New York, NY USA. p. 329 - 366.
38. Sonenberg, N. and A.G. Hinnebusch, Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell, 2009. 136(4): p. 731-45.
39. Gilbert, S. and M. Barresi, Defining differential gene expression, in Developmental Biology2016, Sinauer: Sunderland, MA USA. p. 45 - 46.
40. Hahn, S., Structure and mechanism of the RNA polymerase II transcription machinery. Nat Struct Mol Biol, 2004. 11(5): p. 394-403.
41. Hampsey, M., Molecular genetics of the RNA polymerase II general transcriptional machinery. Microbiol Mol Biol Rev, 1998. 62(2): p. 465-503.
42. Tan, N.Y. and L.M. Khachigian, Sp1 phosphorylation and its regulation of gene transcription. Mol Cell Biol, 2009. 29(10): p. 2483-8.
43. Yang, C., et al., Prevalence of the initiator over the TATA box in human and yeast genes and identification of DNA motifs enriched in human TATA-less core promoters. Gene, 2007. 389(1): p. 52-65.
44. Latchman, D.S., Transcription factors: an overview. Int J Exp Pathol, 1993. 74(5): p. 417-22.
45. Phillips, T.H., L., Transcription factors and transcriptional control in eukaryotic cells., in Nature Education 1(1):119, Scitable, Editor 2014, Nature education.
46. SF, G. and M. Barresi, Anatomy of the gene, in Developmental biology2016, Sinauer Associates, Inc: Sunderland, MA. p. 52 - 61.
47. Ong, C.T. and V.G. Corces, Enhancer function: new insights into the regulation of tissue-specific gene expression. Nat Rev Genet, 2011. 12(4): p. 283-93.
48. TW, S., Introduction to molecular regulation and signaling, in Langman’s medical embryology, T. C, Editor 2012, Lippincott Williams & Wilkins: Baltimore. p. 3-9.
49. Shatkin, A.J., Capping of eucaryotic mRNAs. Cell, 1976. 9(4 PT 2): p. 645-53.
50. Gilbert, W., Why genes in pieces? Nature, 1978. 271(5645): p. 501.
51. Graveley, B.R., Alternative splicing: increasing diversity in the proteomic world. Trends Genet, 2001. 17(2): p. 100-7.
52. Wahl, M.C., C.L. Will, and R. Luhrmann, The spliceosome: design principles of a dynamic RNP machine. Cell, 2009. 136(4): p. 701-18.
53. Black, D.L., Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem, 2003. 72: p. 291-336.
54. Chen, M. and J.L. Manley, Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat Rev Mol Cell Biol, 2009. 10(11): p. 741-54.
55. House, A.E. and K.W. Lynch, An exonic splicing silencer represses spliceosome assembly after ATP-dependent exon recognition. Nat Struct Mol Biol, 2006. 13(10): p. 937-44.
56. Sharma, S., et al., Polypyrimidine tract binding protein controls the transition from exon definition to an intron defined spliceosome. Nat Struct Mol Biol, 2008. 15(2): p. 183-91.
57. Batsche, E., M. Yaniv, and C. Muchardt, The human SWI/SNF subunit Brm is a regulator of alternative splicing. Nat Struct Mol Biol, 2006. 13(1): p. 22-9.
58. Sandell, L.J., A.M. Nalin, and R.A. Reife, Alternative splice form of type II procollagen mRNA (IIA) is predominant in skeletal precursors and non-cartilaginous tissues during early mouse development. Dev Dyn, 1994. 199(2): p. 129-40.
59. Ryan, M.C. and L.J. Sandell, Differential expression of a cysteine-rich domain in the amino-terminal propeptide of type II (cartilage) procollagen by alternative splicing of mRNA. J Biol Chem, 1990. 265(18): p. 10334-9.
60. Nonaka, D., et al., Diagnostic utility of thyroid transcription factors Pax8 and TTF-2 (FoxE1) in thyroid epithelial neoplasms. Mod Pathol, 2008. 21(2): p. 192-200.
61. Miettinen, M., et al., Microphthalmia transcription factor in the immunohistochemical diagnosis of metastatic melanoma: comparison with four other melanoma markers. Am J Surg Pathol, 2001. 25(2): p. 205-11.
62. Malouf, G.G., et al., Transcription factor E3 and transcription factor EB renal cell carcinomas: clinical features, biological behavior and prognostic factors. J Urol, 2011. 185(1): p. 24-9.
63. Agoff, S.N., et al., Thyroid transcription factor-1 is expressed in extrapulmonary small cell carcinomas but not in other extrapulmonary neuroendocrine tumors. Mod Pathol, 2000. 13(3): p. 238-42.
64. Takahashi, K. and S. Yamanaka, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 2006. 126(4): p. 663-76.
65. Vierbuchen, T., et al., Direct conversion of fibroblasts to functional neurons by defined factors. Nature, 2010. 463(7284): p. 1035-41.
66. Capetian, P., et al., Plasmid-Based Generation of Induced Neural Stem Cells from Adult Human Fibroblasts. Front Cell Neurosci, 2016. 10: p. 245.
67. Shen, T., et al., Clinical applications of next generation sequencing in cancer: from panels, to exomes, to genomes. Front Genet, 2015. 6: p. 215.
68. Soto, J., et al., The impact of next-generation sequencing on the DNA methylation-based translational cancer research. Transl Res, 2016. 169: p. 1-18 e1.
69. Kamps, R., et al., Next-Generation Sequencing in Oncology: Genetic Diagnosis, Risk Prediction and Cancer Classification. Int J Mol Sci, 2017. 18(2).
70. Baylin, S.B., et al., Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet, 2001. 10(7): p. 687-92.
71. Kvaratskhelia, E., T. Tkemaladze, and E. Abzianidze, Expression pattern of DNA-methyltransferases and its health implication (short review). Georgian Med News, 2014(228): p. 76-81.
72. Yi, J.M. and T.O. Kim, Epigenetic alterations in inflammatory bowel disease and cancer. Intest Res, 2015. 13(2): p. 112-21.
73. Merlo, A., et al., 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med, 1995. 1(7): p. 686-92.
74. Baylin, S.B. and J.G. Herman, DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet, 2000. 16(4): p. 168-74.
75. Teng, Y., et al., DNMT1 ablation suppresses tumorigenesis by inhibiting the self-renewal of esophageal cancer stem cells. Oncotarget, 2018. 9(27): p. 18896-18907.
76. Kareta, M.S., et al., Reconstitution and mechanism of the stimulation of de novo methylation by human DNMT3L. J Biol Chem, 2006. 281(36): p. 25893-902.
77. Shallis, R.M. and A.M. Zeidan, More is less, less is more, or does it really matter? The curious case of impact of azacitidine administration schedules on outcomes in patients with myelodysplastic syndromes. BMC Hematol, 2018. 18: p. 4.
78. Buchheit, T., T. Van de Ven, and A. Shaw, Epigenetics and the transition from acute to chronic pain. Pain Med, 2012. 13(11): p. 1474-90.
79. Doehring, A., G. Geisslinger, and J. Lotsch, Epigenetics in pain and analgesia: an imminent research field. Eur J Pain, 2011. 15(1): p. 11-6.
80. Sarnico, I., et al., NF-kappaB and epigenetic mechanisms as integrative regulators of brain resilience to anoxic stress. Brain Res, 2012. 1476: p. 203-10.
81. Geranton, S.M., Targeting epigenetic mechanisms for pain relief. Curr Opin Pharmacol, 2012. 12(1): p. 35-41.
82. Aspeslagh, S., et al., Epigenetic modifiers as new immunomodulatory therapies in solid tumours. Ann Oncol, 2018. 29(4): p. 812-824.
83. Qi, Y., et al., HEDD: the human epigenetic drug database. Database (Oxford), 2016. 2016.
84. S, G., General principles of differentiation and morphogenesis, in The Molecular Basis of Clinical Disorders of Morphogenesis, A.J. Charles JE, Editor 2004, Oxford University Press: New York. p. 10-24.
85. Cox, D.B., R.J. Platt, and F. Zhang, Therapeutic genome editing: prospects and challenges. Nat Med, 2015. 21(2): p. 121-31.
How to Cite
Gutierrez Gómez, M. L., Calixto Nuñez, C. A., Gómez, A. M., Mesa, V. L., García Guete, M. M., Vivas Ramírez, N., Andrade Moreno, M. D. la P., Bejarano Rodríguez, J. P., Moros Martín, N., Farfan Robles, C. A., & Daza Daza, M. B. (2019). Filling the gap: Beyond molecules . what clinicians ignore. Universitas Medica, 60(2), 1–25. https://doi.org/10.11144/Javeriana.umed60-2.mole
Issue
Section
Short Reviews