DNA甲基化修飾與DNA二級結構G-quadruplex皆被認為具有抑制基因表現的可能。但兩者之交互作用是否會調控基因表現，卻尚未有文獻證實此一現象。由於與癌症發展有極高關聯性的hTERT基因，其啟動子區域受DNA甲基化調控機制已被廣為探討，並且該區域也存在具有G-quadruplex結構等特性，故合適做為探討G-quadruplex和DNA甲基化兩者可能的交互作用是否影響轉錄因子結合調控基因表現，進而改變細胞生理功能，並深具進一步的探討其作用機制的重要性。本研究首先以QGRS Mapper (Quadruplex forming G-Rich Sequences)進行分析後hTERT基因後，發現主要受到甲基化調控的區域CTCF (CCCTC-binding factor) 結合位序列會形成G-quadruplex結構，隨後以核磁共振(Nuclear Magnetic Resonance, NMR)確認此一事實。我們建構了含hTERT 啟動子區域且包含不同甲基化修飾之報導基因質體，從報導基因表現結果證實位於CTCF結合位之G-quadruplex結構，會和hTERT甲基化調控有交互影響而改變基因表現。我們也利用ChIP assay確認CTCF結合能力會因為此交互作用影響而改變。本研究證明了G-quadruplex結構和甲基化之間的互相影響會透過影響轉錄因子CTCF的結合，改變hTERT基因表現。未來也將透過相同模式探討其他已知有G-quadruplex結構且同樣會受到甲基化調控的基因，確認此現象為普遍存在並深入探討。

It has been shown that gene expression will be affected by DNA methylation and secondary structures in the promoter region. However, the gene expression profile has not been addressed when the DNA methylation occurs at the G-quadruplex secondary structures. DNA methylation and G-quadruplex structures has been found in the promoter region of hTERT (human telomerase reverse transcriptase) gene. In this study, we investigated whether the methylation of G-quadruplex will occur at the promoter region of hTERT and further modulate its gene expression level. Using QGRS Mapper (Quadruplex forming G-Rich Sequences), a G-quadruplex structure was identified on the CTCF (CCCTC-binding factor) binding site of hTERT gene. NMR (nuclear magnetic resonance) analysis further confirmed this possible G-quadruplex structure. Reporter plasmids were constructed under the control of different hTERT promoter region. Here we further showed that the expression of hTERT was regulated by the G-quadruplex at the CTCF binding site and DNA methylation at the G-quadruplex further modulate the gene expression.

目錄
摘要 I
Abstract II
第一章 緒論 1
1.1 DNA二級結構 – G-quadruplex 1
1.1.1 G-quadruplex基本介紹 1
1.1.2 G-quadruplex對啟動子活性的影響 2
1.2 DNA甲基化 4
1.2.1 DNA甲基化與轉錄調控 4
1.2.2 DNA甲基化相關酵素 5
1.2.3 藥物對於DNA甲基化調控的影響 7
1.3 hTERT基因表現 8
1.3.1 端粒與端粒&;#37238; 8
1.3.2 hTERT轉錄調控 8
1.4轉錄因子CTCF（CCCTC-binding factor） 10
1.5研究動機與目的 12
第二章 材料與方法 13
2.1藥品與儀器 13
2.1.1藥品 13
2.1.2細胞培養試劑 15
2.1.3儀器 15
2.2細胞株 16
2.2.1 細胞繼代培養 17
2.2.2 細胞冷凍與解凍 17
2.2.3 細胞計數 17
2.3 核磁共振光譜 NMR spectra 18
2.4 甲基化調控 18
2.4.1 ALA光動力處理 18
2.4.2 Trichostatin A (TSA) 處理 19
2.5 mRNA定量分析 19
2.5.1 RNA 萃取 (RNA extraction) 19
2.5.2 反轉錄 (Reverse Transcription, RT) 19
2.5.3 聚合&;#37238;鏈鎖反應 (Polymerase Chain Reaction, PCR) 20
2.5.4 洋菜膠體電泳分析 21
2.6 Methylation cassette assay 21
2.6.1 以CpG-free vector建構hTERT promoter質體 21
2.6.1.1 目標基因序列的PCR放大 21
2.6.1.2 TA cloning 22
2.6.1.3 質體建構 23
2.6.2 定點突變 (site-directed mutagenesis) 24
2.6.3 甲基化 25
2.6.4 建構partial-methylation質體 25
2.6.5 細胞轉染 26
2.7 亞硫酸鹽定序 (Bisulfite sequencing) 26
2.8 染色質免疫沉澱 (chromatin immunoprecipitation) 28
2.9 螢光素&;#37238;報導基因分析 (Luciferase reporter assay) 29
2.10 統計分析 30
第三章 結果 31
3.1 分析CTCF結合位序列是否形成G-quadruplex 31
3.2 確認hTERT表現量和甲基化相關酵素之間的影響 32
3.2.1 TSA處理細胞後DNMT1/hTERT表現量的改變 33
3.2.2 ALA-PDT處理細胞後DNMT1 / Gadd45α / hTERT表現量的改變 34
3.2.3 ALA-PDT處理對hTERT啟動子甲基化程度之影響 35
3.3 探討甲基化和G-quadruplex的交互作用是否影響hTERT基因表現 35
3.3.1 hTERT啟動子質體之報導基因表現 36
3.3.2 TSA處理對於報導基因影響 37
3.3.3 ALA-PDT處理對於報導基因影響 38
3.4 CTCF結合能力差異 39
3.5 G-quadruplex影響hTERT基因表現 40
第四章 討論 43
4.1 為何選擇hTERT之CTCF結合位作為主要研究對象 43
4.2 G-quadruplex分析方法 44
4.3 定點突變影響 45
4.4 ALA-PDT所引發hTERT可能調控機制 45
4.5 RT-PCR實驗結果與報導基因實驗結果之差異 47
4.5.1 TSA處理 47
4.5.2 ALA-PDT處理 49
4.6 G-quadruplex影響hTERT基因甲基化程度 50
第五章 結論與未來工作 52
圖 53
附錄 67
參考文獻 75

1.Wells, R.D., Unusual DNA structures. J Biol Chem, 1988. 263(3): p. 1095-8.
2.Wells, R.D., Non-B DNA conformations, mutagenesis and disease. Trends Biochem Sci, 2007. 32(6): p. 271-8.
3.Raghavan, S.C. and M.R. Lieber, DNA structure and human diseases. Front Biosci, 2007. 12: p. 4402-8.
4.Bacolla, A. and R.D. Wells, Non-B DNA conformations, genomic rearrangements, and human disease. J Biol Chem, 2004. 279(46): p. 47411-4.
5.Majumdar, A. and D.J. Patel, Identifying hydrogen bond alignments in multistranded DNA architectures by NMR. Acc Chem Res, 2002. 35(1): p. 1-11.
6.Wells, R.D., et al., The role of DNA structure in genetic regulation. CRC Crit Rev Biochem, 1977. 4(3): p. 305-40.
7.De, S. and F. Michor, DNA secondary structures and epigenetic determinants of cancer genome evolution. Nat Struct Mol Biol, 2011. 18(8): p. 950-5.
8.Henderson, E., et al., Telomeric DNA oligonucleotides form novel intramolecular structures containing guanine-guanine base pairs. Cell, 1987. 51(6): p. 899-908.
9.Williamson, J.R., M.K. Raghuraman, and T.R. Cech, Monovalent cation-induced structure of telomeric DNA: the G-quartet model. Cell, 1989. 59(5): p. 871-80.
10.Gellert, M., M.N. Lipsett, and D.R. Davies, Helix formation by guanylic acid. Proc Natl Acad Sci U S A, 1962. 48: p. 2013-8.
11.Guschlbauer, W., J.F. Chantot, and D. Thiele, Four-stranded nucleic acid structures 25 years later: from guanosine gels to telomer DNA. J Biomol Struct Dyn, 1990. 8(3): p. 491-511.
12.Sen, D. and W. Gilbert, A sodium-potassium switch in the formation of four-stranded G4-DNA. Nature, 1990. 344(6265): p. 410-4.
13.Simonsson, T., G-quadruplex DNA structures--variations on a theme. Biol Chem, 2001. 382(4): p. 621-8.
14.Keniry, M.A., Quadruplex structures in nucleic acids. Biopolymers, 2000. 56(3): p. 123-46.
15.Burge, S., et al., Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res, 2006. 34(19): p. 5402-15.
16.Arthanari, H. and P.H. Bolton, Functional and dysfunctional roles of quadruplex DNA in cells. Chem Biol, 2001. 8(3): p. 221-30.
17.Qin, Y. and L.H. Hurley, Structures, folding patterns, and functions of intramolecular DNA G-quadruplexes found in eukaryotic promoter regions. Biochimie, 2008. 90(8): p. 1149-71.
18.Eddy, J. and N. Maizels, Gene function correlates with potential for G4 DNA formation in the human genome. Nucleic Acids Res, 2006. 34(14): p. 3887-96.
19.Huppert, J.L. and S. Balasubramanian, Prevalence of quadruplexes in the human genome. Nucleic Acids Res, 2005. 33(9): p. 2908-16.
20.Huppert, J.L. and S. Balasubramanian, G-quadruplexes in promoters throughout the human genome. Nucleic Acids Res, 2007. 35(2): p. 406-13.
21.Todd, A.K., M. Johnston, and S. Neidle, Highly prevalent putative quadruplex sequence motifs in human DNA. Nucleic Acids Res, 2005. 33(9): p. 2901-7.
22.Zhang, R., Y. Lin, and C.T. Zhang, Greglist: a database listing potential G-quadruplex regulated genes. Nucleic Acids Res, 2008. 36(Database issue): p. D372-6.
23.Lim, K.W., et al., Coexistence of two distinct G-quadruplex conformations in the hTERT promoter. J Am Chem Soc, 2010. 132(35): p. 12331-42.
24.Palumbo, S.L., S.W. Ebbinghaus, and L.H. Hurley, Formation of a unique end-to-end stacked pair of G-quadruplexes in the hTERT core promoter with implications for inhibition of telomerase by G-quadruplex-interactive ligands. J Am Chem Soc, 2009. 131(31): p. 10878-91.
25.Han, H. and L.H. Hurley, G-quadruplex DNA: a potential target for anti-cancer drug design. Trends Pharmacol Sci, 2000. 21(4): p. 136-42.
26.Mergny, J.L. and C. Helene, G-quadruplex DNA: a target for drug design. Nat Med, 1998. 4(12): p. 1366-7.
27.Marcu, K.B., S.A. Bossone, and A.J. Patel, myc function and regulation. Annu Rev Biochem, 1992. 61: p. 809-60.
28.Pelengaris, S., B. Rudolph, and T. Littlewood, Action of Myc in vivo - proliferation and apoptosis. Curr Opin Genet Dev, 2000. 10(1): p. 100-5.
29.Pelengaris, S. and M. Khan, The many faces of c-MYC. Arch Biochem Biophys, 2003. 416(2): p. 129-36.
30.Pelengaris, S. and M. Khan, The c-MYC oncoprotein as a treatment target in cancer and other disorders of cell growth. Expert Opin Ther Targets, 2003. 7(5): p. 623-42.
31.Cole, M.D. and S.B. McMahon, The Myc oncoprotein: a critical evaluation of transactivation and target gene regulation. Oncogene, 1999. 18(19): p. 2916-24.
32.Spencer, C.A. and M. Groudine, Control of c-myc regulation in normal and neoplastic cells. Adv Cancer Res, 1991. 56: p. 1-48.
33.Yang, D. and L.H. Hurley, Structure of the biologically relevant G-quadruplex in the c-MYC promoter. Nucleosides Nucleotides Nucleic Acids, 2006. 25(8): p. 951-68.
34.Sakatsume, O., et al., Binding of THZif-1, a MAZ-like zinc finger protein to the nuclease-hypersensitive element in the promoter region of the c-MYC protooncogene. J Biol Chem, 1996. 271(49): p. 31322-33.
35.Cooney, M., et al., Site-specific oligonucleotide binding represses transcription of the human c-myc gene in vitro. Science, 1988. 241(4864): p. 456-9.
36.Siebenlist, U., et al., Chromatin structure and protein binding in the putative regulatory region of the c-myc gene in Burkitt lymphoma. Cell, 1984. 37(2): p. 381-91.
37.Boles, T.C. and M.E. Hogan, DNA structure equilibria in the human c-myc gene. Biochemistry, 1987. 26(2): p. 367-76.
38.Simonsson, T., P. Pecinka, and M. Kubista, DNA tetraplex formation in the control region of c-myc. Nucleic Acids Res, 1998. 26(5): p. 1167-72.
39.Siddiqui-Jain, A., et al., Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. Proc Natl Acad Sci U S A, 2002. 99(18): p. 11593-8.
40.Grand, C.L., et al., The cationic porphyrin TMPyP4 down-regulates c-MYC and human telomerase reverse transcriptase expression and inhibits tumor growth in vivo. Mol Cancer Ther, 2002. 1(8): p. 565-73.
41.Han, H., et al., Selective interactions of cationic porphyrins with G-quadruplex structures. J Am Chem Soc, 2001. 123(37): p. 8902-13.
42.Seenisamy, J., et al., Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure. J Am Chem Soc, 2005. 127(9): p. 2944-59.
43.Fry, M., Tetraplex DNA and its interacting proteins. Front Biosci, 2007. 12: p. 4336-51.
44.Chao, D.T. and S.J. Korsmeyer, BCL-2 family: regulators of cell death. Annu Rev Immunol, 1998. 16: p. 395-419.
45.Zhu, Q., et al., Impact of MTHFR gene C677T polymorphism on Bcl-2 gene methylation and protein expression in colorectal cancer. Scand J Gastroenterol, 2011. 46(4): p. 436-45.
46.Reed, J.C., Apoptosis-based therapies. Nat Rev Drug Discov, 2002. 1(2): p. 111-21.
47.Seto, M., et al., Alternative promoters and exons, somatic mutation and deregulation of the Bcl-2-Ig fusion gene in lymphoma. EMBO J, 1988. 7(1): p. 123-31.
48.Dexheimer, T.S., D. Sun, and L.H. Hurley, Deconvoluting the structural and drug-recognition complexity of the G-quadruplex-forming region upstream of the bcl-2 P1 promoter. J Am Chem Soc, 2006. 128(16): p. 5404-15.
49.Hoffman, A.R. and J.F. Hu, Directing DNA methylation to inhibit gene expression. Cell Mol Neurobiol, 2006. 26(4-6): p. 425-38.
50.Lin, J., et al., Stabilization of G-quadruplex DNA by C-5-methyl-cytosine in bcl-2 promoter: implications for epigenetic regulation. Biochem Biophys Res Commun, 2013. 433(4): p. 368-73.
51.Kim, N.W., et al., Specific association of human telomerase activity with immortal cells and cancer. Science, 1994. 266(5193): p. 2011-5.
52.Bird, A.P., Functions for DNA methylation in vertebrates. Cold Spring Harb Symp Quant Biol, 1993. 58: p. 281-5.
53.Singal, R. and G.D. Ginder, DNA methylation. Blood, 1999. 93(12): p. 4059-70.
54.De Smet, C., et al., DNA methylation is the primary silencing mechanism for a set of germ line- and tumor-specific genes with a CpG-rich promoter. Mol Cell Biol, 1999. 19(11): p. 7327-35.
55.Suzuki, M.M. and A. Bird, DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet, 2008. 9(6): p. 465-76.
56.Nichol, K. and C.E. Pearson, CpG methylation modifies the genetic stability of cloned repeat sequences. Genome Res, 2002. 12(8): p. 1246-56.
57.Ehrlich, M., DNA hypomethylation in cancer cells. Epigenomics, 2009. 1(2): p. 239-59.
58.Mizuno, S., et al., Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood, 2001. 97(5): p. 1172-9.
59.Li, S., et al., DNA hypomethylation and imbalanced expression of DNA methyltransferases (DNMT1, 3A, and 3B) in human uterine leiomyoma. Gynecol Oncol, 2003. 90(1): p. 123-30.
60.Miremadi, A., et al., Cancer genetics of epigenetic genes. Hum Mol Genet, 2007. 16 Spec No 1: p. R28-49.
61.Hermann, A., R. Goyal, and A. Jeltsch, The Dnmt1 DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites. J Biol Chem, 2004. 279(46): p. 48350-9.
62.Bird, A., DNA methylation patterns and epigenetic memory. Genes Dev, 2002. 16(1): p. 6-21.
63.Klose, R.J. and A.P. Bird, Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci, 2006. 31(2): p. 89-97.
64.Goll, M.G., et al., Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science, 2006. 311(5759): p. 395-8.
65.Gao, Z., et al., Promoter demethylation of WIF-1 by epigallocatechin-3-gallate in lung cancer cells. Anticancer Res, 2009. 29(6): p. 2025-30.
66.Barreto, G., et al., Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature, 2007. 445(7128): p. 671-5.
67.Jin, S.G., C. Guo, and G.P. Pfeifer, GADD45A does not promote DNA demethylation. PLoS Genet, 2008. 4(3): p. e1000013.
68.Engel, N., et al., Conserved DNA methylation in Gadd45a(-/-) mice. Epigenetics, 2009. 4(2): p. 98-9.
69.Schafer, A., et al., Gemcitabine functions epigenetically by inhibiting repair mediated DNA demethylation. PLoS One, 2010. 5(11): p. e14060.
70.Schafer, A., et al., Ing1 functions in DNA demethylation by directing Gadd45a to H3K4me3. Genes Dev, 2013. 27(3): p. 261-73.
71.Chiba, T., et al., Cell growth inhibition and gene expression induced by the histone deacetylase inhibitor, trichostatin A, on human hepatoma cells. Oncology, 2004. 66(6): p. 481-91.
72.Choi, J.H., et al., TSA-induced DNMT1 down-regulation represses hTERT expression via recruiting CTCF into demethylated core promoter region of hTERT in HCT116. Biochem Biophys Res Commun, 2010. 391(1): p. 449-54.
73.江珮琪, 探討 CLIC4 於光動力致氧化壓力下之調控機制及其對細胞生物效應之影響 國立臺灣大學, 2013.
74.Boldrini, L., et al., Evaluation of telomerase mRNA (hTERT) in colon cancer. Int J Oncol, 2002. 21(3): p. 493-7.
75.Devereux, T.R., et al., DNA methylation analysis of the promoter region of the human telomerase reverse transcriptase (hTERT) gene. Cancer Res, 1999. 59(24): p. 6087-90.
76.Guilleret, I., et al., Hypermethylation of the human telomerase catalytic subunit (hTERT) gene correlates with telomerase activity. Int J Cancer, 2002. 101(4): p. 335-41.
77.Zinn, R.L., et al., hTERT is expressed in cancer cell lines despite promoter DNA methylation by preservation of unmethylated DNA and active chromatin around the transcription start site. Cancer Res, 2007. 67(1): p. 194-201.
78.Renaud, S., et al., Dual role of DNA methylation inside and outside of CTCF-binding regions in the transcriptional regulation of the telomerase hTERT gene. Nucleic Acids Res, 2007. 35(4): p. 1245-56.
79.Kyo, S., et al., Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers. Cancer Sci, 2008. 99(8): p. 1528-38.
80.Cong, Y.S. and S. Bacchetti, Histone deacetylation is involved in the transcriptional repression of hTERT in normal human cells. J Biol Chem, 2000. 275(46): p. 35665-8.
81.Takakura, M., et al., Telomerase activation by histone deacetylase inhibitor in normal cells. Nucleic Acids Res, 2001. 29(14): p. 3006-11.
82.Doetzlhofer, A., et al., Histone deacetylase 1 can repress transcription by binding to Sp1. Mol Cell Biol, 1999. 19(8): p. 5504-11.
83.Lobanenkov, V.V., et al., A novel sequence-specific DNA binding protein which interacts with three regularly spaced direct repeats of the CCCTC-motif in the 5''-flanking sequence of the chicken c-myc gene. Oncogene, 1990. 5(12): p. 1743-53.
84.Bell, A.C. and G. Felsenfeld, Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature, 2000. 405(6785): p. 482-5.
85.Hark, A.T., et al., CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature, 2000. 405(6785): p. 486-9.
86.Kanduri, C., et al., Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive. Curr Biol, 2000. 10(14): p. 853-6.
87.Vostrov, A.A. and W.W. Quitschke, The zinc finger protein CTCF binds to the APBbeta domain of the amyloid beta-protein precursor promoter. Evidence for a role in transcriptional activation. J Biol Chem, 1997. 272(52): p. 33353-9.
88.Kim, T.H., et al., Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell, 2007. 128(6): p. 1231-45.
89.Davalos-Salas, M., et al., Gain of DNA methylation is enhanced in the absence of CTCF at the human retinoblastoma gene promoter. BMC Cancer, 2011. 11: p. 232.
90.Shukla, S., et al., CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature, 2011. 479(7371): p. 74-9.
91.Lai, A.Y., et al., DNA methylation prevents CTCF-mediated silencing of the oncogene BCL6 in B cell lymphomas. J Exp Med, 2010. 207(9): p. 1939-50.
92.Filippova, G.N., et al., An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes. Mol Cell Biol, 1996. 16(6): p. 2802-13.
93.Arnold, R., et al., DNA bending by the silencer protein NeP1 is modulated by TR and RXR. Nucleic Acids Res, 1996. 24(14): p. 2640-7.
94.Bell, A.C., A.G. West, and G. Felsenfeld, The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell, 1999. 98(3): p. 387-96.
95.Vostrov, A.A., M.J. Taheny, and W.W. Quitschke, A region to the N-terminal side of the CTCF zinc finger domain is essential for activating transcription from the amyloid precursor protein promoter. J Biol Chem, 2002. 277(2): p. 1619-27.
96.Izumi, R., et al., Positive and negative regulatory elements for the expression of the Alzheimer''s disease amyloid precursor-encoding gene in mouse. Gene, 1992. 112(2): p. 189-95.
97.Chernak, J.M., Structural features of the 5'' upstream regulatory region of the gene encoding rat amyloid precursor protein. Gene, 1993. 133(2): p. 255-60.
98.Baniahmad, A., et al., Modular structure of a chicken lysozyme silencer: involvement of an unusual thyroid hormone receptor binding site. Cell, 1990. 61(3): p. 505-14.
99.Kohne, A.C., A. Baniahmad, and R. Renkawitz, NeP1. A ubiquitous transcription factor synergizes with v-ERBA in transcriptional silencing. J Mol Biol, 1993. 232(3): p. 747-55.
100.Filippova, G.N., et al., Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter tts DNA-binding specificity. Cancer Res, 2002. 62(1): p. 48-52.
101.Yeh, A., et al., Chromosome arm 16q in Wilms tumors: unbalanced chromosomal translocations, loss of heterozygosity, and assessment of the CTCF gene. Genes Chromosomes Cancer, 2002. 35(2): p. 156-63.
102.Chu, E.S. and C.M. Yow, Modulation of telomerase and signal transduction proteins by hexyl-ALA-photodynamic therapy (PDT) in human doxorubicin resistant cancer cell models. Photodiagnosis Photodyn Ther, 2012. 9(3): p. 243-55.
103.Chu, E.S., T.K. Wong, and C.M. Yow, Photodynamic effect in medulloblastoma: downregulation of matrix metalloproteinases and human telomerase reverse transcriptase expressions. Photochem Photobiol Sci, 2008. 7(1): p. 76-83.
104.Ngan, C.Y.L.M. and E.C.S. Meir, Modulation of COX2 and hTERT expression by Photodynamic Therapy in human colon cancer cells. Proceedings of SPIE, 2009. 7380: p. 738065-1-13.
105.Renaud, S., et al., CTCF binds the proximal exonic region of hTERT and inhibits its transcription. Nucleic Acids Res, 2005. 33(21): p. 6850-60.
106.Klenova, E.M., et al., CTCF, a conserved nuclear factor required for optimal transcriptional activity of the chicken c-myc gene, is an 11-Zn-finger protein differentially expressed in multiple forms. Mol Cell Biol, 1993. 13(12): p. 7612-24.
107.Micheli, E., et al., Selective G-quadruplex ligands: the significant role of side chain charge density in a series of perylene derivatives. Bioorg Med Chem Lett, 2009. 19(14): p. 3903-8.
108.Frees, S., et al., QGRS-Conserve: a computational method for discovering evolutionarily conserved G-quadruplex motifs. Hum Genomics, 2014. 8(1): p. 8.
109.Wang, Y. and D.J. Patel, Solution structure of the human telomeric repeat d[AG3(T2AG3)3] G-tetraplex. Structure, 1993. 1(4): p. 263-82.
110.Ambrus, A., et al., Human telomeric sequence forms a hybrid-type intramolecular G-quadruplex structure with mixed parallel/antiparallel strands in potassium solution. Nucleic Acids Res, 2006. 34(9): p. 2723-35.
111.Dolmans, D.E., D. Fukumura, and R.K. Jain, Photodynamic therapy for cancer. Nat Rev Cancer, 2003. 3(5): p. 380-7.
112.Jeltsch, A. and R.Z. Jurkowska, New concepts in DNA methylation. Trends Biochem Sci, 2014.
113.Subramaniam, D., et al., DNA methyltransferases: a novel target for prevention and therapy. Front Oncol, 2014. 4: p. 80.
114.Ou, J.N., et al., Histone deacetylase inhibitor Trichostatin A induces global and gene-specific DNA demethylation in human cancer cell lines. Biochem Pharmacol, 2007. 73(9): p. 1297-307.
115.Sui, X., et al., Epigenetic regulation of the human telomerase reverse transciptase gene: A potential therapeutic target for the treatment of leukemia (Review). Oncol Lett, 2013. 6(2): p. 317-322.
116.Mladenova, V., E. Mladenov, and G. Russev, Organization of Plasmid DNA into Nucleosome-Like Structures after Transfection in Eukaryotic Cells. Biotechnology &; Biotechnological Equipment, 2009. 23(1): p. 1044-1047.
117.Uhlen, M., et al., A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol Cell Proteomics, 2005. 4(12): p. 1920-32.
118.Halder, R., et al., Guanine quadruplex DNA structure restricts methylation of CpG dinucleotides genome-wide. Mol Biosyst, 2010. 6(12): p. 2439-47.
119.Guerrero-Bosagna, C., S. Weeks, and M.K. Skinner, Identification of genomic features in environmentally induced epigenetic transgenerational inherited sperm epimutations. PLoS One, 2014. 9(6): p. e100194.