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» Epigenomics and genomics in normal, aging and cancer cells (DNA methylation and histone modifications; genome wide genetic changes)

» Basic mechanisms in epigenetics

» Tumor-suppressor genes

» Translational studies in cancer

» Pre-clinical and clinical research in epigenetic therapy

My laboratory is involved in both basic and translational research in the field of molecular epigenetics, which refers to stable gene expression states such as X-inactivation, imprinting etc. Specifically, we are interested in epigenetic mechanisms - a DNA modification termed DNA methylation that is commonly abnormal in aging tissues and in various malignancies; and histone modifications involved in determining gene expression states.

Current projects include:

» Large scale mapping of epigenomics patterns in normal, aging and cancer cells

» Investigating the causes of aberrant methylation in cancer, focusing on aging; genetic changes; a particular hypermethylator phenotype we described called CpG Island methylator phenotype; environmental exposures and familial predisposition

» Basic mechanisms governing the establishment of DNA methylation in normal and cancer cells

» Studying the causes and consequences of DNA methylation changes in normal aging tissues. Does reducing methylation prevent tumor formation and prolong lifespan?

» Clinical implications of methylation profiling in cancer. Can we identify subgroups with particular characteristics, prognosis, etc.?

» Clinical trials of drugs that affect histone modifications and DNA methylation are ongoing. Can we predict who will respond to the drugs? Can we make the therapy better? Does it work the way it is supposed to?

» Screens for drugs that affect epigenetics, alone or in synergy with current FDA approved molecules.

1. Jelinek J, Liang S, Lu Y, He R, Ramagli LS, Shpall EJ, Estecio MR, Issa JP, Conserved DNA methylation patterns in healthy blood cells and extensive changes in leukemia measured by a new quantitative technique. Epigenetics 7:12()2012 Oct 17. PubMed
2. Yamazaki J, Issa JP, Epigenetic aspects of MDS and its molecular targeted therapy. Int J Hematol :()2012 Oct 10. PubMed
3. Estécio MR, Gallegos J, Dekmezian M, Lu Y, Liang S, Issa JP, SINE Retrotransposons Cause Epigenetic Reprogramming of Adjacent Gene Promoters. Mol Cancer Res 10:10(1332-42)2012 Oct. PubMed
4. Ulrich CM, Toriola AT, Koepl LM, Sandifer T, Poole EM, Duggan C, McTiernan A, Issa JP, Metabolic, hormonal and immunological associations with global DNA methylation among postmenopausal women. Epigenetics 7:9(1020-8)2012 Sep 1. PubMed
5. Xu J, Shetty PB, Feng W, Chenault C, Bast RC Jr, Issa JP, Hilsenbeck SG, Yu Y, Methylation of HIN-1, RASSF1A, RIL and CDH13 in breast cancer is associated with clinical characteristics, but only RASSF1A methylation is associated with outcome. BMC Cancer 12:(243)2012 Jun 13. PubMed
6. Boumber Y, Kantarjian H, Jorgensen J, Wen S, Faderl S, Castoro R, Autry J, Garcia-Manero G, Borthakur G, Jabbour E, Estrov Z, Cortes J, Issa JP, Ravandi F, A randomized study of decitabine versus conventional care for maintenance therapy in patients with acute myeloid leukemia in complete remission. Leukemia 26:11(2428-31)2012 Nov. PubMed
7. Zhang Y, Shu J, Si J, Shen L, Estecio MR, Issa JP, Repetitive elements and enforced transcriptional repression co-operate to enhance DNA methylation spreading into a promoter CpG-island. Nucleic Acids Res 40:15(7257-68)2012 Aug. PubMed
8. Issa JP, DNA methylation as a clinical marker in oncology. J Clin Oncol 30:20(2566-8)2012 Jul 10. PubMed
9. Tsai HC, Li H, Van Neste L, Cai Y, Robert C, Rassool FV, Shin JJ, Harbom KM, Beaty R, Pappou E, Harris J, Yen RW, Ahuja N, Brock MV, Stearns V, Feller-Kopman D, Yarmus LB, Lin YC, Welm AL, Issa JP, Minn I, Matsui W, Jang YY, Sharkis SJ, Baylin SB, Zahnow CA, Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21:3(430-46)2012 Mar 20. PubMed
10. Yamazaki J, Taby R, Vasanthakumar A, Macrae T, Ostler KR, Shen L, Kantarjian HM, Estecio MR, Jelinek J, Godley LA, Issa JP, Effects of TET2 mutations on DNA methylation in chronic myelomonocytic leukemia. Epigenetics 7:2(201-7)2012 Feb. PubMed
11. Bhardwaj A, Song HW, Beildeck M, Kerkhofs S, Castoro R, Shanker S, De Gendt K, Suzuki K, Claessens F, Issa JP, Orgebin-Crist MC, Wilkinson MF, DNA demethylation-dependent AR recruitment and GATA factors drive Rhox5 homeobox gene transcription in the epididymis. Mol Endocrinol 26:4(538-49)2012 Apr. PubMed
12. Raynal NJ, Si J, Taby RF, Gharibyan V, Ahmed S, Jelinek J, Estécio MR, Issa JP, DNA methylation does not stably lock gene expression but instead serves as a molecular mark for gene silencing memory. Cancer Res 72:5(1170-81)2012 Mar 1. PubMed
13. Challen GA, Sun D, Jeong M, Luo M, Jelinek J, Berg JS, Bock C, Vasanthakumar A, Gu H, Xi Y, Liang S, Lu Y, Darlington GJ, Meissner A, Issa JP, Godley LA, Li W, Goodell MA, Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 44:1(23-31)2011 Dec 4. PubMed
14. Konishi K, Watanabe Y, Shen L, Guo Y, Castoro RJ, Kondo K, Chung W, Ahmed S, Jelinek J, Boumber YA, Estecio MR, Maegawa S, Kondo Y, Itoh F, Imawari M, Hamilton SR, Issa JP, DNA methylation profiles of primary colorectal carcinoma and matched liver metastasis. PLoS One 6:11(e27889)2011. PubMed
15. Qin T, Castoro R, El Ahdab S, Jelinek J, Wang X, Si J, Shu J, He R, Zhang N, Chung W, Kantarjian HM, Issa JP, Mechanisms of resistance to decitabine in the myelodysplastic syndrome. PLoS One 6:8(e23372)2011. PubMed
16. Watanabe Y, Castoro RJ, Kim HS, North B, Oikawa R, Hiraishi T, Ahmed SS, Chung W, Cho MY, Toyota M, Itoh F, Estecio MR, Shen L, Jelinek J, Issa JP, Frequent alteration of MLL3 frameshift mutations in microsatellite deficient colorectal cancer. PLoS One 6:8(e23320)2011. PubMed
17. Issa JP, Epigenetic variation and cellular Darwinism. Nat Genet 43:8(724-6)2011 Jul 27. PubMed
18. Jelinek J, Gharibyan V, Estecio MR, Kondo K, He R, Chung W, Lu Y, Zhang N, Liang S, Kantarjian HM, Cortes JE, Issa JP, Aberrant DNA methylation is associated with disease progression, resistance to imatinib and shortened survival in chronic myelogenous leukemia. PLoS One 6:7(e22110)2011. PubMed
19. Issa JP, Just W, Epigenetics. FEBS Lett 585:13(1993)2011 Jul 7. PubMed
20. Chung W, Bondaruk J, Jelinek J, Lotan Y, Liang S, Czerniak B, Issa JP, Detection of bladder cancer using novel DNA methylation biomarkers in urine sediments. Cancer Epidemiol Biomarkers Prev 20:7(1483-91)2011 Jul. PubMed
21. Boumber Y, Issa JP, Epigenetics in cancer: what's the future? Oncology (Williston Park) 25:3(220-6, 228)2011 Mar. PubMed
22. Ahn JB, Chung WB, Maeda O, Shin SJ, Kim HS, Chung HC, Kim NK, Issa JP, DNA methylation predicts recurrence from resected stage III proximal colon cancer. Cancer 117:9(1847-54)2011 May 1. PubMed
23. Pathiraja TN, Shetty PB, Jelinek J, He R, Hartmaier R, Margossian AL, Hilsenbeck SG, Issa JP, Oesterreich S, Progesterone receptor isoform-specific promoter methylation: association of PRA promoter methylation with worse outcome in breast cancer patients. Clin Cancer Res 17:12(4177-86)2011 Jun 15. PubMed
24. Cogdell D, Chung W, Liu Y, McDonald JM, Aldape K, Issa JP, Fuller GN, Zhang W, Tumor-associated methylation of the putative tumor suppressor AJAP1 gene and association between decreased AJAP1 expression and shorter survival in patients with glioma. Chin J Cancer 30:4(247-53)2011 Apr. PubMed
25. Fini L, Piazzi G, Daoud Y, Selgrad M, Maegawa S, Garcia M, Fogliano V, Romano M, Graziani G, Vitaglione P, Carmack SW, Gasbarrini A, Genta RM, Issa JP, Boland CR, Ricciardiello L, Chemoprevention of intestinal polyps in ApcMin/+ mice fed with western or balanced diets by drinking annurca apple polyphenol extract. Cancer Prev Res (Phila) 4:6(907-15)2011 Jun. PubMed
26. Spannhoff A, Kim YK, Raynal NJ, Gharibyan V, Su MB, Zhou YY, Li J, Castellano S, Sbardella G, Issa JP, Bedford MT, Histone deacetylase inhibitor activity in royal jelly might facilitate caste switching in bees. EMBO Rep 12:3(238-43)2011 Mar. PubMed
27. Issa JP, Garber JE, Time to think outside the (genetic) box. Cancer Prev Res (Phila) 4:1(6-8)2011 Jan. PubMed
28. Wallace K, Grau MV, Levine AJ, Shen L, Hamdan R, Chen X, Gui J, Haile RW, Barry EL, Ahnen D, McKeown-Eyssen G, Baron JA, Issa JP, Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa. Cancer Prev Res (Phila) 3:12(1552-64)2010 Dec. PubMed
29. Estécio MR, Issa JP, Dissecting DNA hypermethylation in cancer. FEBS Lett 585:13(2078-86)2011 Jul 7. PubMed
30. Taby R, Issa JP, Cancer epigenetics. CA Cancer J Clin 60:6(376-92)2010 Nov-Dec. PubMed
31. Mahlknecht U, Issa JP, Introductory editorial. Clin Epigenetics 1:1-2(1)2010 Sep. PubMed
32. Estécio MR, Gallegos J, Vallot C, Castoro RJ, Chung W, Maegawa S, Oki Y, Kondo Y, Jelinek J, Shen L, Hartung H, Aplan PD, Czerniak BA, Liang S, Issa JP, Genome architecture marked by retrotransposons modulates predisposition to DNA methylation in cancer. Genome Res 20:10(1369-82)2010 Oct. PubMed
33. Si J, Boumber YA, Shu J, Qin T, Ahmed S, He R, Jelinek J, Issa JP, Chromatin remodeling is required for gene reactivation after decitabine-mediated DNA hypomethylation. Cancer Res 70:17(6968-77)2010 Sep 1. PubMed
34. Kondo Y, Issa JP, DNA methylation profiling in cancer. Expert Rev Mol Med 12:(e23)2010 Jul 28. PubMed
35. Bryan J, Jabbour E, Prescott H, Garcia-Manero G, Issa JP, Kantarjian H, Current and future management options for myelodysplastic syndromes. Drugs 70:11(1381-94)2010 Jul 30. PubMed
36. Kwabi-Addo B, Wang S, Chung W, Jelinek J, Patierno SR, Wang BD, Andrawis R, Lee NH, Apprey V, Issa JP, Ittmann M, Identification of differentially methylated genes in normal prostate tissues from African American and Caucasian men. Clin Cancer Res 16:14(3539-47)2010 Jul 15. PubMed
37. Jabbour E, Garcia-Manero G, Batty N, Shan J, O'Brien S, Cortes J, Ravandi F, Issa JP, Kantarjian H, Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer 116:16(3830-4)2010 Aug 15. PubMed
38. Batty GN, Kantarjian H, Issa JP, Jabbour E, Santos FP, McCue D, Garcia-Manero G, Pierce S, O'Brien S, Cortés JE, Ravandi F, Feasibility of therapy with hypomethylating agents in patients with renal insufficiency. Clin Lymphoma Myeloma Leuk 10:3(205-10)2010 Jun. PubMed
39. Issa JP, Epigenetic changes in the myelodysplastic syndrome. Hematol Oncol Clin North Am 24:2(317-30)2010 Apr. PubMed
40. Cleyrat C, Jelinek J, Girodon F, Boissinot M, Ponge T, Harousseau JL, Issa JP, Hermouet S, JAK2 mutation and disease phenotype: a double L611V/V617F in cis mutation of JAK2 is associated with isolated erythrocytosis and increased activation of AKT and ERK1/2 rather than STAT5. Leukemia 24:5(1069-73)2010 May. PubMed
41. Cecílio FA, Regalo SC, Palinkas M, Issa JP, Siéssere S, Hallak JE, Machado-de-Sousa JP, Semprini M, Ageing and surface EMG activity patterns of masticatory muscles. J Oral Rehabil 37:4(248-55)2010 Apr. PubMed
42. An B, Kondo Y, Okamoto Y, Shinjo K, Kanemitsu Y, Komori K, Hirai T, Sawaki A, Tajika M, Nakamura T, Yamao K, Yatabe Y, Fujii M, Murakami H, Osada H, Tani T, Matsuo K, Shen L, Issa JP, Sekido Y, Characteristic methylation profile in CpG island methylator phenotype-negative distal colorectal cancers. Int J Cancer 127:9(2095-105)2010 Nov 1. PubMed
43. Maegawa S, Hinkal G, Kim HS, Shen L, Zhang L, Zhang J, Zhang N, Liang S, Donehower LA, Issa JP, Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res 20:3(332-40)2010 Mar. PubMed
44. Shen L, Kantarjian H, Guo Y, Lin E, Shan J, Huang X, Berry D, Ahmed S, Zhu W, Pierce S, Kondo Y, Oki Y, Jelinek J, Saba H, Estey E, Issa JP, DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol 28:4(605-13)2010 Feb 1. PubMed
45. Borthakur G, Huang X, Kantarjian H, Faderl S, Ravandi F, Ferrajoli A, Torma R, Morris G, Berry D, Issa JP, Report of a phase 1/2 study of a combination of azacitidine and cytarabine in acute myelogenous leukemia and high-risk myelodysplastic syndromes. Leuk Lymphoma 51:1(73-8)2010 Jan. PubMed
46. Santos FP, Kantarjian H, Garcia-Manero G, Issa JP, Ravandi F, Decitabine in the treatment of myelodysplastic syndromes. Expert Rev Anticancer Ther 10:1(9-22)2010 Jan. PubMed
47. Liang S, Lu Y, Jelinek J, Estecio M, Li H, Issa JP, Analysis of epigenetic modifications by next generation sequencing. Conf Proc IEEE Eng Med Biol Soc 2009:(6730)2009. PubMed
48. Estécio MR, Issa JP, Tackling the methylome: recent methodological advances in genome-wide methylation profiling. Genome Med 1:11(106)2009 Nov 16. PubMed