Joseph Costello PhD
Associate Professor in Residence of Neurological Surgery
Karen Osney Brownstein Endowed Chair in Molecular Neuro-Oncology
Principal Investigator, Brain Tumor Research Center
Member, UCSF Helen Diller Family Comprehensive Cancer Center
Dr. Costello's laboratory investigates the role of genetic and epigenetic alterations in the development of sporadic cancers, with a focus on brain tumors. Most sporadic cancers have been described by molecular pathways involving gain and loss of chromosomal regions corresponding to oncogene activation and tumor suppressor gene inactivation, respectively. Such genetic characterizations of sporadic tumors do not take into account epigenetic alterations that may similarly result in abnormal loss or gain of gene activity. Methylation of cytosine in DNA is such a modification that can influence gene expression and chromosome stability. Although DNA methylation patterns can be significantly altered in human cancers, such changes are not detected by typical genetic screening methods.
The Costello lab uses a DNA fingerprinting technique termed Restriction Landmark Genomic Scanning (RLGS) to simultaneously assess the genetic and epigenetic (methylation) status of thousands of gene-associated CpG islands. Their studies have shown that in many human tumor types, the pattern of methylation of CpG island-containing genes is non-random and displays distinct tumor type-specificity. Further results suggested that there are a large number of genes in which methylation, rather than genetic alteration, is the primary mechanism of inactivation. These findings support the proposal that many potentially important cancer genes have remained undiscovered for decades due to the exclusively genetic screening methods used. It is now critically important to identify these genes to determine how the aberrant methylation contributes to malignancy.
Education, Training, and Previous Positions
- 1994: PhD, Loyola University
1994-1999: Postdoctoral Fellow, Ludwig Institute for Cancer Research, San Diego
2000-Present: Department of Neurological Surgery, UCSF
Selected Honors and Awards
- 2003: Board of Directors, Epigenetics Society
2005: Director, Epigenetics Division of the UCSF CCC Program in Cell Cycling and Signaling
2005: Karen Osney Brownstein Endowed Chair in Molecular Neuro-Oncology
2005: Human Epigenome Project
2006: Scientific Advisory Council, Brain Tumor Society
2006: External Advisory Board, University of Tokyo; UAB Heflin Center for Human Genetics
2007: International Epigenome Project (AHEAD), committee member
2008: Nature, Invited Reader Panelist
Selected Recent Publications
Ohi Y, Qin H, Hong C, Blouin L, Polo JM, Guo T, Qi Z, Downey SL, Manos PD, Rossi DJ, Yu J, Hebrok M, Hochedlinger K, Costello JF, Song JS, Ramalho-Santos M. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat Cell Biol 2011;13(5):541-9.
Leng S, Bernauer AM, Hong C, Do KC, Yingling CM, Flores KG, Tessema M, Tellez CS, Willink RP, Burki EA, Picchi MA, Stidley CA, Prados MD, Costello JF, Gilliland FD, Crowell RE, Belinsky SA. The A/G allele of rs16906252 predicts for MGMT methylation and is selectively silenced in premalignant lesions from smokers and in lung adenocarcinomas. Clin Cancer Res 2011;17(7):2014-23.
Harris RA, Wang T, Coarfa C, Nagarajan RP, Hong C, Downey SL, Johnson BE, Fouse SD, Delaney A, Zhao Y, Olshen A, Ballinger T, Zhou X, Forsberg KJ, Gu J, Echipare L, O'Geen H, Lister R, Pelizzola M, Xi Y, Epstein CB, Bernstein BE, Hawkins RD, Ren B, Chung WY, Gu H, Bock C, Gnirke A, Zhang MQ, Haussler D, Ecker JR, Li W, Farnham PJ, Waterland RA, Meissner A, Marra MA, Hirst M, Milosavljevic A, Costello JF. Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications. Nat Biotechnol 2010;28(10):1097-105.
Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A, Kellis M, Marra MA, Beaudet AL, Ecker JR, Farnham PJ, Hirst M, Lander ES, Mikkelsen TS, Thomson JA. The NIH Roadmap Epigenomics Mapping Consortium. Nat Biotechnol 2010;28(10):1045-8.
Blahnik KR, Dou L, Echipare L, Iyengar S, O'Geen H, Sanchez E, Zhao Y, Marra MA, Hirst M, Costello JF, Korf I, Farnham PJ. Characterization of the contradictory chromatin signatures at the 3' exons of zinc finger genes. PLoS One 2011;6(2):e17121.
Fouse SD, Nagarajan RP, Costello JF. Genome-scale DNA methylation analysis. Epigenomics 2010;2(1):105-117.
Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D'Souza C, Fouse SD, Johnson BE, Hong C, Nielsen C, Zhao Y, Turecki G, Delaney A, Varhol R, Thiessen N, Shchors K, Heine VM, Rowitch DH, Xing X, Fiore C, Schillebeeckx M, Jones SJ, Haussler D, Marra MA, Hirst M, Wang T, Costello JF. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 2010;466(7303):253-7.
Chen R, Nishimura MC, Bumbaca SM, Kharbanda S, Forrest WF, Kasman IM, Greve JM, Soriano RH, Gilmour LL, Rivers CS, Modrusan Z, Nacu S, Guerrero S, Edgar KA, Wallin JJ, Lamszus K, Westphal M, Heim S, James CD, VandenBerg SR, Costello JF, Moorefield S, Cowdrey CJ, Prados M, Phillips HS. A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell 2010;17(4):362-75.
Chim CS, Wong KY, Qi Y, Loong F, Lam WL, Wong LG, Jin DY, Costello JF, Liang R. Epigenetic inactivation of the miR-34a in hematological malignancies. Carcinogenesis 2010;31(4):745-50.
Costa BM, Smith JS, Chen Y, Chen J, Phillips HS, Aldape KD, Zardo G, Nigro J, James CD, Fridlyand J, Reis RM, Costello JF. Reversing HOXA9 oncogene activation by PI3K inhibition: epigenetic mechanism and prognostic significance in human glioblastoma. Cancer Res 2010;70(2):453-62.
Costello JF, Krzywinski M, Marra MA. A first look at entire human methylomes. Nat Biotechnol 2009;27(12):1130-2.
Fouse SD, Costello JF. Epigenetics of neurological cancers [Review]. Future Oncol 2009;5(10):1615-29.
Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, Vandenberg SR, Ginzinger DG, James CD, Costello JF, Bergers G, Weiss WA, Alvarez-Buylla A, Hodgson JG. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 2008;6:14.
Costello JF. Stem cells: Tips for priming potency. Nature 2008;454(7200):45-6.
Yi JM, Tsai HC, Glöckner SC, Lin S, Ohm JE, Easwaran H, James CD, Costello JF, Riggins G, Eberhart CG, Laterra J, Vescovi AL, Ahuja N, Herman JG, Schuebel KE, Baylin SB. Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors. Cancer Res 2008;68(19):8094-103.
Smith JF, Mahmood S, Song F, Morrow A, Smiraglia D, Zhang X, Rajput A, Higgins MJ, Krumm A, Petrelli NJ, Costello JF, Nagase H, Plass C, Held WA. Identification of DNA methylation in 3' genomic regions that are associated with upregulation of gene expression in colorectal cancer. Epigenetics 2007;2(3):161-72.
Carvalho LH, Smirnov I, Baia GS, Modrusan Z, Smith JS, Jun P, Costello JF, McDermott MW, Vandenberg SR, Lal A. Molecular signatures define two main classes of meningiomas. Mol Cancer 2007;6:64.
Brena RM, Costello JF. Genome-epigenome interactions in cancer [Review]. Hum Mol Genet 2007;16 Spec No 1:R96-105.
Hong C, Moorefield KS, Jun P, Aldape KD, Kharbanda S, Phillips HS, Costello JF. Epigenome scans and cancer genome sequencing converge on WNK2, a kinase-independent suppressor of cell growth. Proc Natl Acad Sci U S A. 2007;104(26):10974-9.
Brena RM, Plass C, Costello JF. Mining methylation for early detection of common cancers. PLoS Med 2006;3(12):e479.
Cadieux B, Ching TT, VandenBerg SR, Costello JF. Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. Cancer Res 2006;66(17):8469-76.
Reynolds PA, Sigaroudinia M, Zardo G, Wilson MB, Benton GM, Miller CJ, Hong C, Fridlyand J, Costello JF, Tlsty TD. Tumor suppressor p16INK4A regulates polycomb-mediated DNA hypermethylation in human mammary epithelial cells. J Biol Chem 2006;281(34):24790-802.
Smith JS, Costello JF. A broad band of silence. Nat Genet 2006;38(5):504-6.
Feltus FA, Lee EK, Costello JF, Plass C, Vertino PM. DNA motifs associated with aberrant CpG island methylation. Genomics 2006;87(5):572-9.