Jinhua Wang, Ph.D.

EPIGENETIC REPROGRAMMING ENDOWS CHEMOSENSITIVITY IN LEUKEMIA CELL LINES
Bhatla, Teena; Wang, Jinhua; Morrison, Debra; Raetz, Elizabeth; Carroll, William
2011 JUN ;56(6):900-900, Pediatric blood & cancer
— id: 129014, year: 2011, vol: 56, page: 900, stat: Journal Article,

Association of overexpression of TIF1gamma with colorectal carcinogenesis and advanced colorectal adenocarcinoma
Jain, Shilpa; Singhal, Shashideep; Francis, Franto; Hajdu, Cristina; Wang, Jin-Hua; Suriawinata, Arief; Wang, Yin-Quan; Zhang, Miao; Weinshel, Elizabeth H; Francois, Fritz; Pei, Zhi-Heng; Lee, Peng; Xu, Ru-Liang
2011 Sep 21;17(35):3994-4000, World journal of gastroenterology : WJG
AIM: To determine the expression and clinical significance of transcriptional intermediary factor 1 gamma (TIF1gamma), Smad4 and transforming growth factor-beta (TGFbetaR) across a spectrum representing colorectal cancer (CRC) development. METHODS: Tissue microarrays were prepared from archival paraffin embedded tissue, including 51 colorectal carcinomas, 25 tubular adenomas (TA) and 26 HPs, each with matched normal colonic epithelium. Immunohistochemistry was performed using antibodies against TIF1gamma, Smad4 and TGFbetaRII. The levels of expression were scored semi-quantitatively (score 0-3 or loss and retention for Smad4). RESULTS: Overexpression of TIF1gamma was detected in 5/26 (19%) HP; however, it was seen in a significantly higher proportion of neoplasms, 15/25 (60%) TAs and 24/51 (47%) CRCs (P < 0.05). Normal colonic mucosa, HP, and TAs showed strong Smad4 expression, while its expression was absent in 22/51 (43%) CRCs. Overexpression of TGFbetaRII was more commonly seen in neoplasms, 13/25 (52%) TAs and 29/51 (57%) CRCs compared to 9/26 (35%) HP (P < 0.05). Furthermore, there was a correlation between TIF1gamma overexpression and Smad4 loss in CRC (Kendall tau rank correlation value = 0.35, P < 0.05). The levels of TIF1gamma overexpression were significantly higher in stage III than in stage I and II CRC (P < 0.05). CONCLUSION: The findings suggest that over-expression of TIF1gamma occurs in early stages of colorectal carcinogenesis, is inversely related with Smad4 loss, and may be a prognostic indicator for poor outcome
— id: 140416, year: 2011, vol: 17, page: 3994, stat: Journal Article,

Natura-Alpha Targets Forkhead Box M1 and Inhibits Androgen-Dependent and -Independent Prostate Cancer Growth and Invasion
Lee P; Li Y; Ligr M; McCarron J; Daniels G; Zhang D; Zhao X; Ye F; Wang J; Liu X; Osman I; Mencher S; Lepor H; Wang LG
2011 Jul 1;17(13):4414-4424, Clinical cancer research
PURPOSE: The development of new effective therapeutic agents with minimal side effects for prostate cancer treatment is much needed. Indirubin, an active molecule identified in the traditional Chinese herbal medicine - Qing Dai (Indigo Naturalis), has been used to treat leukemia for decades. However, the anti-cancer properties of Natura-alpha, an indirubin derivative, are not well studied in solid tumors, particularly in prostate cancer.EXPERIMENTAL DESIGN: Human prostate cancer cell lines were treated with or without Natura-alpha followed by cell growth and invasion assays measured. The anti-tumor effects of Natura-alpha were examined in nude mice tumor xenograft models, as well as in a patient with advanced hormone refractory metastatic prostate cancer. Signal network proteins targeted by Natura-alpha were analyzed using Proteomic Pathway Array Analysis (PPAA) on xenografts.RESULTS: Natura-alpha inhibited the growth of both androgen-dependent (LNCaP), and androgen-independent (LNCaP-AI, PC-3, and DU145) prostate cancer cells with IC50 between 4 to 10 Mum, also inhibits invasion of androgen-independent prostate cancer cells. Its anti-tumor effects were further evident in vivo tumor reduction in androgen-dependent and -independent nude mice tumor xenograft models as well as reduced tumor volume in the patient with hormone refractory metastatic prostate cancer. PPAA revealed that anti-proliferative and anti-invasive activities of Natura-alpha on prostate cancer might primarily be through its down-regulation of Forkhead box M1 (FOXM1) protein. Forced over-expression of FOXM1 largely reversed the inhibition by Natura-alpha.CONCLUSIONS: Natura-alpha could serve as a novel and effective therapeutic agent for treatment of both hormone sensitive and hormone refractory prostate cancer with minimal side effects
— id: 133174, year: 2011, vol: 17, page: 4414, stat: Journal Article,

Histologic characteristics of pancreatic intraepithelial neoplasia associated with different pancreatic lesions
Recavarren, Claudia; Labow, Daniel M; Liang, John; Zhang, Lanjing; Wong, Melisa; Zhu, Hongfa; Wang, Jinhua; Francis, Franto; Xu, Ruliang
2011 Jan;42(1):18-24, Human pathology
Pancreatic intraepithelial neoplasia (PanIN) has been found in association with pancreatic ductal adenocarcinoma, intraductal papillary-mucinous neoplasm (IPMN), mucinous cystic neoplasm, and other pancreatic lesions, but the characteristics of PanINs associated with these lesions are not well characterized. In this study, 185 partial or total pancreatectomy specimens were collected, and 173 had complete slides for reviewed, which included 74 pancreatic ductal adenocarcinomas, 28 IPMNs, 7 mucinous cystic neoplasms, 44 other nonductal tumors, and 20 nontumorous lesions. Differences in grade, extent, and duct involvement among PanINs associated with different lesions were analyzed. Patients with PanINs were older than those without, regardless of associated tumor or lesions. No sex predilection was noted. PanINs were found in 89%, 96%, 86%, 64%, and 55% pancreata with ductal adenocarcinomas, IPMNs, mucinous cystic neoplasm, other nonductal tumors, and nontumorous lesions, respectively. PanIN 1 and 2 were commonly associated with all types of lesions, but high-grade PanIN 3 was more frequently associated with ductal adenocarcinomas. Ductal involvement of PanINs was more extensive in association with ductal adenocarcinomas than in any other types of pancreatic tumors or lesions. PanINs associated with pancreatic ductal adenocarcinomas affected both the main and branched ducts, whereas PanINs associated with other types of pancreatic tumors or lesions were mainly present in the branch ducts. No statistical differences were observed in distribution, extent, and grade of PanINs among IPMNs, mucinous cystic neoplasms, other nonductal tumors, and nontumorous lesions. Our study demonstrated a high concurrence between PanINs and other precancerous lesions and histologic features of PanINs associated with different pancreatic diseases
— id: 134195, year: 2011, vol: 42, page: 18, stat: Journal Article,

Integrative genomics identifies molecular alterations that challenge the linear model of melanoma progression
Rose AE; Poliseno L; Wang J; Clark M; Pearlman A; Wang G; Vega Y Saenz de Miera EC; Medicherla R; Christos PJ; Shapiro RL; Pavlick AC; Darvishian F; Zavadil J; Polsky D; Hernando E; Ostrer H; Osman I
2011 Apr 1;71(7):2561-2571, Cancer research
Superficial spreading melanoma (SSM) and nodular melanoma (NM) are believed to represent sequential phases of linear progression from radial to vertical growth. Several lines of clinical, pathological and epidemiologic evidence suggest, however, that SSM and NM might be the result of independent pathways of tumor development. We utilized an integrative genomic approach that combines single nucleotide polymorphism array (SNP 6.0, Affymetrix) with gene expression array (U133A 2.0, Affymetrix) to examine molecular differences between SSM and NM. Pathway analysis of the most differentially expressed genes between SSM and NM (N=114) revealed significant differences related to metabolic processes. We identified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, ZNF668) in which NM/SSM-specific copy number alterations correlated with differential gene expression (P<0.05, Spearman's rank). SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two external data sets. Forced overexpression of metabolism-related gene methylthioadenosine phosphorylase (MTAP) in SSM resulted in reduced cell growth. The differential expression of another metabolic related gene, aldehyde dehydrogenase 7A1 (ALDH7A1), was validated at the protein level using tissue microarrays of human melanoma. In addition, we show that the decreased ALDH7A1 expression in SSM may be the result of epigenetic modifications. Our data reveal recurrent genomic deletions in SSM not present in NM, which challenge the linear model of melanoma progression. Furthermore, our data suggest a role for altered regulation of metabolism-related genes as a possible cause of the different clinical behavior of SSM and NM
— id: 124135, year: 2011, vol: 71, page: 2561, stat: Journal Article,

Vorinostat Reverses Relapse Specific Drug Resistance Gene Expression Signatures In Childhood Acute Lymphoblastic Leukemia (ALL)
Bhatla, Teena; Wang, Jinhua; Morrison, Debra J.; Zaky, Wafik T.; Raetz, Elizabeth A.; Carroll, William L.
2010 NOV 19 ;116(21):1493-1494, Blood
— id: 130870, year: 2010, vol: 116, page: 1493, stat: Journal Article,

GENE EXPRESSION ANALYSIS REVEALS DISTINCT SIGNATURES FOR EARLY AND LATE RELAPSE IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
Hogan, L; Meyer, J; Wang, JH; Morrison, D; Yang, J; Hunger, S; Willman, C; Relling, M; Raetz, E; Bhojwani, D; Carroll, W
2010 JUN ;54(6):790-791, Pediatric blood & cancer
— id: 110438, year: 2010, vol: 54, page: 790, stat: Journal Article,

Overexpression of Transcription Intermediary Factor 1 gamma(TIF1 gamma) Is an Early Event in Colorectal Carcinogenesis and Inversely Related to Smad4 Inactivation in Colorectal Carcinoma
Jain, S; Yu, M; Singhal, S; Francis, F; Hajdu, C; Suriawinata, S; Zhang, M; Aladhamy, N; Chiriboga, L; Pan, R; Lee, P; Wang, J; Xu, R
2010 FEB ;23(3):149A-149A, Modern pathology
— id: 109933, year: 2010, vol: 23, page: 149A, stat: Journal Article,

Overexpression of Transcription Intermediary Factor 1 gamma(TIF1 gamma) Is an Early Event in Colorectal Carcinogenesis and Inversely Related to Smad4 Inactivation in Colorectal Carcinoma
Jain, S; Yu, M; Singhal, S; Francis, F; Hajdu, C; Suriawinata, S; Zhang, M; Aladhamy, N; Chiriboga, L; Pan, R; Lee, P; Wang, J; Xu, R
2010 FEB ;90(11):149A-149A, Laboratory investigation
— id: 109952, year: 2010, vol: 90, page: 149A, stat: Journal Article,

Higher Expression of Serine-213 Phosphorylated Androgen Receptor Level Is Associated With Prostate Cancer Recurrence
Jain, Shilpa; Ruoff, Rachael; Ha, Susan; Melamed, Jonathan; Wang, Jinhua; Ren, Qinghu; Lee, Peng; Logan, Susan
2010 OCT ;134(4):674-674, American journal of clinical pathology
— id: 113734, year: 2010, vol: 134, page: 674, stat: Journal Article,

The Expression of the Androgen Receptor Coactivator P44 in Proliferative Inflammatory Atrophy
Kabiawu, OE; Melamed, J; Yu, M; Wang, J; Jain, S; Aladhamy, N; Wang, Z; Lee, P
2010 FEB ;23(3):199A-199A, Modern pathology
— id: 109935, year: 2010, vol: 23, page: 199A, stat: Journal Article,

The Expression of the Androgen Receptor Coactivator P44 in Proliferative Inflammatory Atrophy
Kabiawu, OE; Melamed, J; Yu, M; Wang, J; Jain, S; Aladhamy, N; Wang, Z; Lee, P
2010 FEB ;90(11):199A-199A, Laboratory investigation
— id: 109954, year: 2010, vol: 90, page: 199A, stat: Journal Article,

Tumor Suppressor Function of Androgen Receptor Coactivator ARA70{alpha} in Prostate Cancer
Ligr, Martin; Li, Yirong; Zou, Xuanyi; Daniels, Garrett; Melamed, Jonathan; Peng, Yi; Wang, Wei; Wang, Jinhua; Ostrer, Harry; Pagano, Michele; Wang, Zhengxin; Garabedian, Michael J; Lee, Peng
2010 Apr;176(4):1891-1900, American journal of pathology
Androgen receptor (AR), a member of the steroid receptor family, is a transcription factor that has an important role in the regulation of both prostate cell proliferation and growth suppression. AR coactivators may influence the transition between cell growth and growth suppression. We have shown previously that the internally spliced ARA70 isoform, ARA70beta, promotes prostate cancer cell growth and invasion. Here we report that the full length ARA70alpha, in contrast, represses prostate cancer cell proliferation and anchorage-independent growth in vitro and inhibits tumor growth in nude mice xenograft experiments in vivo. Further, the growth inhibition by ARA70alpha is AR-dependent and mediated through induction of apoptosis rather than cell cycle arrest. Interestingly, AR with T877A mutation in LNCaP cells decreased its physical and functional interaction with ARA70alpha, facilitating the growth of LNCaP cells. This is consistent with our previous findings that ARA70alpha expression is decreased in prostate cancer cells compared with benign prostate. ARA70alpha also reduced the invasion ability of LNCaP cells. Although growth inhibition by ARA70alpha is AR-dependent, the inhibition of cell invasion is an androgen-independent process. These results strongly suggest that ARA70alpha functions as a tumor suppressor gene
— id: 107298, year: 2010, vol: 176, page: 1891, stat: Journal Article,

High Throughput Transcriptome Sequencing of Pediatric Relapsed Acute Lymphoblastic Leukemia (ALL) Identifies Relapse Specific Mutations and Expression
Meyer, Julia A.; Hogan, Laura E.; Wang, Jinhua; Yang, Jun J.; Patel, Jay; Levine, Ross L.; Hunger, Stephen P.; Raetz, Elizabeth; Mason, Christopher; Carroll, William L.
2010 NOV 19 ;116(21):1326-1326, Blood
— id: 130868, year: 2010, vol: 116, page: 1326, stat: Journal Article,

Reducing SAR and enhancing cerebral signal-to-noise ratio with high permittivity padding at 3 T
Yang QX; Wang J; Wang J; Collins CM; Wang C; Smith MB
2010 Nov 30;:?-?, Magnetic resonance in medicine
Previous works have shown that placement of a high-dielectric pad can improve image intensity in a region adjacent to the pad, or that placement of dielectric pads around a large surface of the head can improve image homogeneity on an entire plane through the head in high-field MRI. Here, experimental results show that use of high-dielectric pads around the human head can reduce the required input radiofrequency power by 50% while enhancing image signal-to-noise ratio by 20-40% throughout the cerebrum at 3 T. Thus, dielectric pads may be used to provide a relatively simple and low-cost method for improving quality and safety of MRI in a variety of applications at 3 T. Magn Reson Med, 2010. (c) 2010 Wiley-Liss, Inc
— id: 148973, year: 2010, vol: , page: ?, stat: Journal Article,

IKAROS DELETION LEADS TO CHEMOTHERAPY RESISTANCE IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA
Zaky, W; Chen, Z; Meyer, J; Bhatla, T; Yang, J; Relling, M; Yang, WJ; Wang, JH; Morrison, D; Raetz, E; Carroll, W
2010 JUN ;54(6):789-789, Pediatric blood & cancer
— id: 110437, year: 2010, vol: 54, page: 789, stat: Journal Article,

The Expression of GPR 30, a G Protein-Coupled Receptor, in Prostate Cancer
Zhang, M; Lam, HM; Yu, MQ; Wang, JH; Ouyang, B; Jain, S; Daniels, G; Reuter, V; Gopalan, A; Osman, I; Lee, P; Ho, SM
2010 FEB ;23(3):231A-231A, Modern pathology
— id: 109938, year: 2010, vol: 23, page: 231A, stat: Journal Article,

The Expression of GPR 30, a G Protein-Coupled Receptor, in Prostate Cancer
Zhang, M; Lam, HM; Yu, MQ; Wang, JH; Ouyang, B; Jain, S; Daniels, G; Reuter, V; Gopalan, A; Osman, I; Lee, P; Ho, SM
2010 FEB ;90(11):231A-231A, Laboratory investigation
— id: 109957, year: 2010, vol: 90, page: 231A, stat: Journal Article,

Up-Regulation of Genes Involved in Folate Metabolism Characterize Late but Not Early Relapse in Childhood Acute Lymphoblastic Leukemia
Hogan, L; Bhojwani, D; Wang, JH; Morrison, D; Yang, JJ; Zhang, YT; Zavadil, J; Condos, G; Hunger, SP; Willman, CL; Relling, MV; Raetz, E; Carroll, WL
2009 NOV 20 ;114(22):689-690, Blood
— id: 109987, year: 2009, vol: 114, page: 689, stat: Journal Article,

(PLATFORM 302C) ANTISENSE TECHNOLOGY TARGETING AN ANTI-APOPTOTIC GENE IMPROVES LEUKEMIC CELL DEATH IN ALL CELL LINES AND MICE
Hogan, LE; Teachey, DT; Germino, N; Moskowitz, N; Condos, G; Belitskaya-Levy, H; Wang, JH; Bhojwani, D; Horton, TM; Sapra, P; Horak, I; Raetz, E; Grupp, SA; Carroll, W; Morrison, D
2009 JUN ;52(6):695-695, Pediatric blood & cancer
— id: 97794, year: 2009, vol: 52, page: 695, stat: Journal Article,

Gene Expression Profiling in Down Syndrome Acute Lymphoblastic Leukemia Identifies Distinct Profiles Associated with CRLF2 Expression Status
Rabin, KR; Wang, JH; Meyer, J; Loudin, MG; Bhojwani, D; Morrison, D; Heerema, NA; Carroll, AJ; Pession, A; Basso, G; Mullighan, CG; Hunger, SP; Carroll, WL
2009 NOV 20 ;114(22):943-943, Blood
— id: 109990, year: 2009, vol: 114, page: 943, stat: Journal Article,

Identification of pax6-dependent gene regulatory networks in the mouse lens
Wolf, Louise V; Yang, Ying; Wang, Jinhua; Xie, Qing; Braunger, Barbara; Tamm, Ernst R; Zavadil, Jiri; Cvekl, Ales
2009 ;4(1):e4159-e4159, PLoS ONE
Lineage-specific DNA-binding transcription factors regulate development by activating and repressing particular set of genes required for the acquisition of a specific cell type. Pax6 is a paired domain and homeodomain-containing transcription factor essential for development of central nervous, olfactory and visual systems, as well as endocrine pancreas. Haploinsufficiency of Pax6 results in perturbed lens development and homeostasis. Loss-of-function of Pax6 is incompatible with lens lineage formation and results in abnormal telencephalic development. Using DNA microarrays, we have identified 559 genes expressed differentially between 1-day old mouse Pax6 heterozygous and wild type lenses. Of these, 178 (31.8%) were similarly increased and decreased in Pax6 homozygous embryonic telencephalon [Holm PC, Mader MT, Haubst N, Wizenmann A, Sigvardsson M, Gotz M (2007) Loss- and gain-of-function analyses reveals targets of Pax6 in the developing mouse telencephalon. Mol Cell Neurosci 34: 99-119]. In contrast, 381 (68.2%) genes were differently regulated between the lens and embryonic telencephalon. Differential expression of nine genes implicated in lens development and homeostasis: Cspg2, Igfbp5, Mab21l2, Nrf2f, Olfm3, Spag5, Spock1, Spon1 and Tgfb2, was confirmed by quantitative RT-PCR, with five of these genes: Cspg2, Mab21l2, Olfm3, Spag5 and Tgfb2, identified as candidate direct Pax6 target genes by quantitative chromatin immunoprecipitation (qChIP). In Mab21l2 and Tgfb2 promoter regions, twelve putative individual Pax6-binding sites were tested by electrophoretic mobility shift assays (EMSAs) with recombinant Pax6 proteins. This led to the identification of two and three sites in the respective Mab21l2 and Tgfb2 promoter regions identified by qChIPs. Collectively, the present studies represent an integrative genome-wide approach to identify downstream networks controlled by Pax6 that control mouse lens and forebrain development
— id: 94110, year: 2009, vol: 4, page: e4159, stat: Journal Article,

Proteomics, Pathway Array and Signaling Network-Based Medicine in Cancer
Zhang, David Y; Ye, Fei; Gao, Ling; Liu, Xiaoliang; Zhao, Xin; Che, Yufang; Wang, Hongxia; Wang, Libo; Wu, Josephine; Song, Dong; Liu, Wei; Xu, Hong; Jiang, Bo; Zhang, Weijia; Wang, Jinhua; Lee, Peng
2009 Oct 28;4(1):20-20, Cell division
ABSTRACT: Cancer is a multifaceted disease that results from dysregulated normal cellular signaling networks caused by genetic, genomic and epigenetic alterations at cell or tissue levels. Uncovering the underlying protein signaling network changes, including cell cycle gene networks in cancer, aids in understanding the molecular mechanism of carcinogenesis and identifies the characteristic signaling network signatures unique for different cancers and specific cancer subtypes. The identified signatures can be used for cancer diagnosis, prognosis, and personalized treatment. During the past several decades, the available technology to study signaling networks has significantly evolved to include such platforms as genomic microarray (expression array, SNP array, CGH array, etc.) and proteomic analysis, which globally assesses genetic, epigenetic, and proteomic alterations in cancer. In this review, we compared Pathway Array analysis with other proteomic approaches in analyzing protein network involved in cancer and its utility serving as cancer biomarkers in diagnosis, prognosis and therapeutic target identification. With the advent of bioinformatics, constructing high complexity signaling networks is possible. As the use of signaling network-based cancer diagnosis, prognosis and treatment is anticipated in the near future, medical and scientific communities should be prepared to apply these techniques to further enhance personalized medicine
— id: 104874, year: 2009, vol: 4, page: 20, stat: Journal Article,

Evolution of Gene Expression Signatures in Relapsed Childhood Acute Lymphoblastic Leukemia Differs Based on Timing of Relapse
Bhojwani, D; Wang, J; Yang, JJ; Morrison, D; Devidas, M; Raetz, E; Hunger, SP; Relling, MV; Carroll, WL
2008 NOV 16 ;112(11):1149-1149, Blood
— id: 93293, year: 2008, vol: 112, page: 1149, stat: Journal Article,

Gene Expression Profiling Differentiates Childhood Acute Lymphoblastic Leukemia in Down Syndrome Versus Non-Down Syndrome Patients
Rabin, KR; Wang, JH; Tsimelzon, A; Morrison, D; Gaikwad, AS; Hogan, L; Rye, CL; Hilsenbeck, SG; Devidas, M; Heerema, NA; Carroll, AJ; Basso, G; Carroll, WL; Pession, A; Bhojwani, D
2008 NOV 16 ;112(11):438-439, Blood
— id: 93287, year: 2008, vol: 112, page: 438, stat: Journal Article,

A role for mammalian Sin3 in permanent gene silencing
van Oevelen, Chris; Wang, Jinhua; Asp, Patrik; Yan, Qin; Kaelin, William G Jr; Kluger, Yuval; Dynlacht, Brian David
2008 Nov 7;32(3):359-370, Molecular cell
The multisubunit Sin3 corepressor complex regulates gene transcription through deacetylation of nucleosomes. However, the full range of Sin3 activities and targets is not well understood. Here, we have investigated genome-wide binding of mouse Sin3 and RBP2 as well as histone modifications and nucleosome positioning as a function of myogenic differentiation. Remarkably, we find that Sin3 complexes spread immediately downstream of the transcription start site on repressed and transcribed genes during differentiation. We show that RBP2 is part of a Sin3 complex and that on a subset of E2F4 target genes, the coordinated activity of Sin3 and RBP2 leads to deacetylation, demethylation, and repositioning of nucleosomes. Our work provides evidence for coordinated binding of Sin3, chromatin modifications, and chromatin remodeling within discrete regulatory regions, suggesting a model in which spreading of Sin3 binding is ultimately linked to permanent gene silencing on a subset of E2F4 target genes
— id: 90059, year: 2008, vol: 32, page: 359, stat: Journal Article,

Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia
Yang, Jun J; Bhojwani, Deepa; Yang, Wenjian; Cai, Xiangjun; Stocco, Gabriele; Crews, Kristine; Wang, Jinhua; Morrison, Debra; Devidas, Meenakshi; Hunger, Stephen P; Willman, Cheryl L; Raetz, Elizabeth A; Pui, Ching-Hon; Evans, William E; Relling, Mary V; Carroll, William L
2008 Nov 15;112(10):4178-4183, Blood
The underlying pathways that lead to relapse in childhood acute lymphoblastic leukemia (ALL) are unknown. To comprehensively characterize the molecular evolution of relapsed childhood B-precursor ALL, we utilized human 500K single-nucleotide polymorphism (SNP) arrays to identify somatic copy number alterations (CNA) in 20 diagnosis/relapse pairs relative to germline. In total, we identified 758 CNAs, 66.4% of which were < 1Mb, and deletions outnumbered amplifications by ~2.5:1. While CNAs persisting from diagnosis to relapse were observed in all 20 cases, 17 patients exhibited differential CNA patterns from diagnosis to relapse. Of the 396 CNAs observed in 20 relapse samples, only 69 (17.4%) were novel (i.e. absent in the matched diagnosis samples). EBF1 and IKZF1 deletions were particularly frequent in this relapsed ALL cohort (25.0% and 35.0%, respectively), suggesting their role in disease recurrence. Additionally, we noted concordance in global gene expression and DNA copy number changes (P=2.2 x 10(-16)). Finally, relapse-specific focal deletion of MSH6 and consequently reduced gene expression was found in 2 of 20 cases. In an independent cohort of children with ALL, reduced expression of MSH6 was associated with resistance to mercaptopurine and prednisone, thereby providing a plausible mechanism by which this acquired deletion contributes to drug resistance at relapse
— id: 86639, year: 2008, vol: 112, page: 4178, stat: Journal Article,

Gene expression profiles of mouse retinas during the second and third postnatal weeks
Liu, Jiewu; Wang, Jinhua; Huang, Qian; Higdon, Jason; Magdaleno, Susan; Curran, Thomas; Zuo, Jian
2006 Jul 7;1098(1):113-125, Brain research
Mouse retina undergoes crucial changes during early postnatal development. By using Affymetrix microarrays, we analyzed gene expression profiles of wild-type 129SvEv/C57BL/6 mouse retinas at postnatal days (P) 7, 10, 14, 18, and 21 and found significantly altered expression of 355 genes. Characterization of these 355 genes provided insight into physiologic and pathologic processes of mouse retinal development during the second and third postnatal weeks, a period that corresponds to human embryogenesis between weeks 12 and 28. These genes formed 6 groups with similar change patterns. Among the genes, sixteen cause retinal diseases when mutated; most of these 16 genes were upregulated in retina during this period. Using the PathArt program, we identified the biological processes in which many of the 355 gene products function. Among the most active processes in the P7-P21 retina are those involved in neurogenesis, obesity, diabetes type II, apoptosis, growth and differentiation, and protein kinase activity. We examined the expression patterns of 58 genes in P7 and adult retinas by searching the Brain Gene Expression Map database. Although most genes were present in various cell types in retinas, many displayed high levels of expression specifically in the outer nuclear, inner nuclear, and/or ganglion cell layers. By combining our 3 analyses, we demonstrated that during this period of mouse retinal development, many genes play important roles in various cell types, multiple pathways are involved, and some genes in a pathway are expressed in coordinated patterns. Our results thus provide foundation for future detailed studies of specific genes and pathways in various genetic and environmental conditions during retinal development
— id: 78707, year: 2006, vol: 1098, page: 113, stat: Journal Article,

Large-scale sequence analysis of avian influenza isolates
Obenauer, John C; Denson, Jackie; Mehta, Perdeep K; Su, Xiaoping; Mukatira, Suraj; Finkelstein, David B; Xu, Xiequn; Wang, Jinhua; Ma, Jing; Fan, Yiping; Rakestraw, Karen M; Webster, Robert G; Hoffmann, Erich; Krauss, Scott; Zheng, Jie; Zhang, Ziwei; Naeve, Clayton W
2006 Mar 17;311(5767):1576-1580, Science
The spread of H5N1 avian influenza viruses (AIVs) from China to Europe has raised global concern about their potential to infect humans and cause a pandemic. In spite of their substantial threat to human health, remarkably little AIV whole-genome information is available. We report here a preliminary analysis of the first large-scale sequencing of AIVs, including 2196 AIV genes and 169 complete genomes. We combine this new information with public AIV data to identify new gene alleles, persistent genotypes, compensatory mutations, and a potential virulence determinant
— id: 78702, year: 2006, vol: 311, page: 1576, stat: Journal Article,

An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers
Smith, Philip J; Zhang, Chaolin; Wang, Jinhua; Chew, Shern L; Zhang, Michael Q; Krainer, Adrian R
2006 Aug 15;15(16):2490-2508, Human molecular genetics
Numerous disease-associated point mutations exert their effects by disrupting the activity of exonic splicing enhancers (ESEs). We previously derived position weight matrices to predict putative ESEs specific for four human SR proteins. The score matrices are part of ESEfinder, an online resource to identify ESEs in query sequences. We have now carried out a refined functional SELEX screen for motifs that can act as ESEs in response to the human SR protein SF2/ASF. The test BRCA1 exon under selection was internal, rather than the 3'-terminal IGHM exon used in our earlier studies. A naturally occurring heptameric ESE in BRCA1 exon 18 was replaced with two libraries of random sequences, one seven nucleotides in length, the other 14. Following three rounds of selection for in vitro splicing via internal exon inclusion, new consensus motifs and score matrices were derived. Many winner sequences were demonstrated to be functional ESEs in S100-extract-complementation assays with recombinant SF2/ASF. Motif-score threshold values were derived from both experimental and statistical analyses. Motif scores were shown to correlate with levels of exon inclusion, both in vitro and in vivo. Our results confirm and extend our earlier data, as many of the same motifs are recognized as ESEs by both the original and our new score matrix, despite the different context used for selection. Finally, we have derived an increased specificity score matrix that incorporates information from both of our SF2/ASF-specific matrices and that accurately predicts the exon-skipping phenotypes of deleterious point mutations
— id: 78703, year: 2006, vol: 15, page: 2490, stat: Journal Article,

Characterization of RNase R-digested cellular RNA source that consists of lariat and circular RNAs from pre-mRNA splicing
Suzuki, Hitoshi; Zuo, Yuhong; Wang, Jinhua; Zhang, Michael Q; Malhotra, Arun; Mayeda, Akila
2006 ;34(8):e63-e63, Nucleic acids research
Besides linear RNAs, pre-mRNA splicing generates three forms of RNAs: lariat introns, Y-structure introns from trans-splicing, and circular exons through exon skipping. To study the persistence of excised introns in total cellular RNA, we used three Escherichia coli 3' to 5' exoribonucleases. Ribonuclease R (RNase R) thoroughly degrades the abundant linear RNAs and the Y-structure RNA, while preserving the loop portion of a lariat RNA. Ribonuclease II (RNase II) and polynucleotide phosphorylase (PNPase) also preserve the lariat loop, but are less efficient in degrading linear RNAs. RNase R digestion of the total RNA from human skeletal muscle generates an RNA pool consisting of lariat and circular RNAs. RT-PCR across the branch sites confirmed lariat RNAs and circular RNAs in the pool generated by constitutive and alternative splicing of the dystrophin pre-mRNA. Our results indicate that RNase R treatment can be used to construct an intronic cDNA library, in which majority of the intron lariats are represented. The highly specific activity of RNase R implies its ability to screen for rare intragenic trans-splicing in any target gene with a large background of cis-splicing. Further analysis of the intronic RNA pool from a specific tissue or cell will provide insights into the global profile of alternative splicing
— id: 78706, year: 2006, vol: 34, page: e63, stat: Journal Article,

Distribution of SR protein exonic splicing enhancer motifs in human protein-coding genes
Wang, Jinhua; Smith, Philip J; Krainer, Adrian R; Zhang, Michael Q
2005 ;33(16):5053-5062, Nucleic acids research
Exonic splicing enhancers (ESEs) are pre-mRNA cis-acting elements required for splice-site recognition. We previously developed a web-based program called ESEfinder that scores any sequence for the presence of ESE motifs recognized by the human SR proteins SF2/ASF, SRp40, SRp55 and SC35 (http://rulai.cshl.edu/tools/ESE/). Using ESEfinder, we have undertaken a large-scale analysis of ESE motif distribution in human protein-coding genes. Significantly higher frequencies of ESE motifs were observed in constitutive internal protein-coding exons, compared with both their flanking intronic regions and with pseudo exons. Statistical analysis of ESE motif frequency distributions revealed a complex relationship between splice-site strength and increased or decreased frequencies of particular SR protein motifs. Comparison of constitutively and alternatively spliced exons demonstrated slightly weaker splice-site scores, as well as significantly fewer ESE motifs, in the alternatively spliced group. Our results underline the importance of ESE-mediated SR protein function in the process of exon definition, in the context of both constitutive splicing and regulated alternative splicing
— id: 78704, year: 2005, vol: 33, page: 5053, stat: Journal Article,

Genome-wide promoter extraction and analysis in human, mouse, and rat
Xuan, Zhenyu; Zhao, Fang; Wang, Jinhua; Chen, Gengxin; Zhang, Michael Q
2005 ;6(8):R72-R72, Genome biology
Large-scale and high-throughput genomics research needs reliable and comprehensive genome-wide promoter annotation resources. We have conducted a systematic investigation on how to improve mammalian promoter prediction by incorporating both transcript and conservation information. This enabled us to build a better multispecies promoter annotation pipeline and hence to create CSHLmpd (Cold Spring Harbor Laboratory Mammalian Promoter Database) for the biomedical research community, which can act as a starting reference system for more refined functional annotations
— id: 78710, year: 2005, vol: 6, page: R72, stat: Journal Article,

ESEfinder: A web resource to identify exonic splicing enhancers
Cartegni, Luca; Wang, Jinhua; Zhu, Zhengwei; Zhang, Michael Q; Krainer, Adrian R
2003 Jul 1;31(13):3568-3571, Nucleic acids research
Point mutations frequently cause genetic diseases by disrupting the correct pattern of pre-mRNA splicing. The effect of a point mutation within a coding sequence is traditionally attributed to the deduced change in the corresponding amino acid. However, some point mutations can have much more severe effects on the structure of the encoded protein, for example when they inactivate an exonic splicing enhancer (ESE), thereby resulting in exon skipping. ESEs also appear to be especially important in exons that normally undergo alternative splicing. Different classes of ESE consensus motifs have been described, but they are not always easily identified. ESEfinder (http://exon.cshl.edu/ESE/) is a web-based resource that facilitates rapid analysis of exon sequences to identify putative ESEs responsive to the human SR proteins SF2/ASF, SC35, SRp40 and SRp55, and to predict whether exonic mutations disrupt such elements
— id: 78705, year: 2003, vol: 31, page: 3568, stat: Journal Article,

Computational comparison of two mouse draft genomes and the human golden path
Xuan, Zhenyu; Wang, Jinhua; Zhang, Michael Q
2003 ;4(1):R1-R1, Genome biology
BACKGROUND: The availability of both mouse and human draft genomes has marked the beginning of a new era of comparative mammalian genomics. The two available mouse genome assemblies, from the public mouse genome sequencing consortium and Celera Genomics, were obtained using different clone libraries and different assembly methods. RESULTS: We present here a critical comparison of the two latest mouse genome assemblies. The utility of the combined genomes is further demonstrated by comparing them with the human 'golden path' and through a subsequent analysis of a resulting conserved sequence element (CSE) database, which allows us to identify over 6,000 potential novel genes and to derive independent estimates of the number of human protein-coding genes. CONCLUSION: The Celera and public mouse assemblies differ in about 10% of the mouse genome. Each assembly has advantages over the other: Celera has higher accuracy in base-pairs and overall higher coverage of the genome; the public assembly, however, has higher sequence quality in some newly finished bacterial artificial chromosome clone (BAC) regions and the data are freely accessible. Perhaps most important, by combining both assemblies, we can get a better annotation of the human genome; in particular, we can obtain the most complete set of CSEs, one third of which are related to known genes and some others are related to other functional genomic regions. More than half the CSEs are of unknown function. From the CSEs, we estimate the total number of human protein-coding genes to be about 40,000. This searchable publicly available online CSEdb will expedite new discoveries through comparative genomics
— id: 78711, year: 2003, vol: 4, page: R1, stat: Journal Article,

Identification and characterization of simple sequence repeats in the genomes of Shigella species
Yang, Jian; Wang, Jinhua; Chen, Lihong; Yu, Jun; Dong, Jie; Yao, Zhi Jian; Shen, Yan; Jin, Qi; Chen, Runsheng
2003 Dec 11;322:85-92, Gene
A variety of simple sequence repeats (SSRs) have been identified in the genome of Shigella flexneri serotype 2a (strain Sf301), an enteric pathogen that causes bacillary dysentery in man. The distribution of SSRs, with unit length ranging from 1 to 9 nucleotides, was biased in different regions of the genome. The tri-, tetra- and hexanucleotide SSRs prevailed in the coding regions while the mono- and dinucleotide SSRs were more common in the noncoding regions. Many intergenic SSRs are less than 30 bp away from the downstream open reading frames (ORFs), suggesting a potential role in transcriptional regulation. To study polymorphism of SSRs, we compared 17 coding-region SSRs from strain Sf301 with the corresponding sequences from 23 other strains of four Shigella species. Five chromosomal loci were found to be polymorphic, of which those from S. flexneri strains were most variable. Particularly interesting is the C5-1 locus in the coding sequence of the hcaD gene encoding a subunit of ferredoxin reductase. Depending on the insertion of variable numbers of the unit sequence (CGCAG), the Shigella hcaD genes can encode truncated products due to premature stop codons or frame shifts, or products with extended core alpha helices that leads to radical alterations in the predicted tertiary structure. Hence, SSRs may serve as genotyping markers for epidemiological investigations, and may offer insights into evolutionary adaptation of the pathogens
— id: 78714, year: 2003, vol: 322, page: 85, stat: Journal Article,

GenomeComp: a visualization tool for microbial genome comparison
Yang, Jian; Wang, Jinhua; Yao, Zhi-Jian; Jin, Qi; Shen, Yan; Chen, Runsheng
2003 Sep;54(3):423-426, Journal of microbiological methods
We have developed a software tool, GenomeComp, for summarizing, parsing and visualizing the genome sequences comparison results derived from voluminous BLAST textual output. With GenomeComp, the variation between genomes can be easily highlighted, such as repeat regions, insertions, deletions and rearrangements of genomic segments. This software provides a new visualizing tool for microbe comparative genomics
— id: 78713, year: 2003, vol: 54, page: 423, stat: Journal Article,

Genome sequence of Shigella flexneri 2a: insights into pathogenicity through comparison with genomes of Escherichia coli K12 and O157
Jin, Qi; Yuan, Zhenghong; Xu, Jianguo; Wang, Yu; Shen, Yan; Lu, Weichuan; Wang, Jinhua; Liu, Hong; Yang, Jian; Yang, Fan; Zhang, Xiaobing; Zhang, Jiyu; Yang, Guowei; Wu, Hongtao; Qu, Di; Dong, Jie; Sun, Lilian; Xue, Ying; Zhao, Ailan; Gao, Yishan; Zhu, Junping; Kan, Biao; Ding, Keyue; Chen, Shuxia; Cheng, Hongsong; Yao, Zhijian; He, Bingkun; Chen, Runsheng; Ma, Dalong; Qiang, Boqin; Wen, Yumei; Hou, Yunde; Yu, Jun
2002 Oct 15;30(20):4432-4441, Nucleic acids research
We have sequenced the genome of Shigella flexneri serotype 2a, the most prevalent species and serotype that causes bacillary dysentery or shigellosis in man. The whole genome is composed of a 4 607 203 bp chromosome and a 221 618 bp virulence plasmid, designated pCP301. While the plasmid shows minor divergence from that sequenced in serotype 5a, striking characteristics of the chromosome have been revealed. The S.flexneri chromosome has, astonishingly, 314 IS elements, more than 7-fold over those possessed by its close relatives, the non-pathogenic K12 strain and enterohemorrhagic O157:H7 strain of Escherichia coli. There are 13 translocations and inversions compared with the E.coli sequences, all involve a segment larger than 5 kb, and most are associated with deletions or acquired DNA sequences, of which several are likely to be bacteriophage-transmitted pathogenicity islands. Furthermore, S.flexneri, resembling another human-restricted enteric pathogen, Salmonella typhi, also has hundreds of pseudogenes compared with the E.coli strains. All of these could be subjected to investigations towards novel preventative and treatment strategies against shigellosis
— id: 78715, year: 2002, vol: 30, page: 4432, stat: Journal Article,

Proteome-wide analysis of protein function composition reveals the clustering and phylogenetic properties of organisms
Ling, Lunjiang; Wang, Jinhua; Cui, Yan; Li, Wei; Chen, Runsheng
2002 Oct;25(1):101-111, Molecular phylogenetics & evolution
A 17-dimensional vector named the proteome vector is defined to represent an organism. The components of the vector reflect the relative contents of protein-encoding genes of the 17 cluster of orthologous groups of proteins (COGs) classes in the whole genome of the relevant organism. Based on the definition of this proteome vector, the fuzzy clustering of 36 completely sequenced organisms (8 archaea, 24 bacteria, and 4 eukarya) was performed and a proteome tree was constructed. Our results show that (1) the 36 organisms can be 100% correctly classified into three clusters corresponding to the three primary kingdoms, (2) our proteome tree is remarkably similar to that derived from 16S rRNA, and (3) the chromosomes and/or plasmids belonging to the same organism have very similar gene composition. Based on these results, we argue that the 17-dimensional proteome vector could be a good criterion for clustering approaches and to a large extent reveals the phylogenetic properties of organisms; the Three Primary Kingdoms Hypothesis is trustworthy although the existence of lateral gene transfer (LGT) brings controversy to the construction of the 'universal tree of life.'
— id: 78712, year: 2002, vol: 25, page: 101, stat: Journal Article,

Gene's functional arrangement as a measure of the phylogenetic relationships of microorganisms
Wang, JH; Fang, WW; Ling, LJ; Chen, RS
2002 ;28(1):55-62, Journal of biological physics
With the development of genome sequencing more whole genomes of microorganisms were completed, many methods were introduced to reconstruct the phylogenetic tree of those microorganisms with the information extracted from the whole genomes through various ways of transforming or mapping the whole genome sequences into other forms which can describe the evolutionary distance in a new way. We think it might be possible that there exists information buried in the whole genome transferred along lineage, which remains stable and is more essential than sequence conservation of individual genes or the arrangement of some genes of a selected set. We need to find one measurement that can involve as many phylogenetic features as possible that are beyond the genome sequence itself. We converted each genome sequence of the microorganisms into another linear sequence to represent the functional structure of the sequence, and we used a new information function to calculate the discrepancy of sequences and to get one distance matrix of the genomes, and built one phylogenetic tree with a neighbor joining method. The resulting tree shows that the major lineages are consistent with the result based on their 16srRNA sequences. Our method discovered one phylogenetic feature derived from the genome sequences and the encoded genes that can rebuild the phylogenetic tree correctly. The mapping of one genome sequence to its new form representing the relative positions of the functional genes provides a new way to measure the phylogenetic relationships, and with the more specific classification of gene functions the result could be more sensitive. $$:
— id: 78716, year: 2002, vol: 28, page: 55, stat: Journal Article,

Construction and structural modeling of a single-chain Fv-asparaginase fusion protein resistant to proteolysis
Guo, L; Wang, J; Qian, S; Yan, X; Chen, R; Meng, G
2000 Nov 20;70(4):456-463, Biotechnology & Bioengineering
In this study, we construct a fusion protein composed of L-asparaginase (ASNase; from Escherichia coli AS 1.357) and a protective single-chain Fv (scFv), which was selected from a phage-display scFv library from our previous studies. The antibody moiety of the fusion protein was fused to the N-terminus of the enzyme moiety via a linker peptide, (Gly(4)Ser)(6). Recombinant plasmid pET-SLA was constructed to express scFv-ASNase fusion to high levels in E. coli and the expressed product was found to form inclusion bodies. We obtained a soluble fusion protein by refolding and purification. The soluble fusion protein exhibited about 82% of the enzymatic activity of the native ASNase at the same molar concentration, and had a K(m) value similar to that of the native enzyme for the substrate L-asparagine. Importantly, the fusion protein was more stable than native ASNase. In addition: (1) following treatment with trypsin, alpha-chymotrypsin, and rennet, at 37 degrees C for 30 min, scFv-ASNase fusion retained 94.0%, 88.8%, and 84.5% of its original activity, respectively, whereas native ASNase became inactive; and (2) ScFv-ASNase fusion had a much longer in vitro half-life (9 h) in serum than the native enzyme (2 h). The three-dimensional structure of the fusion protein was obtained by modeling with the Homology and Discover modules of the INSIGHT II software package. On the basis of the structural evidence and biochemical properties, we propose that the scFv moiety of the fusion protein may confer ASNase moiety resistance to proteolysis as a result of both steric hindrance and a change in the electrostatic surface of the enzyme
— id: 78708, year: 2000, vol: 70, page: 456, stat: Journal Article,

Characterization of l-asparaginase fused with a protective ScFv and the protection mechanism
Guo, L; Wang, J; Yan, X; Chen, R; Qian, S; Meng, G
2000 Sep 16;276(1):197-203, Biochemical & biophysical research communications
A fusion protein of the protective scFv linked to the C-terminus of ASNase via (Gly(4)Ser)(6) peptide was constructed. The ASNase-scFv fusion protein expressed in Escherichia coli exists mainly in the form of inclusion bodies, and a small amount of it was soluble. The soluble form was purified by four-step purification and it has been demonstrated that ASNase-scFv fusion exists as a dimer. By assay of the stability against proteolysis, the ASNase-scFv fusion was found to be more stable than native ASNase but less stable than scFv-ASNase fusion. The results of immunological assay indicated that the immunogenicity of the fusion proteins increased while their binding capacity with the anti-ASNase serum decreased by comparison to the native ASNase. Moreover, here the comparison of the basic physical and chemical properties of the ASNase-scFv fusion, scFv-ASNase fusion, and native ASNase is presented. Based on the structural evidence and the biochemical analysis described in this paper, the protection mechanism proposed in our previous study was further supported. The scFv moiety of the fusion protein may confer the ASNase moiety resistance to proteolysis as a result of both steric hindrance such as blocking the cleavage sites of trypsin and a change in the electrostatic potential surface of the enzyme
— id: 78709, year: 2000, vol: 276, page: 197, stat: Journal Article,