Li-San Wang

Publications (76) View all

• Article: High-throughput identification of long-range regulatory elements and their target promoters in the human genome.

  Yih-Chii Hwang, Qi Zheng, Brian D Gregory, Li-San Wang
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  ABSTRACT: Enhancer elements are essential for tissue-specific gene regulation during mammalian development. Although these regulatory elements are often distant from their target genes, they affect gene expression by recruiting transcription factors to specific promoter regions. Because of this long-range action, the annotation of enhancer element-target promoter pairs remains elusive. Here, we developed a novel analysis methodology that takes advantage of Hi-C data to comprehensively identify these interactions throughout the human genome. To do this, we used a geometric distribution-based model to identify DNA-DNA interaction hotspots that contact gene promoters with high confidence. We observed that these promoter-interacting hotspots significantly overlap with known enhancer-associated histone modifications and DNase I hypersensitive sites. Thus, we defined thousands of candidate enhancer elements by incorporating these features, and found that they have a significant propensity to be bound by p300, an enhancer binding transcription factor. Furthermore, we revealed that their target genes are significantly bound by RNA Polymerase II and demonstrate tissue-specific expression. Finally, we uncovered that these elements are generally found within 1 Mb of their targets, and often regulate multiple genes. In total, our study presents a novel high-throughput workflow for confident, genome-wide discovery of enhancer-target promoter pairs, which will significantly improve our understanding of these regulatory interactions.
  Nucleic Acids Research 03/2013; · 8.03 Impact Factor
• Article: Potent obatoclax cytotoxicity and activation of triple death mode killing across infant acute lymphoblastic leukemia (ALL).

  Karen A Urtishak, Alena Y Z Edwards, Li-San Wang, Amanda Hudome, Blaine W Robinson, Jeffrey S Barrett, Kajia Cao, Lori Cory, Jonni S Moore, Andrew D Bantly, [......], Cheryl L Willman, Mondira Kundu, Andrew J Carroll, Nyla A Heerema, Meenakshi Devidas, Joanne M Hilden, Zoann E Dreyer, Stephen P Hunger, Gregory H Reaman, Carolyn A Felix
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  ABSTRACT: Survival in infants <1 year old with ALL is inferior whether MLL is rearranged (R) or germline (G). MLL translocations confer chemotherapy resistance and infants experience excess complications. We characterized in vitro sensitivity to the pan-anti-apoptotic BCL-2 family inhibitor obatoclax mesylate in diagnostic leukemia cells from 54 infants with ALL/bilineal acute leukemia because of the role of prosurvival BCL-2 proteins in resistance, their imbalanced expression in infant ALL, and evidence of obatoclax activity with a favorable toxicity profile in early adult leukemia trials. Overall, EC(50)s were <176 nM (C(max) with recommended adult dose) in 76% of samples whether in MLL-AF4, MLL-ENL, other MLL-R or MLL-G subsets, and regardless of patients' poor prognostic features. However, MLL status and partner genes correlated with EC(50). Combined approaches including flow cytometry, Western blot, obatoclax treatment with death pathway inhibition, microarray analyses and/or electron microscopy indicated a unique killing mechanism involving apoptosis, necroptosis and autophagy in MLL-AF4 ALL cell lines and primary MLL-R and MLL-G infant ALL cells. This in vitro obatoclax activity and its multiple killing mechanisms across molecular cytogenetic subsets provide rationale to incorporate a similarly acting compound into combination strategies to combat infant ALL.
  Blood 02/2013; · 9.90 Impact Factor
• Article: Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.

  Elaine T Lim, Soumya Raychaudhuri, Stephan J Sanders, Christine Stevens, Aniko Sabo, Daniel G Macarthur, Benjamin M Neale, Andrew Kirby, Douglas M Ruderfer, Menachem Fromer, [......], Matthew W State, Eric Boerwinkle, Joseph D Buxbaum, Edwin H Cook, Richard A Gibbs, Gerard D Schellenberg, James S Sutcliffe, Bernie Devlin, Kathryn Roeder, Mark J Daly
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  ABSTRACT: To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD.
  Neuron 01/2013; 77(2):235-42. · 14.74 Impact Factor
• Source

  Available from: Hong-Hee Won

  Article: SORL1 Is Genetically Associated with Late-Onset Alzheimer's Disease in Japanese, Koreans and Caucasians.

  Akinori Miyashita, Asako Koike, Gyungah Jun, Li-San Wang, Satoshi Takahashi, Etsuro Matsubara, Takeshi Kawarabayashi, Mikio Shoji, Naoki Tomita, Hiroyuki Arai, [......], Makiko Yoshida, Nao Nishida, Katsushi Tokunaga, Ken Yamamoto, Shoji Tsuji, Ichiro Kanazawa, Yasuo Ihara, Gerard D Schellenberg, Lindsay A Farrer, Ryozo Kuwano
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  ABSTRACT: To discover susceptibility genes of late-onset Alzheimer's disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10(-5) were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10(-7) in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10(-9)) and rs3781834 (P = 1.04×10(-8)). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10(-5)) and rs744373 near BIN1 (P = 1.39×10(-4)). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.
  PLoS ONE 01/2013; 8(4):e58618. · 4.09 Impact Factor
• Source

  Available from: Joshua William Miller

  Article: Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis.

  David C Whitcomb, Jessica Larusch, Alyssa M Krasinskas, Lambertus Klei, Jill P Smith, Randall E Brand, John P Neoptolemos, Markus M Lerch, Matt Tector, Bimaljit S Sandhu, [......], Frank Ulrich Weiss, C Mel Wilcox, Narcis Octavian Zarnescu, Stephen R Wisniewski, Michael R O'Connell, Michelle L Kienholz, Kathryn Roeder, M Michael Barmada, Dhiraj Yadav, Bernie Devlin
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  ABSTRACT: Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).
  Nature Genetics 11/2012; · 35.53 Impact Factor