Search tips
Search criteria

Results 1-16 (16)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
Document Types
author:("Seo, taekwon")
1.  Antitumor effects in hepatocarcinoma of isoform-selective inhibition of HDAC2 
Cancer research  2014;74(17):4752-4761.
Histone deacetylase 2 (HDAC2) is a chromatin modifier involved in epigenetic regulation of cell cycle, apoptosis and differentiation that is upregulated commonly in human hepatocellular carcinoma (HCC). In this study, we show that specific targeting of this HDAC isoform is sufficient to inhibit HCC progression. siRNA-mediated silencing of HDAC inhibited HCC cell growth by blocking cell cycle progression and inducing apoptosis. These effects were associated with deregulation of HDAC-regulated genes that control cell cycle, apoptosis and lipid metabolism, specifically, by upregulation of p27 and acetylated p53 and by downregulation of CDK6 and BCL-2. We found that HDAC2 silencing in HCC cells also strongly inhibited PPARγ signaling and other regulators of glycolysis (ChREBPα, GLUT4) and lipogenesis (SREBP1C, FAS), eliciting a marked decrease in fat accumulation. Notably, systemic delivery of HDAC2 siRNA encapsulated in lipid nanoparticles was sufficient to blunt the growth human HCC in a murine xenograft model. Our findings offer preclinical proof-of-concept for HDAC2 blockade as a systemic therapy for liver cancer.
PMCID: PMC4155016  PMID: 24958469
hepatocellular carcinoma; HDAC2; isoform selectivity; targeted siRNA therapeutics; p53 acetylation; cancer lipid metabolism
2.  Epigenetic Reprogramming Modulates Malignant Properties of Human Liver Cancer 
Hepatology (Baltimore, Md.)  2014;59(6):2251-2262.
Reversal of DNA hypermethylation and associated gene silencing is an emerging cancer therapy approach. Here we addressed the impact of epigenetic alterations and cellular context on functional and transcriptional reprogramming of HCC cells. Our strategy employed a 3-day treatment of established and primary human HCC-derived cell lines grown as monolayer at various cell densities with the DNMT1 inhibitor Zebularine (ZEB) followed by a 3D culture to identify cells endowed with self-renewal potential. Differences in self-renewal, gene expression, tumorigenicity and metastatic potential of spheres at generations G1-G5 were examined. Transient ZEB exposure produced differential cell density-dependent responses. In cells grown at low density, ZEB caused a remarkable increase in self-renewal and tumorigenicity associated with long-lasting gene expression changes characterized by a stable overexpression of cancer stem cell-related and key epithelial-mesenchymal transition genes. These effects persisted after restoration of DNMT1 expression. In contrast, at high cell density, ZEB caused a gradual decrease in self-renewal and tumorigenicty, and up-regulation of apoptosis- and differentiation-related genes. A permanent reduction of DNMT1 protein using shRNA-mediated DNMT1 silencing rendered HCC cells insensitive both to cell density and ZEB effects. Similarly, WRL68 and HepG2 hepatoblastoma cells expressing low DNMT1 basal levels also possessed a high self renewal irrespective of cell density or ZEB exposure. Spheres formed by low density cells treated with ZEB or shDNMT1A displayed a high molecular similarity which was sustained through consecutive generations, confirming the essential role of DNMT1 depletion in the enhancement of cancer stem cell properties.
These results identify DNA methylation as a key epigenetic regulatory mechanism determining the pool of cancer stem cells in liver cancer and possibly other solid tumors.
PMCID: PMC4043911  PMID: 24449497
Cancer Stem Cells; DNMT1; Microenvironment; Reprogramming; HCC
3.  The ribonuclease activity of SAMHD1 is required for HIV-1 restriction 
Nature medicine  2014;20(8):936-941.
The HIV-1 restriction factor SAMHD11,2 is proposed to inhibit HIV-1 replication by depleting the intracellular dNTP pool3-5. However, the phosphorylation of SAMHD1 regulates its ability to restrict HIV-1 without decreasing cellular dNTP levels6-8, which is not consistent with a role for SAMHD1 dNTPase activity in HIV-1 restriction. Here, we show that SAMHD1 possesses RNase activity and that the RNase but not the dNTPase function is essential for HIV-1 restriction. By enzymatically characterizing Aicardi-Goutières syndrome (AGS)-associated SAMHD1 mutations and mutations in the allosteric dGTP-binding site of SAMHD1, we identify SAMHD1 mutants that are RNase-positive but dNTPase-negative (SAMHD1D137N) or RNase-negative but dNTPase-positive (SAMHD1Q548A). The allosteric mutant SAMHD1D137N is able to restrict HIV-1 infection, whereas the AGS mutant SAMHD1Q548A is defective for HIV-1 restriction. SAMHD1 associates with HIV-1 RNA and degrades it during the early phases of infection. SAMHD1 silencing in macrophages and CD4+ T cells from healthy donors increases HIV-1 RNA stability, rendering the cells permissive for HIV-1 infection. Furthermore, the phosphorylation of SAMHD1 at T592 negatively regulates its RNase activity in vivo and impedes HIV-1 restriction. Our results reveal that the RNase activity of SAMHD1 is responsible for preventing HIV-1 infection by directly degrading the HIV-1 RNA.
PMCID: PMC4318684  PMID: 25038827
SAMHD1; ribonuclease; HIV-1 restriction factor; HIV-1 genomic RNA; Aicardi-Goutières syndrome
4.  Modeling Pathogenesis of Primary Liver Cancer in Lineage-Specific Mouse Cell Types 
Gastroenterology  2013;145(1):221-231.
Human primary liver cancer (PLC) is classified into biologically distinct subgroups, based on cellular origin. Liver cancer stem cells (CSCs) have been recently described. We investigated the ability of distinct lineages of hepatic cells to become liver CSCs and the phenotypic and genetic heterogeneity of PLC.
We transduced mouse primary hepatic progenitor cells (HPC), lineage-committed hepatoblasts, and differentiated adult hepatocytes with transgenes encoding oncogenic H-Ras and simian virus 40 large-T antigen. The CSC properties of transduced cells and their ability to form tumors were tested by standard in vitro and in vivo assays and transcriptome profiling.
Irrespective of origin, all transduced cells acquired markers of CSC/progenitor cells, side populations, and self-renewal capacity in vitro. They also formed a broad spectrum of liver tumors, ranging from cholangiocarcinoma to hepatocellular carcinoma, which resembled human liver tumors, based on genomic and histologic analyses. The tumor cells co-expressed hepatocyte (HNF4A), biliary progenitor cell (keratin 19, EpCAM, A6), and mesenchyme (vimentin) markers and showed disregulation of genes that control the epithelial–mesenchymal transition. Gene expression analyses could distinguish tumors of different cellular origin, indicating the contribution of lineage-stage dependent genetic changes to malignant transformation. Activation of c-Myc and its target genes was required to reprogram adult hepatocytes into CSC and for tumors to develop. Stable knockdown of c-Myc in transformed adult hepatocytes reduced their CSC properties in vitro and suppressed growth of tumors in immunodeficient mice.
Any cell type in the mouse hepatic lineage can undergo oncogenic reprogramming into a CSC, by activating different cell type-specific pathways. Identification of common and cell-of-origin specific phenotypic and genetic changes could provide new therapeutic targets for liver cancer.
PMCID: PMC3913051  PMID: 23523670
Cell of origin; Cancer stem cell; HCC; c-MYC
5.  Contribution of hepatic lineage stage-specific donor memory to the differential potential of induced mouse pluripotent stem cells (iPSC) 
Stem cells (Dayton, Ohio)  2012;30(5):997-1007.
Recent studies suggested that induced pluripotent stem cells (iPSCs) retain a residual donor cell gene expression which may impact their capacity to differentiate into cell of origin. Here we addressed a contribution of a lineage stage-specific donor cell memory in modulating the functional properties of iPSCs. iPSCs were generated from hepatic lineage cells at an early (hepatoblast-derived, HB-iPSCs) and end stage (adult hepatocyte, AH-iPSCs) of hepatocyte differentiation as well as from mouse fetal fibroblasts (MEF-iPSCs) using a lentiviral vector encoding four pluripotency-inducing factors Oct4, Sox2, Klf4, and c-Myc. All resulting iPS cell lines acquired iPSCs phenotype as judged by the accepted criteria including morphology, expression of pluripotency markers, silencing of transducing factors, capacity of multilineage differentiation in teratoma assay and normal diploid karyotype. However, HB-iPSCs were more efficient in directed differentiation towards hepatocytic lineage as compared to AH-iPSCs, MEF-iPSCs or mESCs. Extensive comparative transcriptome analyses of the early passage iPSCs, donor cells and mESCs revealed that despite global similarities in gene expression patterns between generated iPSCs and mESCs, HB-iPSCs retained a transcriptional memory (7 up- and 17 down-regulated genes) typical of the original cells. Continuous passaging of HB-iPSCs erased most of these differences including a superior capacity for hepatic re-differentiation. These results suggest that retention of lineage stage-specific donor memory in iPSCs may facilitate differentiation into donor cell type. The identified gene set help to improve hepatic differentiation for therapeutic applications and contribute to the better understanding of liver development.
PMCID: PMC4017241  PMID: 22378611
induced pluripotent stem cells; donor memory; hepatocyte lineage cells; hepatic differentiation
6.  Optimization of AAV expression cassettes to improve packaging capacity and transgene expression in neurons 
Molecular Brain  2014;7:17.
Adeno-associated virus (AAV) vectors can deliver transgenes to diverse cell types and are therefore useful for basic research and gene therapy. Although AAV has many advantages over other viral vectors, its relatively small packaging capacity limits its use for delivering large genes. The available transgene size is further limited by the existence of additional elements in the expression cassette without which the gene expression level becomes much lower. By using alternative combinations of shorter elements, we generated a series of AAV expression cassettes and systematically evaluated their expression efficiency in neurons to maximize the transgene size available within the AAV packaging capacity while not compromising the transgene expression. We found that the newly developed smaller expression cassette shows comparable expression efficiency with an efficient vector generally used for strong gene expression. This new expression cassette will allow us to package larger transgenes without compromising expression efficiency.
PMCID: PMC3975461  PMID: 24618276
Adeno-associated virus; WPRE; SV40 late polyadenylation signal sequence; Neuron
7.  Loss of c-Met Accelerates Development of Liver Fibrosis in Response to CCl4 Exposure through Deregulation of Multiple Molecular Pathways 
Biochimica et Biophysica Acta  2012;1822(6):942-951.
HGF/c-Met signaling plays a pivotal role in hepatocyte survival and tissue remodeling during liver regeneration. HGF treatment accelerates resolution of fibrosis in experimental animal models. Here, we utilized Metfl/fl;Alb-Cre+/− conditional knockout mice and a carbon tetrachloride(CCl4)-induced liver fibrosis model to formally address the role of c-Met signaling in hepatocytes in the context of chronic tissue injury. Histological changes during injury (4 weeks) and healing phase (4 weeks) were monitored by immunohistochemistry; expression levels of selected key fibrotic molecules were evaluated by western blotting, and time-dependent global transcriptomic changes were examined using a microarray platform. Loss of hepatocyte c-Met signaling altered hepatic microenvironment and aggravated hepatic fibrogenesis. Greater liver damage was associated with decreased hepatocyte proliferation, excessive stellate cell activation and rapid dystrophic calcification of necrotic areas. Global transcriptome analysis revealed a broad impact of c-Met on critical signaling pathways associated with fibrosis. Loss of hepatocyte c-Met caused a strong deregulation of chemotactic and inflammatory signaling (MCP-1, RANTES, Cxcl10) in addition to modulation of genes involved in reorganization of the cytoskeletal network (Actb, Tuba1a, Tuba8), intercellular communications and adhesion (Adam8, Icam1, Itgb2), control of cell proliferation (Ccng2, Csnk2a, Cdc6, cdk10), DNA damage and stress response (Rad9, Rad52, Ercc4, Gsta1 and 2, Jun). Our study demonstrates that deletion of c-Met receptor in hepatocytes results in pronounced changes in hepatic metabolism and microenvironment, and establishes an essential role for c-Met in maintaining the structural integrity and adaptive plasticity of the liver under adverse conditions.
PMCID: PMC3338880  PMID: 22386877
c-met; fibrosis; microarray; CCl4
8.  Hepatocyte Growth Factor (HGF)/c-Met Signaling is required for Stem Cell Mediated Liver Regeneration 
Hepatology (Baltimore, Md.)  2012;55(4):1215-1226.
HGF/c-Met supports a pleiotrophic signal transduction pathway that controls stem cell homeostasis. Here, we directly addressed the role of c-Met in stem cell-mediated liver regeneration by utilizing mice harboring c-met floxed alleles and Alb-Cre or Mx1-Cre transgenes. To activate oval cells, the hepatic stem cell (HSC) progeny, we used a model of liver injury induced by diet containing the porphyrinogenic agent, 3, 5-diethocarbonyl-1,4-dihydrocollidine (DDC). Deletion of c-met in oval cells was confirmed in both models by PCR analysis of FACS- sorted EpCam-positive cells. Loss of c-Met receptor decreased sphere-forming capacity of oval cells in vitro as well as reduced oval cell pool, impaired migration and decreased hepatocytic differentiation in vivo as demonstrated by double immunofluorescence using oval- (A6 and EpCam) and hepatocyte-specific (HNF-4α) antibodies. Furthermore, lack of c-Met had a profound effect on tissue remodeling and overall composition of HSC niche which was associated with greatly reduced MMP9 activity and decreased expression of SDF1. Using a combination of double immunofluorescence of cell type-specific markers with MMP9 and gelatin zymography on the isolated cell populations, we identified macrophages as a major source of MMP9 in DDC-treated livers. The Mx1-Cre-driven c-met deletion caused the greatest phenotypic impact on HSCs response as compared to the selective inactivation in the epithelial cell lineages achieved in c-Metfl/fl; Alb-Cre+/- mice. However, in both models, genetic loss of c-met triggered a similar cascade of events leading to failure of HSCs mobilization and death of the mice. Conclusion: These results establish a direct contribution of c-Met in regulation of HSC response, and support a unique role for HGF/c-Met as an essential growth factor signaling pathway for regeneration of diseased liver.
PMCID: PMC3299882  PMID: 22095660
Oval cell; DDC model; MMP9; hepatic stem cell niche; Kupffer cell
9.  Human Hepatic Cancer Stem Cells are Characterized by Common Stemness Traits and Diverse Oncogenic Pathways 
Hepatology (Baltimore, Md.)  2011;54(3):1031-1042.
Epigenetic mechanisms play critical roles in stem cell biology by maintaining pluripotency of stem cells and promoting differentiation of more mature derivatives. If similar mechanisms are relevant for the cancer stem cell (CSC) model, then epigenetic modulation might enrich the CSC population, thereby facilitating CSC isolation and rigorous evaluation. To test this hypothesis, primary human cancer cells and liver cancer cell lines were treated with zebularine (ZEB), a potent DNA-methyltransferase1-inhibitor and putative CSCs were isolated by the Side Population (SP) approach. The CSC properties of ZEB-treated and untreated subpopulations were tested by standard in vitro and in vivo assays. Whole transcriptome profiling of isolated CSC was performed to generate CSC signatures. Clinical relevance of the CSC signatures was evaluated in diverse primary human cancers. Epigenetic modulation increased frequency of cells with CSC properties in the SP fraction isolated from human cancer cells as judged by self-renewal, superior tumor-initiating capacity in serial transplantations and direct cell tracking experiments. Integrative transcriptome analysis revealed common traits enriched for stemness-associated genes, although each individual CSC gene expression signature exhibited activation of different oncogenic pathways (e.g. EGFR, SRC and MYC). The common CSC signature was associated with malignant progression, enriched in poorly differentiated tumors and was highly predictive of prognosis in liver and other cancers patients.
Epigenetic modulation may provide a tool for prospective isolation and in-depth analysis of CSC. The liver CSC gene signatures are defined by a pernicious interaction of unique oncogene-specific and common stemness traits. These data should facilitate the identifications of therapeutic tools targeting both unique and common features of CSC.
PMCID: PMC3179780  PMID: 21618577
Cancer Stem Cells; Liver Cancer; Side-population; Epigenetics
10.  Identification of genes underlying different methylation profiles in refractory anemia with excess blast and refractory cytopenia with multilineage dysplasia in myelodysplastic syndrome 
The Korean Journal of Hematology  2012;47(3):186-193.
Myelodysplastic syndrome (MDS) is a preleukemic condition that transforms into acute myeloid leukemia. However, the genetic events underlying this transformation remain poorly understood. Aberrant DNA methylation may play a causative role in the disease and its prognosis. Thus, we compared the DNA methylation profiles in refractory anemia with excess blast (RAEB) to those in refractory cytopenia with multilineage dysplasia (RCMD).
Bone marrow samples were collected from 20 patients with primary MDS (9 with RAEB and 11 with RCMD), and peripheral blood samples were collected from 4 healthy controls. These samples were assessed using a commercial whole genome-wide methylation assay. Methylation-specific polymerase chain reaction (PCR) was used to detect the methylation of candidate gene promoters in RAEB and RCMD.
Microarray data revealed significant hypermethylation in 69 genes within RAEB but not RCMD. Candidate genes were mapped to 5 different networks, and network 1 had the highest score due to its involvement in gene expression, cancer, and cell cycle. Five genes (GSTM5, BIK, CENPH, RERG, and ANGPTL2) were associated with malignant disease progression. Among them, the methylated promoter pairs of GSTM5 (55.5% and 20%), BIK (20% and 0%), and ANGPTL2 (44.4% and 10%) were observed more frequently in RAEB.
DNA methylation of GSTM5, BIK, and ANGPTL2 may induce epigenetic silencing and contribute to the increasing blasts and resulting MDS progression; however, the functions of these genes were not determined. Further study focusing on epigenetic silencing using various detection modalities is required.
PMCID: PMC3464335  PMID: 23071473
Myelodysplastic syndrome; DNA methylation; GSTM5; ANGPTL2; BIK
11.  Inactivation of Ras GTPase-activating proteins promotes unrestrained activity of wild-type Ras in human liver cancer 
Journal of hepatology  2010;54(2):311-319.
Background & Aims
Aberrant activation of Ras pathway is ubiquitous in human hepatocarcinogenesis, but the molecular mechanisms leading to Ras induction in the absence of Ras mutations remain underinvestigated. We defined the role of Ras GTPase activating proteins (GAPs) in the constitutive activity of Ras signaling during human hepatocarcinogenesis.
Mutation status of Ras genes and Ras effectors was assessed in a collection of human hepatocellular carcinoma (HCC). Levels of Ras GAPs (RASA1-4, RASAL1, nGAP, SYNGAP1, DAB2IP, and NF1) and the RASAL1 upstream inducer PITX1 were determined by real-time RT-PCR and immunoblotting. Promoter and genomic status of RASAL1, DAB2IP, NF1, and PITX1 were assessed by methylation assays and microsatellite analysis. Effects of RASAL1, DAB2IP, and PITX1 on HCC growth were evaluated by transfection and siRNA analyses of HCC cell lines.
In the absence of Ras mutations, downregulation of at least one Ras GAP (RASAL1, DAB2IP, or NF1) was found in all HCC samples. Low levels of DAB2IP and PITX1 were detected mostly in a HCC subclass from patients with poor survival, indicating that these proteins control tumor aggressiveness. In HCC cells, reactivation of RASAL1, DAB2IP, and PITX1 inhibited proliferation and induced apoptosis, whereas their silencing increased proliferation and resistance to apoptosis.
Selective suppression of RASAL1, DAB2IP, or NF1 Ras GAPs results in unrestrained activation of Ras signaling in the presence of wild-type Ras in HCC.
PMCID: PMC3031080  PMID: 21067840
Ras GAPs; HCC; methylation
12.  Definition of ubiquitination modulator COP1 as a novel therapeutic target in human hepatocellular carcinoma 
Cancer research  2010;70(21):8264-8269.
Development of targeted therapeutics for hepatocellular carcinoma (HCC) remains a major challenge. The ubiquitination modulator COP1 regulates p53 activity by ubiquitination and it is frequently overexpressed in human HCC. In this study we tested the hypothesis that COP1 blockade by siRNA-mediated inhibition could affect the course of HCC progression. The COP1 isoform COP1-1 was selected as the most effective target for siRNAs in terms of growth inhibition and apoptotic induction in several HCC cell lines. Growth inhibition occurred in HCC cells that retained wild-type p53 or expressed mutant p53 (Y220C or R249S), whereas p53 null Hep3B cells were resistant. Microarray expression analysis revealed that the anti-proliferative effects of COPI-1 blockade were driven by a common subset of molecular alterations including a p53-associated functional network. In an orthotopic mouse xenograft model of HCC, systemic delivery of a modified COP1 siRNA by stable nucleic-acid-lipid particles (SNALP) suppressed neoplastic growth in liver without unwanted immune responses. Our findings offer a first proof of principle that COP1 can be a promising target for systemic therapy of HCC.
PMCID: PMC2970744  PMID: 20959491
13.  Is routine nasogastric tube insertion necessary in pancreaticoduodenectomy? 
The necessity of nasogastric decompression after abdominal surgical procedures has been increasingly questioned for several years. Traditionally, nasogastric decompression is a mandatory procedure after classical pancreaticoduodenectomy (PD); however, we still do not know whether or not it is necessary for PD. The present study was designed to assess the clinical benefit of nasogastric decompression after PD.
Between July 2004 and May 2007, 41 consecutive patients who underwent PD were enrolled in this study. Eighteen patients were enrolled in the nasogastric tube (NGT) group and 23 patients were enrolled in the no NGT group.
There were no differences in the demographics, pathology, co-morbid medical conditions, and pre-operative laboratory values between the two groups. In addition, the passage of flatus (P = 0.963) and starting time of oral intake (P = 0.951) were similar in both groups. In the NGT group, 61% of the patients complained of discomfort related to the NGT. Pleural effusions were frequent in the NGT group (P = 0.037); however, other post-operative complications, such as wound dehiscence and anastomotic leakage, occurred similarly in both groups. There was one case of NGT re-insertion in the NGT group.
Routine nasogastric decompression in patients undergoing PD is not mandatory because it has no clinical advantages and increases patient discomfort.
PMCID: PMC3219851  PMID: 22111081
Pancreaticoduodenectomy; Gastrointestinal intubation
14.  An integrated genomic and pharmacoepigenomic approach predicts therapeutic response of zebularine in human liver cancer* 
Science translational medicine  2010;2(54):54ra77.
Epigenomic changes such as aberrant hypermethylation and subsequent atypical gene silencing are characteristic features of human cancer. Here, we report a comprehensive characterization of epigenomic modulation caused by zebularine, an effective DNA methylation inhibitor, in human liver cancer. Using transcriptomic and epigenomic profiling, we identified a zebularine signature that classified liver cancer cell lines into two major subtypes with different drug-responses. In drug-sensitive cell lines, zebularine caused inhibition of proliferation coupled with increased apoptosis, whereas drug-resistant cell lines were associated with upregulation of oncogenic networks (e.g. E2F1, MYC, and TNF) driving liver cancer growth in vitro and in preclinical mouse models. Assessment of zebularine-based therapy in xenograft mouse models demonstrated potent therapeutic effects against tumors established from zebularine-sensitive but not zebularine-resistant liver cancer cells leading to increased survival and decreased pulmonary metastasis. Integration of zebularine gene expression and demethylation response signatures differentiated patients with HCC according to their survival and disease recurrence and identified a subclass of patients within the poor survivors likely to benefit from therapeutic agents that target the cancer epigenome.
PMCID: PMC3077922  PMID: 20962331
15.  Loss of c-Met Disrupts Gene Expression Program Required for G2/M Progression during Liver Regeneration in Mice 
PLoS ONE  2010;5(9):e12739.
Previous work has established that HGF/c-Met signaling plays a pivotal role in regulating the onset of S phase following partial hepatectomy (PH). In this study, we used Metfl/fl;Alb-Cre+/− conditional knockout mice to determine the effects of c-Met dysfunction in hepatocytes on kinetics of liver regeneration.
Methodology/Principal Finding
The priming events appeared to be intact in Metfl/fl;Alb-Cre+/− livers. Up-regulation of stress response (MAFK, IKBZ, SOCS3) and early growth response (c-Myc, c-Jun, c-Fos, DUSP1 and 6) genes as assessed by RT-qPCR and/or microarray profiling was unchanged. This was consistent with an early induction of MAPK/Erk and STAT3. However, after a successful completion of the first round of DNA replication, c-Met deficient hepatocytes were blocked in early/mid G2 phase as shown by staining with phosphorylated form of histone H3. Furthermore, loss of c-Met in hepatocytes diminished the subsequent G1/S progression and delayed liver recovery after partial hepatectomy. Upstream signaling pathways involved in the blockage of G2/M transition included lack of persistent Erk1/2 activation and inability to up-regulate the levels of Cdk1, Plk1, Aurora A and B, and Mad2 along with a defective histone 3 phosphorylation and lack of chromatin condensation. Continuous supplementation with EGF in vitro increased proliferation of Metfl/fl;Alb-Cre+/− primary hepatocytes and partially restored expression levels of mitotic cell cycle regulators albeit to a lesser degree as compared to control cultures.
In conclusion, our results assign a novel non-redundant function for HGF/c-Met signaling in regulation of G2/M gene expression program via maintaining a persistent Erk1/2 activation throughout liver regeneration.
PMCID: PMC2940888  PMID: 20862286
16.  A novel statistical method to estimate the effective SNP size in vertebrate genomes and categorized genomic regions 
BMC Genomics  2006;7:329.
The local environment of single nucleotide polymorphisms (SNPs) contains abundant genetic information for the study of mechanisms of mutation, genome evolution, and causes of diseases. Recent studies revealed that neighboring-nucleotide biases on SNPs were strong and the genome-wide bias patterns could be represented by a small subset of the total SNPs. It remains unsolved for the estimation of the effective SNP size, the number of SNPs that are sufficient to represent the bias patterns observed from the whole SNP data.
To estimate the effective SNP size, we developed a novel statistical method, SNPKS, which considers both the statistical and biological significances. SNPKS consists of two major steps: to obtain an initial effective size by the Kolmogorov-Smirnov test (KS test) and to find an intermediate effective size by interval evaluation. The SNPKS algorithm was implemented in computer programs and applied to the real SNP data. The effective SNP size was estimated to be 38,200, 39,300, 38,000, and 38,700 in the human, chimpanzee, dog, and mouse genomes, respectively, and 39,100, 39,600, 39,200, and 42,200 in human intergenic, genic, intronic, and CpG island regions, respectively.
SNPKS is the first statistical method to estimate the effective SNP size. It runs efficiently and greatly outperforms the algorithm implemented in SNPNB. The application of SNPKS to the real SNP data revealed the similar small effective SNP size (38,000 – 42,200) in the human, chimpanzee, dog, and mouse genomes as well as in human genomic regions. The findings suggest strong influence of genetic factors across vertebrate genomes.
PMCID: PMC1769377  PMID: 17196097

Results 1-16 (16)