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1.  An integrated transcriptome and epigenome analysis identifies a novel candidate gene for pancreatic cancer 
BMC Medical Genomics  2013;6:33.
Pancreatic cancer is a highly lethal cancer with limited diagnostic and therapeutic modalities.
To begin to explore the genomic landscape of pancreatic cancer, we used massively parallel sequencing to catalog and compare transcribed regions and potential regulatory elements in two human cell lines derived from normal and cancerous pancreas.
By RNA-sequencing, we identified 2,146 differentially expressed genes in these cell lines that were enriched in cancer related pathways and biological processes that include cell adhesion, growth factor and receptor activity, signaling, transcription and differentiation. Our high throughput Chromatin immunoprecipitation (ChIP) sequence analysis furthermore identified over 100,000 regions enriched in epigenetic marks, showing either positive (H3K4me1, H3K4me3, RNA Pol II) or negative (H3K27me3) correlation with gene expression. Notably, an overall enrichment of RNA Pol II binding and depletion of H3K27me3 binding were seen in the cancer derived cell line as compared to the normal derived cell line. By selecting genes for further assessment based on this difference, we confirmed enhanced expression of aldehyde dehydrogenase 1A3 (ALDH1A3) in two larger sets of pancreatic cancer cell lines and in tumor tissues as compared to normal derived tissues.
As aldehyde dehydrogenase (ALDH) activity is a key feature of cancer stem cells, our results indicate that a member of the ALDH superfamily, ALDH1A3, may be upregulated in pancreatic cancer, where it could mark pancreatic cancer stem cells.
PMCID: PMC3849454  PMID: 24053169
Pancreatic cancer; Transcriptome; Epigenome; Sequencing; ALDH1A3
2.  Fine mapping the KLK3 locus on chromosome 19q13.33 associated with prostate cancer susceptibility and PSA levels 
Human Genetics  2011;129(6):675-685.
Measurements of serum prostate-specific antigen (PSA) protein levels form the basis for a widely used test to screen men for prostate cancer. Germline variants in the gene that encodes the PSA protein (KLK3) have been shown to be associated with both serum PSA levels and prostate cancer. Based on a resequencing analysis of a 56 kb region on chromosome 19q13.33, centered on the KLK3 gene, we fine mapped this locus by genotyping tag SNPs in 3,522 prostate cancer cases and 3,338 controls from five case–control studies. We did not observe a strong association with the KLK3 variant, reported in previous studies to confer risk for prostate cancer (rs2735839; P = 0.20) but did observe three highly correlated SNPs (rs17632542, rs62113212 and rs62113214) associated with prostate cancer [P = 3.41 × 10−4, per-allele trend odds ratio (OR) = 0.77, 95% CI = 0.67–0.89]. The signal was apparent only for nonaggressive prostate cancer cases with Gleason score <7 and disease stage 8 or stage ≥III (P = 0.31, per-allele trend OR = 1.12, 95% CI = 0.90–1.40). One of the three highly correlated SNPs, rs17632542, introduces a non-synonymous amino acid change in the KLK3 protein with a predicted benign or neutral functional impact. Baseline PSA levels were 43.7% higher in control subjects with no minor alleles (1.61 ng/ml, 95% CI = 1.49–1.72) than in those with one or more minor alleles at any one of the three SNPs (1.12 ng/ml, 95% CI = 0.96–1.28) (P = 9.70 × 10−5). Together our results suggest that germline KLK3 variants could influence the diagnosis of nonaggressive prostate cancer by influencing the likelihood of biopsy.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-011-0953-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3092924  PMID: 21318478
3.  Translating the REACH Caregiver Intervention for Use by Area Agency on Aging Personnel: the REACH OUT Program 
The Gerontologist  2009;49(1):103-116.
Purpose: The aim of this study was to translate the evidence-based Resources for Enhancing Alzheimer's Caregiver Health (REACH) II intervention for use in 4 Area Agencies on Aging (AAAs). A secondary aim was to examine possible moderators of treatment outcome. Design and Methods: We used a quasi-experimental pre–post treatment design with no control group. A partnership was formed between the Alabama Department of Senior Services and the University of Alabama. The partnership trimmed the REACH II intervention used in the clinical trial for feasible use in a social service agency. The condensed REACH intervention, termed REACH OUT, was delivered to 272 dementia caregivers during 4 home visits and 3 phone calls for a period of 4 months. The assessment examined pre–post treatment effects on a number of outcomes, including care recipient risk, mood, memory, and behavior problems; caregiver stress and emotional well-being; caregiver health; and program satisfaction. All aspects of the program except for training, periodic consultation, and data analysis were controlled by the AAA staff. Results: Analyses were conducted on the 236 dyads that completed at least 3 of the 4 planned sessions. Significant positive pre–post effects were found on caregiver subjective burden, social support, caregiver frustration, depression, caregiver health, care recipient behavior problems and mood, and 2 of 4 care recipient risk behaviors. Site of intervention and certain participant characteristics (e.g., caregiver relationship) moderated several pre–post differences. A caregiver survey and interventionist focus group reported high acceptability of the program Implications: This project suggests that the REACH II intervention can be modified for feasible and effective use in AAAs. The next step is to integrate the intervention into usual service delivery to achieve sustainability.
PMCID: PMC3695600  PMID: 19363008
Community–university partnership; Treatment; Caregiving; Dementia; Translation
4.  A comprehensive resequence analysis of the KLK15–KLK3–KLK2 locus on chromosome 19q13.33 
Human Genetics  2009;127(1):91-99.
Single nucleotide polymorphisms (SNPs) in the KLK3 gene on chromosome 19q13.33 are associated with serum prostate-specific antigen (PSA) levels. Recent genome wide association studies of prostate cancer have yielded conflicting results for association of the same SNPs with prostate cancer risk. Since the KLK3 gene encodes the PSA protein that forms the basis for a widely used screening test for prostate cancer, it is critical to fully characterize genetic variation in this region and assess its relationship with the risk of prostate cancer. We have conducted a next-generation sequence analysis in 78 individuals of European ancestry to characterize common (minor allele frequency, MAF >1%) genetic variation in a 56 kb region on chromosome 19q13.33 centered on the KLK3 gene (chr19:56,019,829–56,076,043 bps). We identified 555 polymorphic loci in the process including 116 novel SNPs and 182 novel insertion/deletion polymorphisms (indels). Based on tagging analysis, 144 loci are necessary to tag the region at an r2 threshold of 0.8 and MAF of 1% or higher, while 86 loci are required to tag the region at an r2 threshold of 0.8 and MAF >5%. Our sequence data augments coverage by 35 and 78% as compared to variants in dbSNP and HapMap, respectively. We observed six non-synonymous amino acid or frame shift changes in the KLK3 gene and three changes in each of the neighboring genes, KLK15 and KLK2. Our study has generated a detailed map of common genetic variation in the genomic region surrounding the KLK3 gene, which should be useful for fine-mapping the association signal as well as determining the contribution of this locus to prostate cancer risk and/or regulation of PSA expression.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-009-0751-5) contains supplementary material, which is available to authorized users.
PMCID: PMC2793378  PMID: 19823874
5.  Human promoter genomic composition demonstrates non-random groupings that reflect general cellular function 
BMC Bioinformatics  2005;6:259.
The purpose of this study is to determine whether or not there exists nonrandom grouping of cis-regulatory elements within gene promoters that can be perceived independent of gene expression data and whether or not there is any correlation between this grouping and the biological function of the gene.
Using ProSpector, a web-based promoter search and annotation tool, we have applied an unbiased approach to analyze the transcription factor binding site frequencies of 1400 base pair genomic segments positioned at 1200 base pairs upstream and 200 base pairs downstream of the transcriptional start site of 7298 commonly studied human genes. Partitional clustering of the transcription factor binding site composition within these promoter segments reveals a small number of gene groups that are selectively enriched for gene ontology terms consistent with distinct aspects of cellular function. Significance ranking of the class-determining transcription factor binding sites within these clusters show substantial overlap between the gene ontology terms of the transcriptions factors associated with the binding sites and the gene ontology terms of the regulated genes within each group.
Thus, gene sorting by promoter composition alone produces partitions in which the "regulated" and the "regulators" cosegregate into similar functional classes. These findings demonstrate that the transcription factor binding site composition is non-randomly distributed between gene promoters in a manner that reflects and partially defines general gene class function.
PMCID: PMC1274301  PMID: 16232321
6.  TFIIH Operates through an Expanded Proximal Promoter To Fine-Tune c-myc Expression 
Molecular and Cellular Biology  2005;25(1):147-161.
A continuous stream of activating and repressing signals is processed by the transcription complex paused at the promoter of the c-myc proto-oncogene. The general transcription factor IIH (TFIIH) is held at promoters prior to promoter escape and so is well situated to channel the input of activators and repressors to modulate c-myc expression. We have compared cells expressing only a mutated p89 (xeroderma pigmentosum complementation group B [XPB]), the largest TFIIH subunit, with the same cells functionally complemented with the wild-type protein (XPB/wt-p89). Here, we show structural, compositional, and functional differences in transcription complexes between XPB and XPB/wt-89 cells at the native c-myc promoter. Remarkably, although the mean levels of c-Myc are only modestly elevated in XPB compared to those in XPB/wt-p89 cells, the range of expression and the cell-to-cell variation of c-Myc are markedly increased. Our modeling indicates that the data can be explained if TFIIH integrates inputs from multiple signals, regulating transcription at multiple kinetically equivalent steps between initiation and promoter escape. This helps to suppress the intrinsic noise of transcription and to ensure the steady transcriptional output of c-myc necessary for cellular homeostasis.
PMCID: PMC538784  PMID: 15601838
7.  Transcriptional Consequences of Topoisomerase Inhibition 
Molecular and Cellular Biology  2001;21(24):8437-8451.
In principle, the generation, transmission, and dissipation of supercoiling forces are determined by the arrangement of the physical barriers defining topological boundaries and the disposition of enzymes creating (polymerases and helicases, etc.) or releasing (topoisomerases) torsional strain in DNA. These features are likely to be characteristic for individual genes. By using topoisomerase inhibitors to alter the balance between supercoiling forces in vivo, we monitored changes in the basal transcriptional activity and DNA conformation for several genes. Every gene examined displayed an individualized profile in response to inhibition of topoisomerase I or II. The expression changes elicited by camptothecin (topoisomerase I inhibitor) or adriamycin (topoisomerase II inhibitor) were not equivalent. Camptothecin generally caused transcription complexes to stall in the midst of transcription units, while provoking little response at promoters. Adriamycin, in contrast, caused dramatic changes at or near promoters and prevented transcription. The response to topoisomerase inhibition was also context dependent, differing between chromosomal or episomal c-myc promoters. In addition to being well-characterized DNA-damaging agents, topoisomerase inhibitors may evoke a biological response determined in part from transcriptional effects. The results have ramifications for the use of these drugs as antineoplastic agents.
PMCID: PMC100007  PMID: 11713279

Results 1-7 (7)