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Introduction
Current institution
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July 2017 - present
November 2014 - July 2017
February 2011 - November 2014
Publications
Publications (65)
Expression QTL (eQTL) analyses have suggested many genes mediating genome-wide association study (GWAS) signals but most GWAS signals still lack compelling explanatory genes. We have leveraged an adipose-specific gene regulatory network to infer expression regulator activities and phenotypic master regulators (MRs), which were used to detect activi...
Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610 kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3, and BORA, range in distance from 265-586...
Pancreatic ductal adenocarcinoma (PDAC) is driven by the accumulation of somatic mutations, epigenetic modifications and changes
in the micro-environment. New approaches to investigating disruptions of gene expression networks promise to uncover key regulators
and pathways in carcinogenesis. We performed messenger RNA-sequencing in pancreatic norma...
Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the U.S. Both rare and common germline variants contribute to PDAC risk. Here, we fine-map and functionally characterize a common PDAC risk signal at chr1p36.33 (tagged by rs13303010) identified through a genome wide association study (GWAS). One of the f...
Background
Genome-wide association studies have identified an exon 6 CTRB2 deletion variant proposed to increase pancreatic cancer risk.
Objective
To acquire evidence on its causal role, we developed and analysed a new mouse strain carrying an equivalent variant in Ctrb1 , the mouse CTRB2 orthologue.
Design
We used CRISPR/Cas9 to introduce a 707...
770
Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis and limited treatment options. A 584 bp deletion in CTRB2 , which impairs chymotrypsin B2 function, has been linked to increased PDAC risk. This study investigates the impact of this deletion on progression and survival outcomes in patients with PDAC. Methods:...
This important study presents genome-wide high-resolution chromatin-based 3D genomic interaction maps for over 50 diverse human cell types and integrates these data with pediatric obesity GWAS. The work provides convincing evidence that multiple pancreatic islet cell types are key effector cell types. The authors also perform variant-to-gene mappin...
The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; how...
Identification of somatic driver mutations in the noncoding genome remains challenging. To comprehensively characterize noncoding driver mutations for pancreatic ductal adenocarcinoma (PDAC), we first created genome-scale maps of accessible chromatin regions (ACRs) and histone modification marks (HMMs) in pancreatic cell lines and purified pancreat...
Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the U.S. Both rare and common germline variants contribute to PDAC risk. Here, we fine-map and functionally characterize a common PDAC risk signal at 1p36.33 (tagged by rs13303010) identified through a genome wide association study (GWAS). One of the fine...
Genome-wide association studies (GWAS) have identified independent signals at 5p15.33 across numerous cancers, with protective alleles for one cancer often conferring risk for another. Many of these associations are thought to act via allele-specific alterations in the cis- regulation of target genes. Transcriptomic analyses in multiple tissue type...
Common low effect size germline variants are known to contribute to pancreatic ductal adenocarcinoma (PDAC) susceptibility. Genome-wide association studies (GWAS) for PDAC have identified over 20 loci where common germline variants influence PDAC risk. Understanding the underlying mechanisms of risk could improve detection, prevention, and potentia...
Genetic or epigenetic variations in regulatory enhancer elements increase susceptibility to a range of pathologies, including pancreas cancer. Pinpointing genes affecting pancreas cancer risk holds promise for early detection, prevention, and effective therapies. Despite recent advances, linking enhancer elements to target genes and predicting the...
Background: Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) to pancreatic ductal adenocarcinoma (PDAC) risk at over 20 genomic loci. The Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium are currently expanding on previous GWAS studies for PDAC from ∼9,000 cases and ∼12,000 c...
Genetic and epigenetic variations in regulatory enhancer elements increase susceptibility to a range of pathologies. Despite recent advances, linking enhancer elements to target genes and predicting transcriptional outcomes of enhancer dysfunction remain significant challenges. Using 3D chromatin conformation assays, we generated an extensive enhan...
A portion of the genetic basis for many common autoimmune disorders has been uncovered by genome-wide association studies (GWAS), but GWAS do not reveal causal variants, effector genes, or the cell types impacted by disease-associated variation. We have generated 3D genomic datasets consisting of promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-...
The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; how...
The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; how...
Objective
Genome wide association studies have identified an exon 6 CTRB2 deletion variant that associates with increased risk of pancreatic cancer. To acquire evidence on its causal role, we developed a new mouse strain carrying an equivalent variant in Ctrb1 , the mouse orthologue of CTRB2 .
Design
We used CRISPR/Cas9 to introduce a 707bp deleti...
Importance: The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for th...
Here, we present a protocol to identify transcriptional regulators potentially mediating downstream biological effects of germline variants associated with complex traits of interest, which enables functional hypothesis generation independent of colocalizing expression quantitative trait loci (eQTLs). We describe steps for tissue-/cell-type-specifi...
In western nations, pancreatic ductal adenocarcinoma (PDAC) is set to become second leading cause of cancer mortality over the next decade. Despite advances in treatment, PDAC has a 5-year survival rate of only ~9%, necessitating a better understanding of its etiology. Risk factors for PDAC are both environmental and genetic, with heritability esti...
Genome-wide association studies (GWASs) have discovered 20 risk loci in the human genome where germline variants associate with risk of pancreatic ductal adenocarcinoma (PDAC) in populations of European ancestry. Here, we fine-mapped one such locus on chr16q23.1 (rs72802365, p = 2.51 × 10⁻¹⁷, OR = 1.36, 95% CI = 1.31–1.40) and identified colocaliza...
Genome wide association studies (GWAS) in 9,013 pancreatic cancer patients and 12,452 controls of European ancestry have discovered over 20 risk loci in the human genome. Here, we fine mapped one such locus on chromosome 16q23.1 in the vicinity of two Chymotrypsinogen precursor genes, CTRB1 and CTRB2. We fine-mapped this locus to rs72802365 (P=2.51...
Background:
Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies (GWAS) in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown.
Methods:
To discover novel pancreatic cancer risk loci and possible causal genes, we perform...
Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in United States with a 5-year survival rate of only 8%. Inherited predisposition plays an important role in PDAC risk. Rare, moderately to highly penetrant mutations in hereditary cancer and pancreatitis genes, identified in families with a high incidence o...
This corrects the article DOI: 10.1038/ncomms15034.
In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreat...
In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and theUnited States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreati...
Objective: To elucidate the genetic architecture of gene expression in pancreatic tissues.
Design: We performed expression quantitative trait locus (eQTL) and allele specific expression (ASE) analyses using RNA-sequence data and 1000 Genomes (1000G) imputed GWAS genotypes from 95 fresh frozen histologically normal pancreatic tissue samples. Data fr...
Objective
To elucidate the genetic architecture of gene expression in pancreatic tissues.
Design
We performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue sa...
Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and t...
Supplementary Figures and Supplementary Tables
Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 co...
Genome wide association studies (GWAS) have mapped multiple independent cancer risk loci (n = 6) to a small region on chr5p15.33 for at least ten distinct cancers, including bladder, breast, glioma, lung, melanoma, non-melanoma skin, ovarian, pancreas, prostate, and testicular germ cell cancer. This region harbors two plausible target genes, TERT w...
Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000
bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis.
To investigate further the ge...
Myotonic dystrophy type 1 (DM1) is a dominantly inherited neuromuscular disorder resulting from expression of RNA containing
an expanded CUG repeat (CUGexp). The pathogenic RNA is retained in nuclear foci. Poly-(CUG) binding proteins in the Muscleblind-like (MBNL) family are sequestered
in foci, causing misregulated alternative splicing of specific...
Epidemiological studies have shown that individuals with a family history of pancreatic cancer are themselves at an increased risk of developing pancreatic cancer. The genetic basis for the majority of familial aggregation of pancreatic cancer has yet to be explained. The search for common and rare germline variants that influence risk of pancreati...
Genome wide association studies (GWAS) of ten different cancers have identified pleiotropic cancer predisposition loci across a region of chromosome 5p15.33 that includes the TERT and CLPTM1L genes. Of these, susceptibility alleles for pancreatic cancer have mapped to the CLPTM1L gene, thus prompting an investigation of the function of CLPTM1L in t...
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-...
Pancreatic cancer is the 10th most common cancer and 4th most common cause of cancer mortality in the United States. A genome wide association study has revealed pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. The chr13q22.1 region contains the most significant of all risk SNPs, rs9543325, (P= 3.27 x 10⁻¹¹) which i...
The ability to control pre-mRNA splicing with small molecules could facilitate the development of therapeutics or cell-based circuits that control gene function. Myotonic dystrophy type 1 is caused by the dysregulation of alternative pre-mRNA splicing due to sequestration of muscleblind-like 1 protein (MBNL1) by expanded, non-coding r(CUG) repeats...
Objective:
The objective of this study was to fine-map common pancreatic cancer susceptibility regions.
Methods:
We conducted targeted Roche-454 resequencing across 428 kb in 3 genomic regions identified in genome-wide association studies (GWAS) of pancreatic cancer, on chromosomes 1q32.1, 5p15.33, and 13q22.1.
Results:
An analytical pipeline...
Pancreatic cancer is the fourth leading cause of cancer deaths in the U.S., and its mortality rate is nearly equal to the rate of incidence. This is due largely to poor diagnostic markers and a lack of viable therapeutic options. In an effort to better understand the underlying genetic dysregulation of this complex and insidious disease, we compare...
The myotonic dystrophies (DM) are human diseases in which the accumulation of toxic RNA (CUG or CCUG) repeats in the cell
causes sequestration of splicing factors, including MBNL1, leading to clinical symptoms such as muscle wasting and myotonia.
We previously used Dynamic Combinatorial Chemistry to identify the first compounds known to inhibit (CU...
Myotonic dystrophy type 1 (DM1) is a triplet repeating disorder caused by expanded CTG repeats in the 3'-untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The transcribed repeats fold into an RNA hairpin with multiple copies of a 5'CUG/3'GUC motif that binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1). Se...
RNA is an important drug target, but it is difficult to design or discover small molecules that modulate RNA function. In the present study, we report that rationally designed, modularly assembled small molecules that bind the RNA that causes myotonic dystrophy type 1 (DM1) are potently bioactive in cell culture models. DM1 is caused when an expans...
Myotonic dystrophy type 1 (DM1), the most prevalent form of adult muscular dystrophy, is caused by expansion of a CTG repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene. The pathogenic effects of the CTG expansion arise from the deleterious effects of the mutant transcript. RNA with expanded CUG tracts alters the activities o...
Nat4, also designated NatD, was previously shown to acetylate the N termini of histones H2A and H4, which have SGGKG and SGRGK
N termini (O. K. Song, X. Wang, J. H. Waterborg, and R. Sternglanz, J. Biol. Chem. 278:38109-38112, 2003). The analysis of chimeric proteins with various N-terminal segments of histone H4 fused to iso-1-cytochrome
c reveale...
The chemotherapeutic drug 5-fluorouracil (5FU) disrupts DNA synthesis by inhibiting the enzymatic conversion of dUMP to dTMP. However, mounting evidence indicates that 5FU has important effects on RNA metabolism that contribute significantly to the toxicity of the drug. Strains with mutations in nuclear RNA-processing exosome components, including...
5-Fluorouracil (5FU) is an effective chemotherapeutic drug developed as an inhibitor of thymidylate synthetase (TS). Inhibition of TS leads to 'thymine-less death', a condition resulting from depletion of dTTP pools and misincorporation of dUTP into newly synthesized or repaired DNA. 5FU is also incorporated into RNA and a growing body of evidence...
The antimetabolite 5-fluorouracil (5FU) is a widely used chemotherapeutic for the treatment of solid tumors. Although 5FU
slows DNA synthesis by inhibiting the ability of thymidylate synthetase to produce dTMP, the drug also has significant effects
on RNA metabolism. Recent genome-wide assays for 5FU-induced haploinsufficiency in Saccharomyces cere...
