Peter J Park

Harvard Medical School, Boston, Massachusetts, United States

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Publications (157)2091.56 Total impact

  • Tae-Min Kim, Peter J Park
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    ABSTRACT: Microsatellites are simple tandem repeats that are present at millions of loci in the human genome. Microsatellite instability (MSI) refers to DNA slippage events on microsatellites that occur frequently in cancer genomes when there is a defect in the DNA-mismatch repair system. These somatic mutations can result in inactivation of tumor-suppressor genes or disrupt other noncoding regulatory sequences, thereby playing a role in carcinogenesis. Here, we will discuss the ways in which high-throughput sequencing data can facilitate genome- or exome-wide discovery and more detailed investigation of MSI events in microsatellite-unstable cancer genomes. We will address the methodologic aspects of this approach and highlight insights from recent analyses of colorectal and endometrial cancer genomes from The Cancer Genome Atlas project. These include identification of novel MSI targets within and across tumor types and the relationship between the likelihood of MSI events to chromatin structure. Given the increasing popularity of exome and genome sequencing of cancer genomes, a comprehensive characterization of MSI may serve as a valuable marker of cancer evolution and aid in a search for therapeutic targets. Cancer Res; 74(22); 1-6. ©2014 AACR.
    Cancer research. 11/2014;
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    ABSTRACT: Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.
    Proceedings of the National Academy of Sciences of the United States of America. 10/2014;
  • Nature Methods 08/2014; 11(9):884-885. · 23.57 Impact Factor
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    ABSTRACT: Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms1, 2, 3. Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal ‘arms’, and centromeres distributed along their lengths4, 5. To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.
    Nature 08/2014; 512(7515):449-452. · 38.60 Impact Factor
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    ABSTRACT: The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features. Specifically, we discover co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we use expression patterns to align the stages in worm and fly development and find a novel pairing between worm embryo and fly pupae, in addition to the embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we find that the extent of non-canonical, non-coding transcription is similar in each organism, per base pair. Finally, we find in all three organisms that the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a 'universal model' based on a single set of organism-independent parameters.
    Nature 08/2014; 512(7515):445-448. · 38.60 Impact Factor
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    ABSTRACT: Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK a
    Nature 07/2014; 511(7511):543-550. · 38.60 Impact Factor
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    ABSTRACT: In a chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) experiment, an important consideration in experimental design is the minimum number of sequenced reads required to obtain statistically significant results. We present an extensive evaluation of the impact of sequencing depth on identification of enriched regions for key histone modifications (H3K4me3, H3K36me3, H3K27me3 and H3K9me2/me3) using deep-sequenced datasets in human and fly. We propose to define sufficient sequencing depth as the number of reads at which detected enrichment regions increase <1% for an additional million reads. Although the required depth depends on the nature of the mark and the state of the cell in each experiment, we observe that sufficient depth is often reached at <20 million reads for fly. For human, there are no clear saturation points for the examined datasets, but our analysis suggests 40-50 million reads as a practical minimum for most marks. We also devise a mathematical model to estimate the sufficient depth and total genomic coverage of a mark. Lastly, we find that the five algorithms tested do not agree well for broad enrichment profiles, especially at lower depths. Our findings suggest that sufficient sequencing depth and an appropriate peak-calling algorithm are essential for ensuring robustness of conclusions derived from ChIP-seq data.
    Nucleic Acids Research 03/2014; · 8.81 Impact Factor
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    ABSTRACT: Males and females of many animal species differ in their sex-chromosome karyotype, and this creates imbalances between X-chromosome and autosomal gene products that require compensation. Although distinct molecular mechanisms have evolved in three highly studied systems, they all achieve coordinate regulation of an entire chromosome by differential RNA-polymerase occupancy at X-linked genes. High-throughput genome-wide methods have been pivotal in driving the latest progress in the field. Here we review the emerging models for dosage compensation in mammals, flies and nematodes, with a focus on mechanisms affecting RNA polymerase II activity on the X chromosome.
    Nature Structural & Molecular Biology 02/2014; 21(2):118-25. · 11.90 Impact Factor
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    ABSTRACT: Chromatin structure determines DNA accessibility. We compare nucleosome occupancy in mouse and human embryonic stem cells (ESCs), induced-pluripotent stem cells (iPSCs) and differentiated cell types using MNase-seq. To address variability inherent in this technique, we developed a bioinformatic approach to identify regions of difference (RoD) in nucleosome occupancy between pluripotent and somatic cells. Surprisingly, most chromatin remains unchanged; a majority of rearrangements appear to affect a single nucleosome. RoDs are enriched at genes and regulatory elements, including enhancers associated with pluripotency and differentiation. RoDs co-localize with binding sites of key developmental regulators, including the reprogramming factors Klf4, Oct4/Sox2 and c-Myc. Nucleosomal landscapes in ESC enhancers are extensively altered, exhibiting lower nucleosome occupancy in pluripotent cells than in somatic cells. Most changes are reset during reprogramming. We conclude that changes in nucleosome occupancy are a hallmark of cell differentiation and reprogramming and likely identify regulatory regions essential for these processes.
    Nature Communications 01/2014; 5:4719. · 10.74 Impact Factor
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    ABSTRACT: ChIP-seq has become the primary method for identifying in vivo protein-DNA interactions on a genome-wide scale, with nearly 800 publications involving the technique in PubMed as of December 2012. Individually and in aggregate these data are an important and information-rich resource. However, uncertainties about data quality confound their use by the wider research community. Recently, the Encyclopedia Of DNA Elements (ENCODE) project, developed and applied metrics to objectively measure ChIP-seq data quality. The ENCODE quality analysis was useful for flagging datasets for closer inspection, eliminating or replacing poor data, and for driving changes in experimental pipelines. There had been no similarly systematic quality analysis of the large and disparate body of published ChIP-seq profiles. Here we report a uniform analysis of vertebrate transcription factor ChIP-seq datasets in the Gene Expression Omnibus (GEO) repository as of April 1st 2012. The majority (55%) of datasets scored as highly successful, but a substantial minority (20%) were of apparently poor quality, and another ~25% were of intermediate quality. We discuss how different uses of ChIP-Seq data are affected by specific aspects of data quality, and we highlight exceptional instances for which the metric values should not be taken at face value. Unexpectedly, we discovered that a significant subset of control datasets (i.e. no-immunoprecipitation and mock-immunoprecipitation samples) display an enrichment structure similar to successful ChIP-seq data. This can, in turn, affect peak calling and data interpretation. Published datasets identified here as high quality comprise a large group that users can draw on for large-scale integrated analysis. In the future, ChIP-seq quality assessment similar to that used here could guide experimentalists at early stages in a study, provide useful input in the publication process, and be used to stratify ChIP-seq data for different community-wide uses.
    G3-Genes Genomes Genetics 12/2013; · 1.79 Impact Factor
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    ABSTRACT: We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.
    Cancer Cell 12/2013; 26(3):319-330. · 24.76 Impact Factor
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    ABSTRACT: We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.
    Cancer Cell. 12/2013; 26(3):319-330.
  • Cell cycle (Georgetown, Tex.) 11/2013; 13(2). · 5.24 Impact Factor
  • Tae-Min Kim, Peter W Laird, Peter J Park
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    ABSTRACT: Microsatellites-simple tandem repeats present at millions of sites in the human genome-can shorten or lengthen due to a defect in DNA mismatch repair. We present here a comprehensive genome-wide analysis of the prevalence, mutational spectrum, and functional consequences of microsatellite instability (MSI) in cancer genomes. We analyzed MSI in 277 colorectal and endometrial cancer genomes (including 57 microsatellite-unstable ones) using exome and whole-genome sequencing data. Recurrent MSI events in coding sequences showed tumor type specificity, elevated frameshift-to-inframe ratios, and lower transcript levels than wild-type alleles. Moreover, genome-wide analysis revealed differences in the distribution of MSI versus point mutations, including overrepresentation of MSI in euchromatic and intronic regions compared to heterochromatic and intergenic regions, respectively, and depletion of MSI at nucleosome-occupied sequences. Our results provide a panoramic view of MSI in cancer genomes, highlighting their tumor type specificity, impact on gene expression, and the role of chromatin organization.
    Cell 11/2013; 155(4):858-68. · 31.96 Impact Factor
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    ABSTRACT: Aneuploidy has been recognized as a hallmark of cancer for more than 100 years, yet no general theory to explain the recurring patterns of aneuploidy in cancer has emerged. Here, we develop Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method that analyzes the patterns of mutational signatures in tumors and predicts the likelihood that any individual gene functions as a tumor suppressor (TSG) or oncogene (OG). By analyzing >8,200 tumor-normal pairs, we provide statistical evidence suggesting that many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. Integrating our driver predictions with information on somatic copy number alterations, we find that the distribution and potency of TSGs (STOP genes), OGs, and essential genes (GO genes) on chromosomes can predict the complex patterns of aneuploidy and copy number variation characteristic of cancer genomes. We propose that the cancer genome is shaped through a process of cumulative haploinsufficiency and triplosensitivity.
    Cell 10/2013; · 31.96 Impact Factor
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    ABSTRACT: Dosage compensation in Drosophila is mediated by the MSL complex, which increases male X-linked gene expression approximately 2-fold. The MSL complex preferentially binds the bodies of active genes on the male X, depositing H4K16ac with a 3' bias. Two models have been proposed for the influence of the MSL complex on transcription: one based on promoter recruitment of RNA polymerase II (Pol II), and a second featuring enhanced transcriptional elongation. Here, we utilize nascent RNA sequencing to document dosage compensation during transcriptional elongation. We also compare X and autosomes from published data on paused and elongating polymerase in order to assess the role of Pol II recruitment. Our results support a model for differentially regulated elongation, starting with release from 5' pausing and increasing through X-linked gene bodies. Our results highlight facilitated transcriptional elongation as a key mechanism for the coordinated regulation of a diverse set of genes.
    Cell Reports 10/2013; · 7.21 Impact Factor
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    ABSTRACT: Kidney injury molecule-1 (KIM-1)/T cell Ig and mucin domain-containing protein-1 (TIM-1) is upregulated more than other proteins after AKI, and it is highly expressed in renal damage of various etiologies. In this capacity, KIM-1/TIM-1 acts as a phosphatidylserine receptor on the surface of injured proximal tubular epithelial cells, mediating phagocytosis of apoptotic cells, and it may also act as a costimulatory molecule for immune cells. Despite recognition of KIM-1 as an important therapeutic target for kidney disease, the regulators of KIM-1 transcription in the kidney remain unknown. Using a bioinformatics approach, we identified upstream regulators of KIM-1 after AKI. In response to tubular injury in rat and human kidneys or oxidant stress in human proximal tubular epithelial cells (HPTECs), KIM-1 expression increased significantly in a manner that corresponded temporally and regionally with increased phosphorylation of checkpoint kinase 1 (Chk1) and STAT3. Both ischemic and oxidant stress resulted in a dramatic increase in reactive oxygen species that phosphorylated and activated Chk1, which subsequently bound to STAT3, phosphorylating it at S727. Furthermore, STAT3 bound to the KIM-1 promoter after ischemic and oxidant stress, and pharmacological or genetic induction of STAT3 in HPTECs increased KIM-1 mRNA and protein levels. Conversely, inhibition of STAT3 using siRNAs or dominant negative mutants reduced KIM-1 expression in a kidney cancer cell line (769-P) that expresses high basal levels of KIM-1. These observations highlight Chk1 and STAT3 as critical upstream regulators of KIM-1 expression after AKI and may suggest novel approaches for therapeutic intervention.
    Journal of the American Society of Nephrology 10/2013; · 8.99 Impact Factor
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    ABSTRACT: Spt6 is a highly conserved histone chaperone that interacts directly with both RNA polymerase II and histones to regulate gene expression. To gain a comprehensive understanding of the roles of Spt6, we performed genome-wide analyses of transcription, chromatin structure, and histone modifications in an S. pombe spt6 mutant. Our results demonstrate dramatic changes to transcription and chromatin structure in the mutant, including elevated antisense transcripts at more than 70 percent of all genes and general loss of the +1 nucleosome. Furthermore, Spt6 is required for marks associated with active transcription, including trimethylation of histone H3 on lysine 4, previously observed in humans, but not S. cerevisiae, and lysine 36. Taken together, our results indicate that Spt6 is critical for the accuracy of transcription and the integrity of chromatin, likely via its direct interactions with RNA polymerase II and histones.
    Molecular and cellular biology 10/2013; · 6.06 Impact Factor
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    ABSTRACT: The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.
    Nature Genetics 09/2013; 45(10):1113-20. · 35.21 Impact Factor
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    ABSTRACT: Although nucleotide resolution maps of genomic structural variants (SVs) have provided insights into the origin and impact of phenotypic diversity in humans, comparable maps in nonhuman primates have thus far been lacking. Using massively parallel DNA sequencing, we constructed fine-resolution genomic structural variation maps in five chimpanzees, five orang-utans, and five rhesus macaques. The SV maps, which are comprised of thousands of deletions, duplications, and mobile element insertions, revealed a high activity of retrotransposition in macaques compared with great apes. By comparison, nonallelic homologous recombination is specifically active in the great apes, which is correlated with architectural differences between the genomes of great apes and macaque. Transcriptome analyses across nonhuman primates and humans revealed effects of species-specific whole-gene duplication on gene expression. We identified 13 gene duplications coinciding with the species-specific gain of tissue-specific gene expression in keeping with a role of gene duplication in the promotion of diversification and the acquisition of unique functions. Differences in the present day activity of SV formation mechanisms that our study revealed may contribute to ongoing diversification and adaptation of great ape and Old World monkey lineages.
    Proceedings of the National Academy of Sciences 09/2013; · 9.81 Impact Factor

Publication Stats

10k Citations
2,091.56 Total Impact Points

Institutions

  • 2002–2014
    • Harvard Medical School
      • Center for Biomedical Informatics
      Boston, Massachusetts, United States
  • 2013
    • Catholic University of Korea
      Sŏul, Seoul, South Korea
  • 2010–2013
    • Massachusetts General Hospital
      • • Molecular Biology Laboratory
      • • Department of Molecular Biology
      Boston, MA, United States
    • The Children’s Medical Group
      Poughkeepsie, New York, United States
  • 2008–2013
    • Mayo Clinic - Rochester
      • Department of Neurology
      Rochester, MN, United States
    • Brigham and Women's Hospital
      • • Division of Genetics
      • • Department of Medicine
      • • Center for Brain Mind Medicine
      Boston, MA, United States
    • Riley Hospital for Children
      • Department of Cardiology
      Indianapolis, Indiana, United States
  • 2001–2013
    • Harvard University
      • • Department of Molecular and Cell Biology
      • • Department of Biostatistics
      Cambridge, Massachusetts, United States
  • 2012
    • University of Eastern Finland
      • School of Medicine
      Kuopio, Eastern Finland Province, Finland
    • Brown University
      • Department of Molecular Biology, Cell Biology and Biochemistry
      Providence, RI, United States
  • 2009
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
    • Partners HealthCare
      Boston, Massachusetts, United States
  • 2003–2008
    • Boston Children's Hospital
      • Division of Genetics
      Boston, Massachusetts, United States
  • 2005–2007
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • Northwestern University
      • Department of Preventive Medicine
      Evanston, IL, United States
  • 2004
    • Seoul National University
      • School of Computer Science and Engineering
      Seoul, Seoul, South Korea