Hazelett Laboratory

 

We are attempting to understand the nexus between genetic variation (of all kinds), from both germline and somatic mutations, and disease etiology. One of the keys to unlocking the mechanisms of disease initiation and progression as it relates to the genome is understanding the epigenome—modifications to the packaging of DNA in chromatin that constrain the parameters of gene regulation-- and the effects of genetic variation on its activity. This big-picture problem can be roughly subdivided into smaller related questions: 1) What tissues/cell types are the most relevant to disease etiology for each genetic association, 2) what genes are the targets of altered/disrupted regulatory elements, and 3) what are the fundamental rules governing the interactions between genes and regulatory elements?

Functional interpretation of GWAS

We have been involved in functional studies to interpret and extend the findings of genome-wide association studies (GWAS), particularly in Cancer. This includes functional annotation of variants and enrichment analysis to locate the cell of origin for various diseases, design and analysis of follow up experiments using 3C based chromatin assays, allele-specific binding in ChIP assays, luciferase assays and other approaches.Mutations in Cancer As an extension of our work on germline variants in cancer, we are investigating the \functional significance of non-coding mutations that have accumulated in high-grade serous ovarian cancer and post-treatment recurrences. We would like to discover how predictable the post-treatment selection process is, and whether/how it might be addressed in the clinic. We are partnered with the Women’s Cancer Program at Cedars-Sinai for this work.

Bioinformatics tools

As  a critical component of our work, we are continuously developing bioinformatics tools to service unmet needs in the fields of regulatory genomics and variant annotation. Following is a list of Bioconductor packages generated by members of our group.

Gene Regulation

One of our goals is to understand the rules underlying intrachromosomal looping interactions discovered from 3C-based methods, using epigenomics and machine learning techniques. Hopefully this will lead to mechanistic insight into the causal links between variation in non-coding DNA and disease.

 

TEAM MEMBERS

Dennis Hazelett, PhD - Assistant Professor - Bioinformatics and Functional Genomics at Cedars-Sinai Medical Center (Dennis.Hazelett@cshs.org)

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Originally trained as a geneticist in the field of developmental biology, I have a broad background in both experimental and computational biology. I rely on a systems-biology approach involving the analysis and synthesis of next-generation sequencing data. My most recent contributions are highlighted by efforts to annotate and draw inference from the functional consequences of genetic associations from genome-wide association studies (GWAS) for prostate cancer, Hodgkins lymphoma and ovarian cancers. Toward this goal, I integrated GWAS and next-generation sequencing data from my collaborators with public datasets such as1000 genomes and the Encyclopedia of DNA elements (ENCODE) to infer new diseases variants outside of transcribed sequences. I have recently begun independent efforts as a principle investigator at Cedars-Sinai Medical Center, using novel approaches to achieve a greater understanding of the relationship between the regulatory code and genetic disease variants.

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Simon Coetzee - Research Bioinformatician II - Bioinformatics and Functional Genomics at Cedars-Sinai Medical Center (Simon.Coetzee@cshs.org)

I began my career doing bioinformatics analysis of GWAS data as part of the U19 GAME-ON consortium at USC. Since then, I have focused on the functional consequences of non-protein coding risk regions within the context of many complex diseases. To this end, we developed a software program called FunciSNP, which is an R/Bioconductor tool integrating functional non-coding datasets with genetic association studies to identify candidate regulatory SNPs (Coetzeeet al., 2012). I have worked on analyzing and interpretation of large genomic datasets, including next-generation sequencing from internal collaborations and downloaded from public datasets such as 1000 genomes, The Encyclopedia of DNA Elements (ENCODE), NIH Epigenomics Roadmap, and The Cancer Genome Atlas. At Cedars-Sinai, I am working with Dr. Ben Berman and Dr. Dennis Hazelett to develop automation tools for analysis and functional annotation of genetic variants from large genome and epigenome sequencing projects. I am also continuing my development of novel algorithms for the analysis of gene regulatory sequences.

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Ivetth Corona de la Fuente, PhD - Post-Doctoral Scientist - Bioinformatics and Functional Genomics at Cedars-Sinai Medical Center (Rosario.CoronadelaFuente@cshs.org

Ivetth has a Bachelor's degree in Electric and Computer Engineering from CETYS Universidad, Mexico and a M.Sc. in Computer Science from CICESE, Mexico. She was first introduced to Computational Biology during her master’s, where she studied protein structure prediction. Continuing in the Structural Bioinformatics field, she did her Ph.D. analyzing protein-DNA complexes and characterized structural features that account for DNA-binding specificity. She then completed an internship at Takeda Pharmaceuticals, Cambridge, MA, where she studied cancer genomics for the first time. Now, under the direction of Drs. Lawrenson and Gayther, she is a Computational Biologist studying the interplay between transcription factors and somatic and germline variants that contribute to the development of ovarian cancer.

 

PUBLICATIONS

  • Bauer H, Meier A, Hild M, Stachel S Economides A, Hazelett D, Harland RM, Hammershchmidt M: Follistatin and Noggin are excluded from the zebrafish organizer. Dev Biol 1998 vol. 204 pp. 488-507. PMID: 9882485
  • Hazelett DJ, Bourouis M, Walldorf U, Treisman JE: decapentaplegic and wingless are regulated by eyes absent and eyegone and interact to direct the pattern of retinal differentiation in the eye disc. Development 1998 vol. 125 (18) pp. 3741-51. PMID: 9716539
  • Zaffran-Maurel C, Hazelett DJ, Lee JD, Benlali A, Treisman JE: The genetic control of early eye development in Drosophila. Dev Biol 1999 vol. 210 pp. 224
  • Benlali A, Draskovic I, Hazelett DJ, Treisman JE: act up controls actin polymerization to alter cell shape and restrict Hedgehog signaling in the Drosophila eye disc. Cell 2000 vol. 101 (3) pp. 271-81. PMID: 10847682
  • Janody F, Lee JD, Jahren N, Hazelett DJ, Benlali A, Miura GI, Draskovic I, Treisman JE: A mosaic genetic screen reveals distinct roles for trithorax and polycomb group genes in Drosophila eye development. Genetics 2004 vol. 166 pp. 187-200. PMID: 15020417
  • Hazelett DJ, Weeks JC: Segment-specific muscle degeneration is triggered directly by a steroid hormone during insect metamorphosis. J Neurobiol 2005 vol. 62 pp.164-77. PMID: 15452849
  • Hazelett DJ, Lakeland DL, Weiss JB: Affinity density: a novel genomic approach to the identification of transcription factor regulatory targets. Bioinformatics 2009 vol. 25 (13) pp. 1617-24. PMID: 19401399
  • Morton DB, Clemens-Grisham R, Hazelett DJ, Vermehren-Schmaedick A: Infertility and male mating behavior deficits associated with Pde1c in Drosophila melanogaster. Genetics 2010 vol. 186 (1) pp. 159-65. PMID: 20551439
  • Pratt EB, Wentzell JS, Maxson JE, Courter L, Hazelett D, Christian JL: The cell giveth and the cell taketh away: an overview of Notch pathwy activation by endocytic trafficking of ligands and receptors. Acta Histochem 2011 vol. 113 (3) pp. 248-55. PMID: 20122714
  • Hazelett DJ, Chang JC, Lakeland DL, Morton DB: Comparison of parallel high-throughput RNA sequencing between knockout of TDP-43 and its overexpression reveals primarily nonreciprocal and nonoverlapping gene expression changes in the central nervous system of Drosophila. G3 (Bethesda) 2012 vol. 2 (7) pp. 789-802. PMID: 22870402 
  • Hazelett DJ, Coetzee SG, Coetzee GA: A rare variant, which destroys a FoxA1 site at 8q24, is associated with prostate cancer risk. Cell Cycle 2013 vol. 12 pp. 379-80. PMID: 23255135
  • Chang JC, Hazelett DJ, Stewart JA, Morton DB: Motor neuron expression of the voltage-gated calcium channel cacophony restores locomotion defects in a Drosophila, TDP-43 loss of function model of ALS. Brain Res 2013 pii: S0006-8993 (13) 01514-X. PMID: 24275199
  • Hazelett DJ, Rhie SK, Gaddis M, Yan C, Lakeland DL, Coetzee SG; Ellipse/GAME-ON consortium; Practical consortium, Henderson BE, Noushmehr H, Cozen W, Kote-Jarai Z, Eeles RA, Easton DF, Haiman CA, Lu W, Farnham PJ, Coetzee GA: Comprehensive functional annotation of 77 prostate cancer risk loci. PLoS Gen 2014 vol. 10 e1004102. PMID: 24497837
  • Rhie SK, Hazelett DJ, Coetzee SG, Yan C, Noushmehr H, Coetzee GA: Nucleosome positioning and histone modifications define relationships between regulatory elements and nearby gene expression in breast epithelial cells. BMC Genomics 2014 vol. 15 (1) pp. 331. PMID: 24885402
  • Cozen W*, Timofeeva MN*, Li D*, Diepstra A*, Hazelett D*, Delahaye-Sourdeix M* and 59 additionla authors: A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus. Nat Commun 2014 vol. 5 pp. 3856. PMID: 24920014
  • Al Olama AA, Kote-Jarai Z, Berndt SI, Conti D, Schumacher F, Han Y, Benlloch S, Hazelett DJ and 160 additional authors: A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet 2014 vol. 46 pp. 1103-9. PMID: 25217961
  • Kuchenbaecker K, Ramus S, Tyrer J, Shen H, Lawrenson K, Beesley J, Lee J, Spindler T, Lin Y, Pejovic T, Bean Y, Li Q, Coetzee S, Hazelett D, and 68 additional authors: Identification of six novel, common variant susceptibility loci for invasive epithelial ovarian cancer. Nat Genet 2015 vol. 47 pp. 164-71. PMID: 25581431 
  • Jeong S, Patel N, Edlund C, Hartiala J, Hazelett DJ, Itakura T, Avery RL, Davis JL, Flynn HW, Lalwani G, Puliafito C, Wafapoor H, Hijikata M, Keicho N, Gao X, Argueso P, Allayee H, Coetzee GA, Pletcher MT, Conti DV, Schwartz SG, Eaton AM, Fini ME: Identification of a novel mucin gene HCG22 associated with steroid-induced ocular hypertension. Invest Opthalmol Vis Sci 2015 vol. 56 (4):2737-48. PMID: 25813999
  • Coetzee SG*, Shen H*, Hazelett DJ*,  and 21 additional authors: Regulatory profiling of ovarian cancer precursor tissues and functional annotation of cancer susceptibility loci Hum Mol Gen 2015 vol. 24 (13):3595-607. PMID: 25804953
  • Al Olama AA, Dadaev T, Hazelett DJ and 74 additional authors. Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans. Hum Mol Gen 2015 vol. 24 (19):5589-602. PMID: 26025378
  • Han Y*, Hazelett DJ* and 80 additional authors. Integration of multiethnic fine mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions. Hum Mol Gen 2015 vol. 24 (19):5603-18. PMID: 26823525
  • Coetzee SG, Coetzee GA, Hazelett DJ. MotifbreakR: an R/Bioconductor package for predicting variant effects at transcription factor binding sites. Bioinformatics 2015 vol. 31 (23):3847-9. PMID: 26272984
  • Lawrenson K, Iversen ES, Tyrer J, Weber RP, Concannon P, Hazelett DJ, and 152 additional authors. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer. Carcinogenesis 2015 vol. 36 (11):1341-53. PMID: 26424751
  • Hazelett DJ, Conti DV, Han Y, Al Oloma AA, Easton D, Eeles RA, Kote-Jarai Z, Haiman CA and Coetzee GA. Reducing GWAS complexity. Cell Cycle 2016 vol. 15 (1):22-24. PMID: 26771711
  • Han Y, Rand KA, Hazelett DJ and 62 additional authors. Prostate Cancer Susceptibility in Men of African Ancestry at 8q24. J Natl Cancer Inst 2016 108 (7):pii PMID: 26823525
  • Rand KA, Song C, Dean E, Serie DJ, Curtin K, + 99 additional authors, Hazelett DJ, Cozen W, Haiman CA. A meta-analysis of multiple myeloma risk regions in African and European ancestry populations identifies putatively functional loci. CEBP 2016
  • Coetzee SG, Brundin P, Hazelett DJ, Coetzee GA. Parkinson’s Disease Risk Functionality. Scientific Reports 2016 6:30509. 
  • Kar S, Adler E, Tyrer J, Hazelett D and 19 other authors. Enrichment of putativ PAX8 target genes at serous epithelial ovarian cancer susceptibility loci. British Journal of Cancer 2016. 
  • Amos C, Dennis J, Wang Z, 17 additional authors, Hazelett DJ, and 63 additional authors. The OncoArray Consortium: a Network for Understanding the Genetic Architecture of Common Cancers. CEBP 2016.