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Engreitz, Jesse

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Engreitz

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Jesse

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Engreitz, Jesse
Author's Publications: search.filters.isAuthorOfPublication.02d1848b-6adc-4ded-87d4-df35692431a1

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    Genome-Wide Enhancer Maps Link Risk Variants to Disease Genes
    (Springer Science and Business Media LLC, 2021-04-07) Nasser, Joseph; Bergman, Drew T.; Fulco, Charles P.; Guckelberger, Philine; Doughty, Benjamin; Patwardhan, Tejal A.; Jones, Thouis; Nguyen, Tung; Ulirsch, Jacob; Lekschas, Fritz; Mualim, Kristy; Natri, Heini M.; Weeks, Elle M.; Munson, Glen; Kane, Michael; Kang, Helen Y.; Cui, Ang; Ray, John P.; Eisenhaure, Thomas M.; Collins, Ryan; Dey, Kushal; Pfister, Hanspeter; Price, Alkes; Epstein, Charles; Kundaje, Anshul; Xavier, Ramnik; Daly, Mark; Huang, Hailiang; Finucane, Hilary; Hacohen, Nir; Lander, Eric; Engreitz, Jesse
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    Publication
    Three-Dimensional Genome Architecture Influences Partner Selection for Chromosomal Translocations in Human Disease
    (Public Library of Science, 2012) Engreitz, Jesse; Agarwala, Vineeta; Mirny, Leonid
    Chromosomal translocations are frequent features of cancer genomes that contribute to disease progression. These rearrangements result from formation and illegitimate repair of DNA double-strand breaks (DSBs), a process that requires spatial colocalization of chromosomal breakpoints. The “contact first” hypothesis suggests that translocation partners colocalize in the nuclei of normal cells, prior to rearrangement. It is unclear, however, the extent to which spatial interactions based on three-dimensional genome architecture contribute to chromosomal rearrangements in human disease. Here we intersect Hi-C maps of three-dimensional chromosome conformation with collections of 1,533 chromosomal translocations from cancer and germline genomes. We show that many translocation-prone pairs of regions genome-wide, including the cancer translocation partners BCR-ABL and MYC-IGH, display elevated Hi-C contact frequencies in normal human cells. Considering tissue specificity, we find that translocation breakpoints reported in human hematologic malignancies have higher Hi-C contact frequencies in lymphoid cells than those reported in sarcomas and epithelial tumors. However, translocations from multiple tissue types show significant correlation with Hi-C contact frequencies, suggesting that both tissue-specific and universal features of chromatin structure contribute to chromosomal alterations. Our results demonstrate that three-dimensional genome architecture shapes the landscape of rearrangements directly observed in human disease and establish Hi-C as a key method for dissecting these effects.
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    Inherited Causes of Clonal Haematopoiesis in 97,691 Whole Genomes
    (Springer Science and Business Media LLC, 2020-10-14) Bick, Alexander; Weinstock, Joshua S.; Nandakumar, Satish K.; Fulco, Charles P.; Bao, Erik; Zekavat, Seyedeh M.; Szeto, Mindy D.; Liao, Xiaotian; Leventhal, Matthew J.; Nasser, Joseph; Chang, Kyle; Laurie, Cecelia; Burugula, Bala Bharathi; Gibson, Christopher J.; Niroula, Abhishek; Lin, Amy; Taub, Margaret A.; Aguet, Francois; Ardlie, Kristin; Mitchell, Braxton D.; Barnes, Kathleen C.; Moscati, Arden; Fornage, Myriam; Redline, Susan; Psaty, Bruce M.; Silverman, Edwin; Weiss, Scott; Palmer, Nicholette D.; Vasan, Ramachandran S.; Burchard, Esteban G.; Kardia, Sharon L. R.; He, Jiang; Kaplan, Robert C.; Smith, Nicholas L.; Arnett, Donna K.; Schwartz, David A.; Correa, Adolfo; de Andrade, Mariza; Guo, Xiuqing; Konkle, Barbara A.; Custer, Brian; Peralta, Juan M.; Gui, Hongsheng; Meyers, Deborah A.; McGarvey, Stephen T.; Chen, Ida Yii-Der; Shoemaker, M. Benjamin; Peyser, Patricia A.; Broome, Jai G.; Gogarten, Stephanie M.; Wang, Fei Fei; Wong, Quenna; Montasser, May E.; Daya, Michelle; Kenny, Eimear E.; North, Kari E.; Launer, Lenore J.; Cade, Brian; Bis, Joshua C.; Cho, Michael; Lasky-Su, Jessica; Bowden, Donald W.; Cupples, L. Adrienne; Mak, Angel C. Y.; Becker, Lewis C.; Smith, Jennifer A.; Kelly, Tanika N.; Aslibekyan, Stella; Heckbert, Susan R.; Tiwari, Hemant K.; Yang, Ivana V.; Heit, John A.; Lubitz, Steven; Johnsen, Jill M.; Curran, Joanne E.; Wenzel, Sally E.; Weeks, Daniel E.; Rao, Dabeeru C.; Darbar, Dawood; Moon, Jee-Young; Tracy, Russell P.; Buth, Erin J.; Rafaels, Nicholas; Loos, Ruth J. F.; Durda, Peter; Liu, Yongmei; Hou, Lifang; Lee, Jiwon; Kachroo, Priyadarshini; Freedman, Barry I.; Levy, Daniel; Bielak, Lawrence F.; Hixson, James E.; Floyd, James S.; Whitsel, Eric A.; Ellinor, Patrick; Irvin, Marguerite R.; Fingerlin, Tasha E.; Raffield, Laura M.; Armasu, Sebastian M.; Wheeler, Marsha M.; Sabino, Ester C.; Blangero, John; Williams, L. Keoki; Levy, Bruce; Sheu, Wayne Huey-Herng; Roden, Dan M.; Boerwinkle, Eric; Manson, JoAnn; Mathias, Rasika A.; Desai, Pinkal; Taylor, Kent D.; Johnson, Andrew D.; Auer, Paul L.; Kooperberg, Charles; Laurie, Cathy C.; Blackwell, Thomas W.; Smith, Albert V.; Zhao, Hongyu; Lange, Ethan; Lange, Leslie; Rich, Stephen S.; Rotter, Jerome I.; Wilson, James G.; Scheet, Paul; Kitzman, Jacob O.; Lander, Eric; Engreitz, Jesse; Ebert, Benjamin; Reiner, Alexander P.; Jaiswal, Siddhartha; Abecasis, Gonçalo; Sankaran, Vijay; Kathiresan, Sekar; Natarajan, Pradeep
    Age is the dominant risk factor for most chronic human diseases; yet the mechanisms by which aging confers this risk are largely unknown. Recently, the age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations leading to clonal expansion was associated with both hematologic cancer and coronary heart disease5, a phenomenon termed ‘Clonal Hematopoiesis of Indeterminate Potential’ (CHIP). Simultaneous germline and somatic whole genome sequence analysis now provides the opportunity to identify root causes of CHIP. Here, we analyze high-coverage whole genome sequences from 97,691 participants of diverse ancestries in the NHLBI TOPMed program and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid, and inflammatory traits specific to different CHIP genes. Association of a genome-wide set of germline genetic variants identified three genetic loci associated with CHIP status, including one locus at TET2 that was African ancestry specific. In silico-informed in vitro evaluation of the TET2 germline locus identified a causal variant that disrupts a TET2 distal enhancer resulting in increased hematopoietic stem cell self-renewal. Overall, we observe that germline genetic variation shapes hematopoietic stem cell function leading to CHIP through mechanisms that are both specific to clonal hematopoiesis and shared mechanisms leading to somatic mutations across tissues.
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    Activity-by-Contact model of enhancer specificity from thousands of CRISPR perturbations
    (Cold Spring Harbor Laboratory, 2019-01-26) Fulco, Charles P.; Nasser, Joseph; Jones, Thouis; Munson, Glen; Bergman, Drew T.; Subramanian, Vidya; Grossman, Sharon; Anyoha, Rockwell; Doughty, Benjamin; Patwardhan, Tejal A.; Nguyen, Tung H.; Kane, Michael; Perez, Elizabeth; Durand, Neva C.; Lareau, Caleb; Stamenova, Elena K.; Aiden, Erez Lieberman; Lander, Eric; Engreitz, Jesse
    Mammalian genomes harbor millions of noncoding elements called enhancers that quantitatively regulate gene expression, but it remains unclear which enhancers regulate which genes. Here we describe an experimental approach, based on CRISPR interference, RNA FISH, and flow cytometry (CRISPRi-FlowFISH), to perturb enhancers in the genome, and apply it to test >3,000 potential regulatory enhancer-gene connections across multiple genomic loci. A simple equation based on a mechanistic model for enhancer function performed remarkably well at predicting the complex patterns of regulatory connections we observe in our CRISPR dataset. This Activity-by-Contact (ABC) model involves multiplying measures of enhancer activity and enhancer-promoter 3D contacts, and can predict enhancer-gene connections in a given cell type based on chromatin state maps. Together, CRISPRi-FlowFISH and the ABC model provide a systematic approach to map and predict which enhancers regulate which genes, and will help to interpret the functions of the thousands of disease risk variants in the noncoding genome.