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Transcriptional Profiling of a Mouse Model of Infectious Colitis: the Role of Host Factors

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Development, Characterization and Transcriptional Profiling of a Mouse Model of Fatal Infectious Diarrhea and Colitis. by Diana Borenshtein M.Sc. Nutritional Sciences, 1999 B.Sc. Nutritional Sciences, 1995 The Hebrew University of Jerusalem, Israel SUBMITTED TO THE DEPARTMENT OF BIOLOGICAL ENGINEERING IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN MOLECULAR AND SYSTEMS TOXICOLOGY at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY February 2007 © 2007 Massachusetts Institute of Technology. All rights reserved Signature of Author Biological Engineering Division December 1, 2006 Certified by David B. Schauer Professor of Biological Engineering Thesis Supervisor Accepted by Ram Sasisekharan Professor of Biological Engineering Chairman, Committee for Graduate Students 2 This doctoral thesis has been examined by a committee of the department of Biological Engineering as follows: Certified by Professor James G. Fox, MIT Chairman Certified by Professor James L. Sherley, MIT Certified by Professor Eric J. Rubin, Harvard School of Public Health 3 4 Development, Characterization and Transcriptional Profiling of a Mouse Model of Fatal Infectious Diarrhea and Colitis by Diana Borenshtein Submitted to the Biological Engineering Division on December 1, 2006 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Molecular and Systems Toxicology Abstract Citrobacter rodentium is a naturally occurring murine bacterial pathogen which is used to model human diarrheagenic E. coli (EPEC and EHEC) infections in mice. C. rodentium causes colonic hyperplasia and a variable degree of colitis and mortality in the majority of inbred and outbred lines of mice. Differences in C. rodentium-induced disease are determined by the genetic background of the host. Here, C. rodentium infection in resistant outbred Swiss Webster (SW) mice was compared with infection in the cognate inbred FVB strain for the first time. In contrast to subclinical infection in SW mice, adult FVB mice developed overt disease with significant weight loss, severe colitis, and over 75% mortality. Fluid therapy intervention completely prevented mortality in FVB mice, and expression of pro-inflammatory and immunomodulatory genes in the colon was similar in both lines of mice, suggesting that mortality in C. rodentium- infected FVB mice is due to hypovolemia resulting from severe dehydration. To identify host factors responsible for the development of mortality, gene expression in the distal colon of FVB and SW mice was investigated using a whole mouse genome Affymetrix array. Transcripts represented by 1,547 probe sets (3.4%) were differentially expressed between FVB and SW mice prior to infection and at 4 and 9 days post-inoculation. Data analysis suggested that intestinal ion disturbances rather than immune-related processes are responsible for susceptibility in C. rodentium-infected FVB mice. Marked impairment in intestinal ion homeostasis predicted by microarray analysis was confirmed by quantitative RT-PCR and serum electrolyte measurements that showed hypochloremia and hyponatremia in susceptible FVB mice. C. rodentium infection was next characterized in additional inbred strains of Swiss origin. SWR and SJL mice developed minimal morbidity and no mortality in response to the pathogen, demonstrating resistance to disease. Furthermore, C3H mice developed severe diarrhea and gene expression changes comparable to those in infected FVB mice, suggesting common pathogenic mechanisms in susceptible strains. In conclusion, C. rodentium infection in FVB mice is a useful model for fatal infectious diarrhea. These studies contribute to our understanding of C. rodentium pathogenesis and identify possible candidates for susceptibility to fatal enteric bacterial infection. Thesis supervisor: David B. Schauer Title: Professor of Biological Engineering 5 6 Acknowledgements I dedicate my Ph.D to my lovely husband, whose support and inspiration were so vital for me. I cannot explain how much his love, patience, and support mean to me. I am grateful for his understanding of my needs and accepting my chosen path. I hope he felt (at least most of the time) that he and our family are still my first priority. We have wonderful kids and, being a busy Ph.D student mother, I’ve enjoyed every moment I spent with my family. I am in deep debt to my parents, who raised me and made all the possible (and impossible) for my education. I also want to recognize my sister, a great friend and which hopefully will follow my steps. I was very fortunate to have a wonderful advisor, Prof. David Schauer. David has guided me in my research and was an excellent mentor the past 5 years of my life at MIT. David’s knowledge and experience were always there for me. Thanks for suffering my annoyance, supporting my crazy ideas and providing the freedom to conduct experiments the way I did. I also thank him for understanding the needs of a mother-student and supporting me during my complicated pregnancy. This meant a lot to me and I am grateful for that. I express my gratitude to my thesis committee members Prof. James Fox, Prof. James Sherley, and Prof. Eric Rubin for giving me their time and input. Their suggestions throughout my dissertation time were valuable and helped to increase the depth of understanding in my research field. I had an opportunity to collaborate with many distinguished scientists. I thank Prof. Leona Samson, Dr. Lisiane Meira, and Dr. Rebecca Fry for their time and fruitful discussions. Selected parts of our collaborative work are presented here and hopefully will be published soon. I’ve become such good friends with Lisi and Becky, and their help and support was valuable to me. I also enjoyed working with Dr. Elena Gostjeva. We found interesting observations and our long chats in the corridors were always interesting to me. Also, I thank Dr. Michael B. Sporn, Dartmouth Medical School for providing anti-inflammatory compounds for our dietary intervention project. In addition, I had an exciting experience collaborating with Dr. Stephen Collins from McMaster University Medical Center, Canada, though not presented in this thesis. I have to recognize help from the microarray facilities of the Whitehead Institute including Tom Volker, the manager, and especially Jen Love, who processed all my microarray samples. Also, I appreciate time and effort of Dr. Sampsa Hautaniemi from BE, MIT, Prof. Vincent Carey from Harvard Medical School, and Prof. Ernest Fraenkel from BE, MIT, who consulted in analysis of the microarray data. One of the very important things in graduate student life is your lab. My time in MIT has flown past with such a pleasure thanks to many past and present members of the Schauer Lab including Jane Sohn, Ming Chen, Katie Schlieper, Hilda “Scooter” Holcombe, Liz Groff (Colgan), Claude Nagamine, Nancy Guillen, Alex Sheh, Rongcong Wu, Allison Vitsky, Kristen Jellison, Steven Luperchio, and Petra Bertilsson. Thanks to their professional expertise and the fun time we all had together. I thank UROP students, Yuri Matsumoto, Maya Hasan, Joanne Lai, Kriti Jain, and Patricia Zheng. I learned a lot from you and my experience working with you. Kim Knox, in addition of being a highly professional technician and lab manager, we spent time being pregnant 7 together and I wish you and all your family happiness and great health. Special thanks to Solveig Ravnum and Megan McBee – my dear chatting friends, you made my life in the lab really enjoyable. I would like to recognize the staff of DCM, especially our veterinary pathologists Dr. Prashant Nambiar, Dr. Barry Rickman and Dr. Arlin Rogers, who collaborated with me on the work presented here. I highly appreciate the professionalism and hard work of the histology lab, managed by Kathy Cormier and staffed with Kate Rydstrom, Chakib Boussahmain, Ernie Smith, Jeff Bajko, Erinn Stefanich, and Bobi Young. I also recognize the hard work and tremendous help by animal facility crew including Gladys Valeriano (Martinez), Kevin Milne, Herber Villanueva, Jarlin Lemus and Melissa Topolszki, Leslie Hopper, Kris Hewes, Kibibi Rwayitare and Jennifer Statile. Other people in DCM that assisted me along the way were Dr. Yan Feng, Dr. Zhonming Ge, Ellen Buckley, Sue Chow, Jim Yang, Glenda Inciong, Dr. Sam Boutin, and Dr. Laura Lemke. Our department benefits from the help of wonderful people. I thank Marcia Weir, Olga Parkin, Amy Francis, Pat Brown, Christian Rheault, Kay Walsh, JoAnn Sorrento, Mariann Murray, Roni Dudley-Cowans, Kerry Forristall, Kim Bond Schaefer, Debra Luchanin, and Dalia Gabour for their help, assistance and great time in MIT. None of this would be possible without the guidance and excellent management by the director of ex-Division and now a Department of Biological Engineering, Doug Lauffenburger. I was privileged to become a Biogen Idec, Inc. fellow in 2004-2005 academic year. Special thanks to Dr. James Green, Dr. David Hutto, my mentor, Sarah Vincent, and Prof. Pete Dedon, the coordinator of the program. There were many people who helped me in my pre-MIT life. I acknowledge my master thesis advisor Prof. Zecharia Madar and Dr. Aliza Stark from the Faculty of Agriculture, The University of Hebrew University, Israel. Their guidance initiated my scientific career. I thank Prof. Leo Herzenberg and Dr. David Voehringer for allowing me to volunteer at Stanford. This experience was very beneficial to me. I also would like to recognize Prof. Michal Schwartz from Weizmann Institute for a great supervision during my work in her biotech company. She served as a model of female scientist I would like to be. I want to acknowledge many numerous MIT friends that walked with me through both good and bad times of graduate school. The list is quite long. But in addition to some of the names mentioned above, I would like to acknowledge specially Rouzbeh Taghizadeh, Sundina Nataliya, and Alina Berdichevsky. They have been wonderful friends and I will always keep the memories about our time together in MIT. I also have many friends in Israel and USA that supported me during this time as well.
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  • Enhanced CRISPR-Based DNA Demethylation by Casilio-ME-Mediated RNA-Guided Coupling of Methylcytosine Oxidation and DNA Repair Pathways

    Enhanced CRISPR-Based DNA Demethylation by Casilio-ME-Mediated RNA-Guided Coupling of Methylcytosine Oxidation and DNA Repair Pathways

    ARTICLE https://doi.org/10.1038/s41467-019-12339-7 OPEN Enhanced CRISPR-based DNA demethylation by Casilio-ME-mediated RNA-guided coupling of methylcytosine oxidation and DNA repair pathways Aziz Taghbalout1, Menghan Du1, Nathaniel Jillette1, Wojciech Rosikiewicz1, Abhijit Rath2, Christopher D. Heinen2, Sheng Li1 & Albert W. Cheng 1,3,4* Casilio-ME 1234567890():,; Here we develop a methylation editing toolbox, , that enables not only RNA-guided methylcytosine editing by targeting TET1 to genomic sites, but also by co-delivering TET1 and protein factors that couple methylcytosine oxidation to DNA repair activities, and/or promote TET1 to achieve enhanced activation of methylation-silenced genes. Delivery of TET1 activity by Casilio-ME1 robustly alters the CpG methylation landscape of promoter regions and activates methylation-silenced genes. We augment Casilio-ME1 to simultaneously deliver the TET1-catalytic domain and GADD45A (Casilio-ME2) or NEIL2 (Casilio-ME3) to streamline removal of oxidized cytosine intermediates to enhance activation of targeted genes. Using two-in-one effectors or modular effectors, Casilio-ME2 and Casilio-ME3 remarkably boost gene activation and methylcytosine demethylation of targeted loci. We expand the toolbox to enable a stable and expression-inducible system for broader application of the Casilio-ME platforms. This work establishes a platform for editing DNA methylation to enable research investigations interrogating DNA methylomes. 1 The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06032, USA. 2 Center for Molecular Oncology, University of Connecticut Health, 263 Farmington Avenue, Farmington, CT 06030, USA. 3 Department of Genetics and Genome Sciences, University of Connecticut Health, 400 Farmington Avenue, Farmington, CT 06030, USA.