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Epigenetic Regulation of the Dlk1-Meg3 Imprinted Locus in Human Islets

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Epigenetic Regulation of the Dlk1-Meg3 Imprinted Locus in Human Islets University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2016 Epigenetic Regulation of the Dlk1-Meg3 Imprinted Locus in Human Islets Vasumathi Kameswaran University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Cell Biology Commons, Genetics Commons, and the Molecular Biology Commons Recommended Citation Kameswaran, Vasumathi, "Epigenetic Regulation of the Dlk1-Meg3 Imprinted Locus in Human Islets" (2016). Publicly Accessible Penn Dissertations. 1798. https://repository.upenn.edu/edissertations/1798 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1798 For more information, please contact [email protected]. Epigenetic Regulation of the Dlk1-Meg3 Imprinted Locus in Human Islets Abstract Type 2 diabetes mellitus (T2DM) is a complex metabolic disease characterized by inadequate insulin secretion by the pancreatic β-cell in response to increased blood glucose levels. Despite compelling evidence that T2DM has a high rate of familial aggregation, known genetic risk variants account for less than 10% of the observed heritability. Consequently, post-transcriptional regulators of gene expression, including microRNAs and other noncoding RNAs, have been implicated in the etiology of T2DM, in part due to their ability to simultaneously regulate the expression of hundreds of targets. To determine if microRNAs are involved in the pathogenesis of human T2DM, I sequenced the small RNAs of human islets from diabetic and non-diabetic organ donors. From this screen, I identified the maternally-expressed genes in the imprinted DLK1-MEG3 locus as highly- and specifically-expressed in human β-cells, but repressed in T2DM islets. Repression of this noncoding transcript was strongly correlated with hyper-methylation of the promoter that drives transcription of all the maternal noncoding RNAs including the long noncoding RNA MEG3, several microRNAs and snoRNAs. Additionally, I identified disease-relevant targets of DLK1-MEG3 microRNAs in vivo using HITS-CLIP, a technique to detect targets of RNA binding proteins. My results provide strong evidence for a role of microRNAs and epigenetic modifications, such as DNA methylation, in the pathogenesis of T2DM. In addition, my data set catalogs human islet microRNAs relevant to human T2DM pathogenesis and characterizes their target transcriptomes. Despite being associated with T2DM and several other diseases, very little is known about the regulation of imprinting of the MEG3-DLK1 locus. Hence, I interrogated a newly described enhancer in this locus, as enhancers are known mediators of mono-allelic expression at other imprinted loci. I discovered allele- specific binding of this enhancer by critical islet transcription factors, including FOXA2 in human islets. In addition, I mapped long-range interactions of this enhancer in human islets using 4C-Seq. Overall, my findings provide novel insights into the regulation of an imprinted locus critical to β-cell health and function. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Klaus H. Kaestner Keywords Beta cell, Diabetes, Enhancer, Epigenetics, Imprinting, Islets Subject Categories Cell Biology | Genetics | Molecular Biology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/1798 EPIGENETIC REGULATION OF THE DLK1-MEG3 IMPRINTED LOCUS IN HUMAN ISLETS Vasumathi Kameswaran A DISSERTATION in Cell and Molecular Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2016 Supervisor of Dissertation ________________________ Klaus H. Kaestner, Ph.D. Thomas and Evelyn Suor Butterworth Professor in Genetics Graduate Group Chairperson ________________________ Daniel S. Kessler, Ph.D. Associate Professor of Cell and Developmental Biology Dissertation Committee Marisa S. Bartolomei, Ph.D., Professor of Cell and Developmental Biology Doris A. Stoffers, M.D., Ph.D., Professor of Medicine Zissimos Mourelatos, M.D., Professor of Pathology and Laboratory Medicine Joshua R. Friedman, M.D., Ph.D., Adjunct Associate Professor of Pediatrics Dedicated to my grandmother, Dr. Lalitha Kameswaran. ii ACKNOWLEDGMENT This thesis work was really only possible due to the love and support of the people I was surrounded by through this time. Through my graduate career at Penn, I had a chance to interact with some of the most smart and humble scientists whom I look up to and feel inspired by every day. First and foremost, I am grateful to my mentor Klaus Kaestner who has been so much more than just a thesis advisor to me. No words can do justice to his role in my life as a friend, supporter and well-wisher. He also has an incredible knack for hiring wonderful and smart people. Thank you to every member of the Kaestner lab for being so warm and helpful through scientific and personal challenges. I am also very grateful to my committee members, Drs. Marisa Bartolomei, Doris Stoffers, Zissimos Mourelatos and Joshua Friedman, as well as my program chair, Dr. David Weiner, for their invaluable advice and encouragement over the years. I am grateful to my friends whose support has kept me going through the years. Diana, Akshay, Srikanth, Senthil, Shravan, Keeru, Dhivya, Esha, Keerthi and Pratha, thank you for being my family away from home. I hope I have been atleast half the friend to you guys that you have been to me. My family has always been my pillar of strength. Ma, Pa, Chinchin, Ammumma, Thatha, Chitra Aunty, Sankar Mama, Maheshpa, Maheshwari Chithi, Lava and Div - thank you for everything you have done for me and for being such incredible role models. Making you guys proud is what drives me every day. In many ways, you all worked harder for this thesis than I did! It would be remiss of me to ignore my sources of caffeine. Gia Pronto, La Colombe and Starbucks, I owe you guys! iii ABSTRACT EPIGENETIC REGULATION OF THE DLK1-MEG3 IMPRINTED LOCUS IN HUMAN ISLETS Vasumathi Kameswaran Klaus H. Kaestner Type 2 diabetes mellitus (T2DM) is a complex metabolic disease characterized by inadequate insulin secretion by the pancreatic β-cell in response to increased blood glucose levels. Despite compelling evidence that T2DM has a high rate of familial aggregation, known genetic risk variants account for less than 10% of the observed heritability. Consequently, post- transcriptional regulators of gene expression, including microRNAs and other noncoding RNAs, have been implicated in the etiology of T2DM, in part due to their ability to simultaneously regulate the expression of hundreds of targets. To determine if microRNAs are involved in the pathogenesis of human T2DM, I sequenced the small RNAs of human islets from diabetic and non-diabetic organ donors. From this screen, I identified the maternally-expressed genes in the imprinted DLK1-MEG3 locus as highly- and specifically-expressed in human β-cells, but repressed in T2DM islets. Repression of this noncoding transcript was strongly correlated with hyper-methylation of the promoter that drives transcription of all the maternal noncoding RNAs including the long noncoding RNA MEG3, several microRNAs and snoRNAs. Additionally, I identified disease-relevant targets of DLK1- MEG3 microRNAs in vivo using HITS-CLIP, a technique to detect targets of RNA binding proteins. My results provide strong evidence for a role of microRNAs and epigenetic modifications, such as DNA methylation, in the pathogenesis of T2DM. In addition, my data set catalogs human islet microRNAs relevant to human T2DM pathogenesis and characterizes their target transcriptomes. Despite being associated with T2DM and several other diseases, very little is known iv about the regulation of imprinting of the MEG3-DLK1 locus. Hence, I interrogated a newly described enhancer in this locus, as enhancers are known mediators of mono-allelic expression at other imprinted loci. I discovered allele-specific binding of this enhancer by critical islet transcription factors, including FOXA2 in human islets. In addition, I mapped long-range interactions of this enhancer in human islets using 4C-Seq. Overall, my findings provide novel insights into the regulation of an imprinted locus critical to β-cell health and function. v TABLE OF CONTENTS ABSTRACT .................................................................................................................................... IV LIST OF TABLES .......................................................................................................................... VII LIST OF ILLUSTRATIONS .......................................................................................................... VIII INTRODUCTION ............................................................................................................................ 1 Diabetes Mellitus ............................................................................................................................. 2 MicroRNAs in β-cell function and T2DM pathogenesis .................................................................. 5 Long non-coding RNAs ................................................................................................................. 13 Epigenetics ................................................................................................................................... 16 The DLK1-MEG3
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