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The Human Integrator Complex Facilitates Transcriptional Elongation by Endonucleolytic Cleavage of Nascent Transcripts

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The Human Integrator Complex Facilitates Transcriptional Elongation by Endonucleolytic Cleavage of Nascent Transcripts Please do not remove this page The Human Integrator Complex Facilitates Transcriptional Elongation by Endonucleolytic Cleavage of Nascent Transcripts Blumenthal, Ezra https://scholarship.miami.edu/discovery/delivery/01UOML_INST:ResearchRepository/12386098540002976?l#13386098530002976 Blumenthal, E. (2021). The Human Integrator Complex Facilitates Transcriptional Elongation by Endonucleolytic Cleavage of Nascent Transcripts [University of Miami]. https://scholarship.miami.edu/discovery/fulldisplay/alma991031605861802976/01UOML_INST:ResearchR epository Open Downloaded On 2021/09/25 13:59:55 -0400 Please do not remove this page UNIVERSITY OF MIAMI THE HUMAN INTEGRATOR COMPLEX FACILITATES TRANSCRIPTIONAL ELONGATION BY ENDONUCLEOLYTIC CLEAVAGE OF NASCENT TRANSCRIPTS By Ezra Blumenthal A DISSERTATION SuBmitteD to the Faculty of the University of Miami in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Coral GaBles, FloriDa August 2021 ©2021 Ezra Blumenthal All Rights ReserveD UNIVERSITY OF MIAMI A Dissertation suBmitteD in partial fulfillment of the requirements for the Degree of Doctor of Philosophy THE HUMAN INTEGRATOR COMPLEX FACILITATES TRANSCRIPTIONAL ELONGATION BY ENDONUCLEOLYTIC CLEAVAGE OF NASCENT TRANSCRIPTS Ezra Blumenthal ApproveD: ________________ _________________ Ramin Shiekhattar, Ph.D. Anthony J. CapoBianco, Ph.D. Professor of Human Genetics Professor of Surgery ________________ _________________ DaviD J. Robbins, Ph.D. Stephen D. Nimer, M.D. Professor of Surgery Professor of MeDicine ________________ ________________ Lluis Morey, Ph.D. Guillermo PraDo, Ph.D. Assistant Professor of Human Genetics Dean of the GraDuate School ________________ SanDra K. Lemmon, Ph.D. Professor of Molecular anD Cellular Pharmacology Blumenthal, Ezra (Ph.D., Cancer Biology) The Human Integrator Complex (August 2021) Facilitates Transcriptional Elongation By EnDonucleolytic Cleavage of Nascent Transcripts. Abstract of a Dissertation at the University of Miami. Dissertation superviseD By Ramin Shiekhattar, Ph.D. No. of pages in text. (109) Transcription By RNA polymerase II (RNAPII) is pervasive in the human genome. However, the mechanisms controlling transcription at promoters anD enhancers remain enigmatic. Here we Demonstrate that INTS11, the catalytic suBunit of the Integrator complex, regulates transcription at these loci through its enDonuclease activity. Promoters of genes require INTS11 to cleave nascent transcripts associateD with pauseD RNAPII anD inDuce their premature termination in the proximity of the +1 nucleosome. The turnover of RNAPII permits the suBsequent recruitment of an elongation-competent RNAPII complex leaDing to proDuctive elongation. In contrast, enhancers Do not require INTS11 catalysis to evict pauseD RNAPII But rather to terminate enhancer RNA transcription Beyond the +1 nucleosome. These finDings are supporteD By the Differential occupancy of NELF, SPT5, anD tyrosine-1-phosphorylateD RNAPII. This stuDy eluciDates the role of Integrator in meDiating transcriptional elongation at human promoters through the enDonucleolytic cleavage of nascent transcripts anD the Dynamic turnover of RNAPII. DEDICATION to Kay; the love of my life, best friend, and quarantine companion iii ACKNOWLEDGEMENTS I must begin by first thanking my mentor, Ramin Shiekhattar, for accepting me into his lab and taking an interest in my scientific and personal development. It is an incredible privilege to have been trained in a lab with a rich history of numerous landmark discoveries including the initial purifications of the Microprocessor, CoREST, and Integrator complexes. Ramin’s work ethic, creativity and approach to answering scientific questions exemplifies the qualities needed to succeed as a premier scientist and I am grateful to have had this exposure during my graduate studies. My deepest gratitude goes to the members of my thesis committee, Tony Capobianco, David Robbins, Lluis Morey, Sandra Lemmon, and Stephen Nimer for their unwavering support throughout my PhD training. Their suggestions and feedback during committee meetings were critical to the progress of my work and growth. There were some personally difficult moments over the years and on many occasions Drs. Morey and Lemmon offered encouraging words and helped me see the big picture. I am also profoundly thankful to Dr. Nimer for the time I spent working in his lab and his continued mentorship after my departure. My interest in hematology was sparked through this experience, which laid the foundation for my future clinical practice. My research career began serendipitously at the age of 16 when my neighbor, Neal Rosen, took me into his lab at Memorial Sloan-Kettering Cancer Center and provided the critical resources for my early development. Over the six summers I worked in his lab, I received mentoring from outstanding physician iv scientists including Christine Pratilas, David Solit, and Sarat Chandarlapaty. Though unbeknownst at the time, my access to these individuals in a rigorous scientific environment was paramount to my early career development and crucial for securing a post-baccalaureate O.R.I.S.E (Oak Ridge Institute for Science Education) fellowship at the F.D.A. and a M.D./Ph.D. fellowship at the University of Miami. Throughout all stages of my career, I received countless hours of technical assistance from dozens senior scientists, post-docs, and technicians for no other reason than pure kindness. I want to express my gratitude to all of these individuals for their selfless contribution to my success. In particular, I want to thank my co- authors Felipe Beckedorff and Lucas da Silva for their tireless efforts analyzing and digesting my genome-wide data. Without their determination, the content presented in this document would simply not exist. Finally, I conclude by thanking my wife Kalynn Cook, my parents George and Barbara Blumenthal, and my brother Avi for being the most supportive family I could ever ask for. Thanks for joining me on this incredibly gratifying journey through the echelons of science and medicine. Cheers. v TABLE OF CONTENTS LIST OF ABBREVIATIONS ix LIST OF FIGURES xi LIST OF TABLES xiii 1. INTRODUCTION 1 1.1. EUKARYOTIC TRANSCRIPTION BY RNAPII AND REGULATION OF GENE EXPRESSION BY ENHANCERS 2 1.1.1. Stages of transcription and RNAPII pause-release 2 1.1.2. Enhancer elements and genomic architecture 7 1.2. COMPOSITION AND FUNCTIONS OF THE INTEGRATOR COMPLEX 13 1.2.1. Core subunits and RNAPII association 13 1.2.2. Endonuclease-dependent functions of Integrator 17 1.2.3. Integrator’s contribution to RNAPII pause-release and the MAPK gene expression program 20 1.2.4. Physiological importance 21 2. KEY RESOURCES AND METHODS 24 2.1. KEY RESOURCES 25 2.2. METHODS 28 3. THE INTEGRATOR CATALYTIC MODULE REGULATES STEADY-STATE GENE EXPRESSION 39 3.1. APPROACH 40 3.2. RESULTS 40 3.2.1. Validation of INTS11, INTS9 and INTS4 depletion for RNA-seq 40 3.2.2. INTS11, INTS9 and INTS4 regulate expression of a core gene set 41 3.3. SUMMARY 46 4. INTEGRATOR MEDIATES TRANSCRIPTIONAL ELONGATION 47 4.1. APPROACH 48 4.2. RESULTS 49 4.2.1. Bioinformatic parameters for gene selection and INTS11 genomic occupancy 49 4.2.2. Integrator facilitates transcriptional elongation 50 4.2.3. The traveling matrix reveals Integrator-dependent transcriptional behavior 51 4.2.4. Class IV genes are enriched in Integrator and RNAPII 53 4.3. SUMMARY 55 vi 5. INTEGRATOR RELIEVES RNAPII PAUSING ADJACENT TO THE +1 NUCLEOSOME 56 5.1. APPROACH 57 5.2. RESULTS 57 5.2.1. Integrator is required for RNAPII recruitment and pause-release 57 5.2.2. The steady-state occupancy of RNAPII recapitulates alterations in nascent transcription at the four classes of genes 59 5.2.3. Integrator functions at promoters with a positioned +1 nucleosome decorated in H3K4me3 60 5.3. SUMMARY 62 6. THE CATALYTIC ACTIVITY OF INTEGRATOR PROMOTES RNAPII PAUSE-RELEASE AND CONTRIBUTES TO TRANSCRIPTIONAL ELONGATION 63 6.1. APPROACH 64 6.2. RESULTS 64 6.2.1. Validation of endogenous INTS11 depletion and shRNA-resistant expression of WT-INTS11 and E203Q-INTS11 64 6.2.2. INTS11 catalysis facilitates transcriptional elongation 65 6.2.3. INTS11 catalysis is required for RNAPII pause-release but not RNAPII recruitment 66 6.3. SUMMARY 68 7. INTS11 CATALYZES THE PREMATURE TERMINATION OF SMALL RNA ASSOCIATED WITH PAUSED RNAPII 69 7.1. APPROACH 70 7.2. RESULTS 70 7.2.1. INTS11 catalysis has a limited role in the stability of RNAPII-associated smRNA 70 7.2.2. INTS11 terminates smRNA associated with paused RNAPII 72 7.2.3. INTS11 generates a 21-nucleotide smRNA product of catalysis 73 7.3. SUMMARY 75 8. INTEGRATOR REGULATES ENHANCER RNA TRANSCRIPTIONAL TERMINATION 76 8.1. APPROACH 77 8.2. RESULTS 77 8.2.1. Integrator recruits RNAPII to enhancers and terminates eRNA transcription but is dispensable for RNAPII pause-release 77 8.2.2. The enhancer traveling matrix conveys the role of Integrator in transcriptional termination beyond the +1 nucleosome 79 vii 8.3. SUMMARY 80 9. PAUSING FACTORS AND RNAPII PHOSPHORLAYTION CONVEY INTEGRATOR FUNCTIONS AT GENES AND ENHANCERS 81 9.1. APPROACH 82 9.2. RESULTS 82 9.2.1. NELF, SPT5 and tyrosine-1 phosphorylated RNAPII affirm Integrator activity at genes and enhancers 82 9.2.2. Integrator localizes in clusters with tyrosine-1 phosphorylated RNAPII 85 9.3. SUMMARY 86 10. DISCUSSION 87 10.1. THE CONTRASTING ROLES OF HUMAN AND DROSOPHILA INTEGRATOR IN TRANSCRIPTIONAL REGULATION 88 10.2. INTEGRATOR MEDIATES THE DYNAMIC TURNOVER OF RNAPII PROXIMAL TO THE +1 NUCLEOSOME
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