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Evaluation of the Epigenetic Regulation of Two X-Linked, Autism Candidate Genes: X-Linked Lymphocyte Regulated 3B and Transketolase-Like 1" (2018)

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Evaluation of the Epigenetic Regulation of Two X-Linked, Autism Candidate Genes: X-Linked Lymphocyte Regulated 3B and Transketolase-Like 1 University of Connecticut OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 11-8-2018 Evaluation of the Epigenetic Regulation of Two X- linked, Autism Candidate Genes: X-linked Lymphocyte Regulated 3b and Transketolase-Like 1 Glenn W. Milton University of Connecticut - Storrs, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Milton, Glenn W., "Evaluation of the Epigenetic Regulation of Two X-linked, Autism Candidate Genes: X-linked Lymphocyte Regulated 3b and Transketolase-Like 1" (2018). Doctoral Dissertations. 1983. https://opencommons.uconn.edu/dissertations/1983 Evaluation of the Epigenetic Regulation of Two X-linked, Autism Candidate Genes: X-linked Lymphocyte Regulated 3b and Transketolase-Like 1 Glenn W. Milton, PhD University of Connecticut 2018 Abstract According to the CDC the prevalence of Autism Spectrum Disorder (ASD) in males compared to females is approximately 5:1. Skuse et al. hypothesized that imprinted genes on the X chromosome could account for this sex bias. Genomic imprinting is defined as differential gene expression dependent upon the parental origin of the allele. While genomic imprinting on autosomes has been well classified, no imprinting mechanism on the sex chromosomes has been discovered. This work presents an investigation into the regulation of expression governing the imprinted locus of X-Linked Lymphocyte Regulated 3b/4b/4c (Xlr3/4), and closely linked ASD candidate gene, Transketolase-Like 1 (TKTL1), in the developing central nervous system of the laboratory mouse. Examination of epigenetic signatures and the chromatin environment including differential DNA methylation, differential nucleosome positioning, H3.3 deposition and G-quadruplex formation, suggests that epimutations in these loci may underlie disease association. Transketolases play a pivotal role in the Pentose Phosphate Pathway (PPP), and dysfunction in the non-oxidative phase of the PPP has been linked to neurodegenerative disorders and cancers. This work explores the expression of TKTL1 in human brain sub-regions of ASD patients compared to neurotypical individuals as well as the functional role TKTL1 plays in the PPP. It is observed that TKTL1 may not Glenn Milton University of Connecticut 2018 function as a transketolase in the pathway, but may play a critical regulatory role as a competitive inhibitor. Evaluation of the Epigenetic Regulation of Two X-linked, Autism Candidate Genes: X-linked Lymphocyte Regulated 3b and Transketolase-Like 1 Glenn W. Milton B.S., Quinnipiac University, 2010 A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy At the University of Connecticut 2018 i APPROVAL PAGE Doctor of Philosophy Dissertation Evaluation of the Epigenetic Regulation of Two X-linked, Autism Candidate Genes: X- linked Lymphocyte Regulated 3b and Transketolase-Like 1 Presented By: Glenn W. Milton B.S. Major Adivsor Michael J. O’Neill Ph.D. Associate Advisor Rachel J. O’Neill Ph.D. Associate Advisor John Malone Ph.D. Associate Advisor Leighton Core Ph.D. Associate Advisor Joseph LoTurco Ph.D. University of Connecticut 2018 ii Acknowledgements First, I would like to thank my P.I., Michael O’Neill. It has been incredible working with you in your laboratory for the duration of my research. From our first meeting before I started at UCONN, I knew your lab was a great fit for growth and support as a scientist. It has been a pleasure being a TA for your courses where you allowed me to grow as an instructor and not just as a scientist. Your door was always open to discuss any and all science ideas, or life in general, and for that I will forever be grateful. To my committee members: Rachel, you have always been an incredible resource in terms of my progress as a scientist. I know if I ever had a question, you would be more than willing to help. You helped shape the course of my research and pointed me in directions I may have otherwise not explored. John, from my very first meeting with you, your enthusiasm for science has been contagious. When we met for my proposal, we spoke for over two hours about my research and you were always happy when we saw each other in the halls to catch up on my progress. Leighton, your NGS and bioinformatics experience have been indispensable to my scientific growth. Joe, your questions pushing me to think critically about neurons and the impact my gene of interest may have has made me a better all-around scientist. To all my committee members, thank you. To all O’Neill members past and present thank you. Especially Sohaib who trained me in lab when I first started. And Rob for being a great friend and person to discuss science with literally any time, day or night. Thank you to my graduate and undergrad students who were integral to my success in the lab, Hannah, Becca, Jessica and Liz. To all of my family, your love and support has helped me through my winding path. To my parents especially, thank you for raising me to be the person I am today and supporting me in accomplishing my goals. I spent over ten years in Connecticut away from my family but every time we spoke or I saw you, you made me feel like the best son, brother, uncle, husband and father in the world. To my friends, particularly Adam and Jeff, thank you for always making me laugh. You have always been there for me and I will never forget how much you mean to my life. Most important of all, thank you to my wife Sami and my son Jack. You are my rock, my inspiration, and my driving force. Sami, you always push me to be better than I ever thought I could be. Without your love and support, I know I would not have been able to accomplish this goal. Jack, all of this is for you. I hope I can be as inspiring to you as the people in my life have been for me. I love you and thank you for being the best thing I have ever done. iii Table of Contents Chapter 1: Introduction ................................................................................................. 1 Overview .............................................................................................................. 1 Background .......................................................................................................... 4 Evidence of a Social Cognitive Deficit Associated with X Chromosome Parent of Origin .................................................................................................................... 7 The Epigenetic Effect on ASD .............................................................................. 9 Evolutionary Origin of Genomic Imprinting ......................................................... 10 Genomic Imprinting in the Context of Disease .................................................... 12 Genomic Imprinting and Behavior....................................................................... 13 Underlying Imprinting Control Mechanisms ........................................................ 14 DNA Methylation and DMRs ............................................................................... 16 Mammalian Dosage Compensation .....................................................................17 Raefski Development of Turner Syndrome Model Mice ...................................... 19 Chapter 2: The Imprinted X-Linked Lymphocyte Regulated (Xlr) ........................... 22 Characterization of the First X-Linked Imprinted Locus (Xlr) .............................. 22 Functional Study of the Xlr3b Protein ................................................................. 24 Regulation of the Imprinted Xlr Cluster (Xlr3/4) .................................................. 25 Chapter 3: Chromatin Architecture at the Imprinted Cluster Xlr3/4 Region ........... 30 Bionano Methylation of XA7.2 ............................................................................ 30 Nucleosome Positioning at XA7.2 ...................................................................... 33 Assay of Nucleosome Positioning by MNase-Seq .............................................. 34 Open Chromatin and Nucleosome Occupancy ................................................... 41 ATAC-Seq DNA Transcription Factor Binding and DNA Footprint Analysis ........ 53 Conclusions ........................................................................................................ 56 Chapter 4: The Transketolase-Like 1 Gene in Neurodevelopment ..........................66 Discovery of the Tktl1 Imprinted Expression in Mouse ....................................... 66 TKTL1 Expression in Human Brain Sub-Regions ............................................... 69 TKTL1 Imprinting Status in Human Brain Sub-Regions. ..................................... 74 Conclusions ........................................................................................................ 75 Chapter 5: Characterization of the TKTL1 Protein ................................................... 77 TKTL1 Protein Interactions ................................................................................. 79 Conclusions ........................................................................................................ 85 Chapter 6: Synthesis and Future Directions ............................................................. 88 Chapter 7: Materials and Methods ........................................................................... 103 iv Table of Figures Figure 1: Skuse et al. Social Cognitive Ability 8
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