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Characterizing the Functional Role and Epigenetic Regulation of Large Tandem Repeats on the Inactive X Chromosome

Title: Characterizing the Functional Role and Epigenetic Regulation of Large Tandem Repeats on the Inactive X Chromosome.
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Name(s): Darrow, Emily M. (Emily Michelle), author
Chadwick, Brian P., professor directing dissertation
Hurt, Myra M., university representative
McGinnis, Karen M., committee member
Deng, Wu-Min, committee member
Bass, Hank W., committee member
Florida State University, degree granting institution
College of Arts and Sciences, degree granting college
Department of Biological Science, degree granting department
Type of Resource: text
Genre: Text
Doctoral Thesis
Issuance: monographic
Date Issued: 2017
Publisher: Florida State University
Place of Publication: Tallahassee, Florida
Physical Form: computer
online resource
Extent: 1 online resource (91 pages)
Language(s): English
Abstract/Description: X chromosome inactivation (XCI), the mammalian form of dosage compensation, is a canonical example of epigenetic regulation and involves the transcriptional repression of nearly an entire chromosome (Xi) while preserving the transcriptional activity of its homologue (Xa) in females. Since the initial report describing a dense nuclear cytological feature in female feline neurons and Mary Lyon’s subsequent hypothesis of random X chromosome inactivation as a means of compensating for the lack of two X chromosomes in males, XCI has yielded decades of insights into the mechanisms of epigenetic regulation. This dissertation focuses on the three-dimensional organization of the Xi and the functional potential of large tandem repeats. The large X-linked tandem repeat, DXZ4, adopts a euchromatic conformation on the Xi in contrast to the largely heterochromatic chromosome and is able to form CTCF-dependent interactions with other euchromatic repeats exclusively on inactive X chromosome in females. We demonstrate here that DXZ4 has a critical role in maintaining the three-dimensional organization of the Xi as well as the separation of multi-megabase domains containing different types of heterochromatin. While characterizing the genomic interval of DXZ4, we uncovered transcriptional activity corresponding to two novel, long non-coding RNAs (lncRNAs) which originate on opposite sides of the DXZ4 and are transcribed antisense to one another. Both of these lncRNAs traverse the array in human embryonic stem cells (hESCs). Developmentally associated transcription suggests a potential connection between their transcription activity and maintenance of a heterochromatic DXZ4 on the Xa and male X prior to differentiation. Mouse and human genomes largely share the same gene content in accordance with Ohno’s law; however, the mouse genome has undergone rearrangements involving large syntenic blocks and has acquired several multi-megabase, lineage-specific regions of repetitive DNA that are absent in human. To further our understanding of the mouse inactive X chromosome and highlight another difference between human and mouse XCI, we characterized an approximately 20-Mb repeat that, similar to DXZ4, displays marks of euchromatin on the Xi and conversely displays marks of heterochromatin on the Xa. Overall, this work gives new insight into the function and epigenetic regulation of macrosatellites as well as the relationship between higher-order chromatin organization and heterochromatin maintenance of the Xi.
Identifier: 2018_Sp_Darrow_fsu_0071E_14252 (IID)
Submitted Note: A Dissertation submitted to the Department of Biological Science in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Degree Awarded: Fall Semester 2017.
Date of Defense: December 4, 2017.
Bibliography Note: Includes bibliographical references.
Advisory Committee: Brian P. Chadwick, Professor Directing Dissertation; Myra M. Hurt, University Representative; Karen M. McGinnis, Committee Member; Wu-Min Deng, Committee Member; Hank W. Bass, Committee Member.
Subject(s): Molecular biology
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/2018_Sp_Darrow_fsu_0071E_14252
Host Institution: FSU

Choose the citation style.
Darrow, E. M. (E. M. ). (2017). Characterizing the Functional Role and Epigenetic Regulation of Large Tandem Repeats on the Inactive X Chromosome. Retrieved from http://purl.flvc.org/fsu/fd/2018_Sp_Darrow_fsu_0071E_14252