Cohesin Promotes the Myelination Transcriptional Program in Oligodendrocytes

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dc.contributor.advisorO'Donnell, Kathryn A.en
dc.contributor.committeeMemberBuszczak, Michaelen
dc.contributor.committeeMemberOlson, Eric N.en
dc.contributor.committeeMemberYu, Hongtaoen
dc.creatorCheng, Ningyanen
dc.creator.orcid0000-0001-8764-552X
dc.date.accessioned2024-01-11T20:04:06Z
dc.date.available2024-01-11T20:04:06Z
dc.date.created2021-12
dc.date.issuedDecember 2021
dc.date.submittedDecember 2021
dc.date.updated2024-01-11T20:04:07Z
dc.descriptionThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.en
dc.description.abstractThe cohesin complex is crucial for sister-chromatid cohesion and chromatin spatial organization in the interphase nucleus. Cohesin-extruded DNA loops have regulatory functions in gene expression. Mutations of cohesin subunits and regulators cause human developmental diseases termed cohesinopathies. The vertebrate cohesin consists of SMC1, SMC3, RAD21, and either STAG1 or STAG2. STAG1-cohesin and STAG2-cohesin are redundant in sister-chromatid cohesion, but appear to exert specific functions in gene regulation. How they achieve their functions in gene expression is poorly understood. I characterized the outcomes of Stag2 loss in the mouse nervous system. Conditional knockout (CKO) of Stag2 in the nervous system causes severe growth retardation, neurological defects, and premature death, in part due to insufficient myelination of nerve fibers. Expression profiling reveals that myelination-related genes are downregulated in oligodendrocytes of Stag2 CKO mice. Chromatin conformational capture experiments (Hi-C) reveal that Stag2-deficient oligodendrocytes contain fewer DNA loops than wild-type cells do. In particular, promoter-anchored DNA loops at downregulated genes are significantly reduced by Stag2 loss. Interestingly, downregulated genes exhibit promoter-anchored "stripes", indicative of strong loop extrusion. We propose that STAG2-cohesin generated promoter-anchored loops at myelination-promoting genes are critical for the proper gene expression during oligodendrocyte differentiation and brain development. Our study implicates defective myelination as a contributing factor to cohesinopathy and establishes oligodendrocytes as a relevant cell type to explore the mechanism by which cohesin regulates transcription.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1417098559
dc.identifier.urihttps://hdl.handle.net/2152.5/10221
dc.language.isoenen
dc.subjectCell Cycle Proteinsen
dc.subjectCohesinsen
dc.subjectGene Expressionen
dc.subjectOligodendrogliaen
dc.titleCohesin Promotes the Myelination Transcriptional Program in Oligodendrocytesen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineGenetics, Development and Diseaseen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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UT Southwestern Graduate School of Biomedical Sciences