The Functional Roles for SWI/SNF Chromatin Remodeling Complexes in Physiology and Disease
| dc.contributor.advisor | Wu, Jiang I. | en |
| dc.contributor.committeeMember | Zhu, Hao | en |
| dc.contributor.committeeMember | Olson, Eric N. | en |
| dc.contributor.committeeMember | Xu, Jian | en |
| dc.creator | Celen, Cemre | en |
| dc.creator.orcid | 0000-0001-8308-3750 | |
| dc.date.accessioned | 2023-01-02T21:43:51Z | |
| dc.date.available | 2023-01-02T21:43:51Z | |
| dc.date.created | 2020-12 | |
| dc.date.issued | 2020-12-01T06:00:00.000Z | |
| dc.date.submitted | December 2020 | |
| dc.date.updated | 2023-01-02T21:43:53Z | |
| dc.description.abstract | Sequencing studies have implicated multiple subunits of SWI/SNF complexes in human neurodevelopmental and psychiatric disorders, as well as in cancers. Particularly haploinsufficiency of ARID1B, a SWI/SNF chromatin-remodeling subunit, has been implicated in short stature, autism spectrum disorder, intellectual disability, and corpus callosum agenesis. In addition, ARID1B is the most common cause of Coffin-Siris Syndrome, a developmental delay syndrome characterized by some of the above abnormalities. However, its role in pathologies is not well characterized due to absence of in vivo models. Therefore, in the first part of this thesis, we generated Arid1b heterozygous mice, which showed social behavior impairment, altered vocalization, anxiety-like behavior, neuroanatomical abnormalities, and growth impairment. In the brain, Arid1b haploinsufficiency resulted in changes in the expression of SWI/SNF-regulated genes implicated in neuropsychiatric disorders. A focus on reversible mechanisms identified insulin-like growth factor deficiency with inadequate compensation by Growth Hormone Releasing Hormone and Growth Hormone, underappreciated findings in ARID1B patients. Therapeutically, GH supplementation was able to correct growth retardation and muscle weakness. This model functionally validates the involvement of ARID1B in human disorders and allows mechanistic dissection of neurodevelopmental diseases linked to chromatin-remodeling. ARID1A is a paralogous subunit that is commonly mutated in cancers and plays critical roles in liver regeneration. Chromatin remodeling mechanisms could be generally important for regeneration in other tissues. Since dynamic regulation of β-cell proliferation in pancreatic islets is poorly understood and better understanding could lead to therapeutic approaches for replenishing β-cell mass in type 1 and type 2 diabetes, in the second part of this thesis we focused on the role of ARID1A in β-cells. Arid1a is physiologically suppressed when β-cells proliferate during pregnancy or after pancreas resection. Whole-body Arid1a knockout mice were protected against streptozotocin induced diabetes. Cell-type and temporally specific genetic dissection showed that β-cell specific Arid1a deletion could potentiate β-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets revealed increased Neuregulin-ERBB-NR4A signaling. Functionally, chemical inhibition of ERBB or NR4A was able to block increased regeneration associated with Arid1a loss. Together, this work defined the role of ARID1A in β-cells and provided new insights into the molecular regulators of β-cell regeneration. Overall, we uncovered important roles of ARID1A and ARID1B-containing SWI/SNF complexes in physiological and disease states. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 1356910546 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/10003 | |
| dc.language.iso | en | en |
| dc.subject | Developmental Disabilities | en |
| dc.subject | DNA-Binding Proteins | en |
| dc.subject | Mental Disorders | en |
| dc.subject | Nuclear Proteins | en |
| dc.subject | Transcription Factors | en |
| dc.title | The Functional Roles for SWI/SNF Chromatin Remodeling Complexes in Physiology and Disease | en |
| dc.type | Thesis | en |
| dc.type.material | text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Genetics, Development and Disease | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |