Small Molecules Modulate Chromatin Accessibility to Promote NEUROG2-Mediated Fibroblast-to-Neuron Reprogramming

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dc.contributor.advisorJohnson, Jane E.en
dc.contributor.committeeMemberKim, Tae-Kyungen
dc.contributor.committeeMemberOlson, Eric N.en
dc.contributor.committeeMemberZhang, Chun-Lien
dc.creatorSmith, Derek Kurtisen
dc.date.accessioned2018-08-24T20:38:26Z
dc.date.available2018-08-24T20:38:26Z
dc.date.created2016-08
dc.date.issued2016-07-12
dc.date.submittedAugust 2016
dc.date.updated2018-08-24T20:31:47Z
dc.description.abstractThe activity of pro-neural signaling molecules and transcription factors is sufficient to induce the transdifferentiation of lineage-restricted fibroblasts into functional neurons; however, a mechanistic model of the immediate-early events that catalyze this conversion has not been well defined. We utilized a high-efficiency reprogramming system of NEUROG2, forskolin (F), and dorsomorphin (D) to characterize the genetic and epigenetic events that initiate an acquisition of neuronal identity in fetal human fibroblasts. NEUROG2 immediately activates a neurogenic program, but is only sufficient to impart a functional identity in the presence of FD. These small molecules promote NEUROG2 and CREB1 co-transcription, induce SOX4 expression, and promote SOX4-dependent chromatin remodeling. Genome-wide occupancy analysis revealed that SOX4 targets numerous SWI/SNF complex subunits and co-binds with NEUROG2 to enhance the expression of diverse neurogenic factors. The overexpression of SWI/SNF chromatin remodeling factors or treatment with small molecules that modify chromatin accessibility enhanced NEUROG2-mediated neuronal reprogramming of adult human skin fibroblasts. This work represents the first comprehensive mechanism for the immediate events that catalyze neuronal transdifferentiation.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1049807580
dc.identifier.urihttps://hdl.handle.net/2152.5/5735
dc.language.isoenen
dc.subjectBasic Helix-Loop-Helix Transcription Factorsen
dc.subjectCell Transdifferentiationen
dc.subjectCellular Reprogrammingen
dc.subjectChromatin Assembly and Disassemblyen
dc.subjectFibroblastsen
dc.subjectNerve Tissue Proteinsen
dc.subjectNeuronsen
dc.titleSmall Molecules Modulate Chromatin Accessibility to Promote NEUROG2-Mediated Fibroblast-to-Neuron Reprogrammingen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineNeuroscienceen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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