Browsing by Subject "Oligodendroglia"
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Item Cohesin Promotes the Myelination Transcriptional Program in Oligodendrocytes(December 2021) Cheng, Ningyan; O'Donnell, Kathryn A.; Buszczak, Michael; Olson, Eric N.; Yu, HongtaoThe 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.Item Epigenetic Regulation of Oligodendrocyte Development and Regeneration in the Central Nervous System(2016-10-26) He, Danyang; Kraus, W. Lee; Lu, Q. Richard; Johnson, Jane E.; Olson, Eric N.Oligodendrocytes (OLs) produce myelin sheaths that electrically insulate axons and promote rapid propagation of action potentials in the CNS. The onset and timing of CNS myelination and remyelination requires precise coordination between epigenetic programming and transcriptional regulation. In this thesis, I present my findings on two epigenetic regulatory complexes Chd7/Sox10 and lncOL1/Suz12 in CNS myelination and remyelination. First, we show that chromatin remodeler Chd7 is required for proper onset of CNS myelination and remyelination. Genome-occupancy analyses, coupled with transcriptome profiling, reveal that Chd7 interacts with Sox10 and targets the enhancers of key myelinogenic genes, and identify novel Chd7 targets including bone formation regulators Osterix/Sp7 and Creb3l2, which are also critical for oligodendrocyte maturation. Thus, Chd7 coordinates with Sox10 to regulate the initiation of myelinogenesis and acts as a molecular nexus of regulatory networks that account for the development of a seemingly diverse array of lineages including oligodendrocytes and osteoblasts, pointing to the hitherto previously uncharacterized Chd7 functions in white matter pathogenesis in CHARGE syndrome. To understand the role of lncRNAs in CNS myelination, we establish dynamic expression profiles of lncRNAs at different stages of oligodendrocyte development and uncover a cohort of stage-specific oligodendrocyte-restricted lncRNAs including a conserved chromatinassociated lncOL1. Genetic inactivation of lncOL1 causes defects in CNS myelination and remyelination following injury. Functional analyses illustrate that lncOL1 interacts with Suz12, a component of PRC2, to promote oligodendrocyte maturation in part through Suz12-mediated repression of a differentiation inhibitory network that maintains the precursor state. Collectively, these studies show that epigenetic circuitry between lncRNAs and transcription factors with chromatin-modifying complexes play roles in balancing inhibitory and activating gene program, allowing the timely CNS myelination and myelin repair.Item Mash1 Defines Lineage Restricted Neuronal and Oligodendrocytic Precursor Cells in Spinal Cord Development(2007-05-21) Battiste, James Douglas; Johnson, Jane E.Recent advances have defined distinct neural progenitor and early interneuron pools in the developing spinal cord and the molecular events that influence progenitor cell fate. However, these early neurons have not been traced to adult neuron types. The transcription factor Mash1 is transiently expressed in a subset of neural progenitors and possesses a pro-neural function. The transient nature of its expression limits the ability to trace Mash1+ progenitors. To study the developing neural tube from progenitor to adult neuron, transgenic mouse strains were generated that express GFP, Cre recombinase, and tamoxifen-inducible Cre recombinase. The M1-GIC mouse line, showed faithful Mash1 expression recapitulation and traces Mash1+ progenitors mainly to dI3 and dI5 interneurons. This supports data from the Mash1 null mutant where these populations are decreased or absent. Using M1-GIC;R26R-lacZ mice, I was able to trace Mash1 expressing cells to neurons and oligodendrocytes in the adult mouse, but tracing to astrocytes was never observed. These data refute the conventional understanding that Mash1 is purely pro-neuronal, and is consistent with recent findings of Mash1 descendents in the early postnatal subventricular zone. Using M1-CRE-ER™;R26RlacZ and M1-CRE-ER™;R26R-YFP, Mash1+ cells trace into adulthood in a temporally-dependant manner. Cells expressing Mash1 at E10.5 become neurons of the dorsal horn in lamina I-IV while cells expressing Mash1 at E15.5 become oligodendrocytes spread over both gray and white matter. As a control, Nestin- CreERT2;R26R-lacZ and Nestin-CreERT2;R26R-YFP mice were used to confirm that common progenitors of all neural cell types can be traced from E10.5 to P21. This data provides evidence that Mash1 defines lineage restricted precursors that exit the cell cycle rapidly, and Mash1 is necessary for efficient loss of common progenitor characteristics as seen in the Mash1 null mutant. This data refines our understanding of progenitor characteristics and Mash1 function in the developing spinal cord.Item The Role of Ascl1 in NG2 Cells in the Spinal Cord(2015-01-26) Kelenis, Demetra; Johnson, Jane; Vue, Tou YiaNG2 cells, one of the major glial cell populations within the central nervous system (CNS), are highly proliferative cells identified by the expression of the NG2 proteoglycan. Throughout life, NG2 cells can differentiate into oligodendrocytes to myelinate axon fibers, or they can be maintained in a proliferative or quiescent state as NG2 cells indefinitely. A recent study showed that deletion of tumor suppressor genes specifically within NG2 cells was sufficient to produce brain tumors in a mouse model, indicating that NG2 cells may serve as a potential cell of origin for gliomas. At present, however, understanding of how NG2 cells are regulated to proliferate or differentiate in the CNS remains incomplete. Interestingly, Ascl1, a proneural basic-helix-loop-helix (bHLH) transcription factor that is highly expressed in neural progenitor cells, is also expressed in NG2 cells. Although previous studies have shown that the loss of Ascl1 affects the initial specification and differentiation of NG2 cells, the specific role of Ascl1 in NG2 cells during embryonic and postnatal development remains unknown. In this study, we investigated the direct requirement of Ascl1 in NG2 cells during embryonic and postnatal development in the grey matter (GM) and white matter (WM) of the spinal cord. More specifically, we conditionally deleted Ascl1 specifically within NG2 cells (Ascl1-CKO) at E14.5 or at P30 using an NG2-CreERT2 mouse strain in which the tdTomato (tdTom) fluorescence reporter was also incorporated to allow direct visualization of the development of NG2-labeled (tdTom+) cells. We found that Ascl1-CKO at E14.5 resulted in a decrease in the number of tdTom+ cells in the GM, but an increased number of tdTom+ cells in the WM. In contrast, Ascl1-CKO at P30 resulted in a significant reduction in the number of tdTom+ cells in both the GM and WM. Quantification of the percentage of tdTOM-labeled cells that had differentiated to mature oligodendrocytes revealed that Ascl1-CKO at E14.5 does not affect NG2 cell differentiation, while Ascl1-CKO at P30 accelerated NG2 cell differentiation. Taken together, these findings indicate that Ascl1 is differentially required to regulate the number of NG2 cells in the GM and WM during embryonic development, whereas Ascl1 is essential for regulating both the differentiation and number of NG2 cells in the adult CNS.