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Title: Role of the chromatin remodeller LSH in oligodendrocyte differentiation and CNS myelination
Author: Belton, Christian Alexander
ISNI:       0000 0004 7969 4438
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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Previous work in embryonic cell lines has implicated LSH in the deposition of DNA methylation, a key regulatory epigenetic modification during mammalian development. We have generated a conditionally reversible knock-out of Lsh (Lshoff) to investigate its role in vivo. Lshoff/off mice survive to adulthood but develop a tremor and ataxia phenotype. Transmission election microscopy of nervous tissue shows this phenotype is concurrent with central nervous system (CNS) hypomyelination. Lshoff/off animals also have a reduction in mature oligodendrocyte (mOL) cell numbers, but similar number of oligodendrocyte (OL) lineage cells in total, indicating the presence of an OL differentiation defect. Conversion to Lshon/on in OPCs leads to complete rescue of the phenotype, suggesting LSH expression in the OL lineage is necessary for terminal differentiation. OPC specific knock-out of Lsh however produces no phenotype. Sequencing of Lshoff/off adult optic nerve RNA reveals under-expression of genes associated with mOLs, the myelinating cells of the CNS, but no cognate upregulation of oligodendrocyte precursor cell (OPC) markers. Interrogation of DNA methylation in rescued OPCs however reveals scant to no rescue in the hypomethylation present in Lshoff/off OPCs. Taken together these results show an essential role for LSH in OL differentiation and that LSH dependent DNA methylation patterns are not required prior to differentiation to mOLs. We hypothesize that early life LSH expression instead establishes a DNA methylation independent chromatin state required for differentiation and this is maintained in the absence of LSH expression following OPC cell cycle exit.
Supervisor: Bird, Adrian ; Ffrench-Constant, Charles Sponsor: Medical Research Council (MRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: LSH ; multiple sclerosis ; DNA methylation ; mature oligodendrocyte ; oligodendrocyte ; mOLs ; OPC cell cycle ; oligodendrocyte precursor cell