Role of the chromatin remodeller LSH in oligodendrocyte differentiation and CNS myelination
dc.contributor.advisor
Bird, Adrian
en
dc.contributor.advisor
Ffrench-Constant, Charles
en
dc.contributor.author
Belton, Christian Alexander
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dc.contributor.sponsor
Medical Research Council (MRC)
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dc.date.accessioned
2019-09-06T10:22:06Z
dc.date.available
2019-09-06T10:22:06Z
dc.date.issued
2019-11-23
dc.description.abstract
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.
en
dc.identifier.uri
http://hdl.handle.net/1842/36100
dc.language.iso
en
dc.publisher
The University of Edinburgh
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dc.subject
LSH
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dc.subject
multiple sclerosis
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dc.subject
DNA methylation
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dc.subject
mature oligodendrocyte
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dc.subject
oligodendrocyte
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dc.subject
mOLs
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dc.subject
OPC cell cycle
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dc.subject
oligodendrocyte precursor cell
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dc.title
Role of the chromatin remodeller LSH in oligodendrocyte differentiation and CNS myelination
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dc.type
Thesis or Dissertation
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dc.type.qualificationlevel
Doctoral
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dc.type.qualificationname
PhD Doctor of Philosophy
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