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Effects of HIRA deficiency on differentiating and dividing mammalian cells

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Title: Effects of HIRA deficiency on differentiating and dividing mammalian cells
Authors: Wise, Philip John Surtees
Item Type: Thesis or dissertation
Abstract: HIRA is one of the chaperones of histone variant H3.3. Deficiency of HIRA or its homologues in S. cerevisiae, S. pombe, Drosophila and chicken has been associated with both activating and repressing effects on euchromatic gene transcription, with gene silencing defects in pericentromeric heterochromatin and with mitotic defects including an extension of cell cycle length. At the organism level, homozygous Hira knockout is embryonically lethal in mice. Several previously established mouse strains have a transgene inserted into a variety of genomic locations including regions of putative facultative heterochromatin and constitutive (pericentromeric) heterochromatin where it displays position effect variegation (PEV) in that the transgene is stochastically silenced in a proportion of T cells. The effects of HIRA deficiency on PEV of this transgene showed that HIRA was necessary for PEV in putative facultative heterochromatin and it appeared that, in this environment, it played a role both in the rate of establishment (during T cell development) and in the maintenance of PEV (in mature T cells). This was in contrast to its effect in constitutive (pericentromeric) heterochromatin where Hira knockout in vivo had no effect on the variegation of a transgene. On the other hand, the reduction in variegation usually induced by T cell activation was lessened by HIRA deficiency in another mouse strain where the transgene was located in close proximity to pericentromeric heterochromatin. The contribution of HIRA to the extent of expression changes in facultative heterochromatin was consistent with delays observed in the normal transcriptional changes of some genes during the differentiation of HIRA deficient murine ES cells. In common with S. pombe and chicken, cell cycle delay in G2/M was seen in HIRA deficient murine cell lines. This is believed to be the first observation of this effect in mammalian cells suggesting evolutionary conservation of this function.
Issue Date: 2011
Date Awarded: Mar-2011
URI: http://hdl.handle.net/10044/1/9570
DOI: https://doi.org/10.25560/9570
Supervisor: Festenstein, Richard
Department: Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses



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