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Epigenetic Regulation of Hepatitis B Virus Biosynthesis
Başlık:
Epigenetic Regulation of Hepatitis B Virus Biosynthesis
Yazar:
Shalaby, Rasha, author.
ISBN:
9780438118799
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (109 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Alan McLachlan Committee members: Nancy Freitag; Bin He; Howard Lipton; Bellur Prabhakar; Pradip Raychaudhuri.
Özet:
Transcription of cellular genes occurs in the context of chromatin and is known to be regulated by DNA and histone modifications, which govern the accessibility of transcription factors and coactivators to their regulated gene promoters and enhancers to modulate transcription. For transcription to take place from a repressed chromatin template, repressive epigenetic modifications including DNA methylation have to be removed. Additionally, associated repressive histone marks have to be replaced by transcriptional activation marks deposited by means of histone modifiers to promote open chromatin conformation which provides accessibility to downstream transcription factors or nuclear receptors and their associated coactivators to get recruited and hence, transcription is activated. The transition from a repressed to a transcriptionally competent chromatin state during development is a role that has been ascribed to pioneer transcription factors which can access their binding sites in compact chromatin such as FOXA pioneer transcription factors. The current study sheds light on a potentially similar mode of regulation connecting HBV epigenome to its transcriptional activation. This study demonstrates that wildtype expression of FOXA transcription factors in the liver of HBV transgenic mouse model of chronic infection during development is required for the loss of repressive HBV transgene DNA methylation and hence, HBV transcriptional activation. The loss of viral DNA methylation presumably promotes a series of events including the formation of open chromatin conformation, the recruitment of nuclear receptors or transcription factors and their associated coactivators such as PGC1 to viral gene promoters to activate viral gene expression. Consistent with that, the current study demonstrates that PGC1 coactivators, by functioning as adaptor molecules, recruit additional coactivators with histone modifying activity such as CBP, SRC1 and PRMT1 which presumably contribute to the active chromatin structure associated with HBV genes by means of covalent histone modifications. The recruitment of PGC1 coactivators to viral gene promoters in this study leads to activation of viral transcription and hence replication. The current study also demonstrates that PGC1-dependent HBV replication seems to be governed by a critical threshold level of HBV core antigen (HBcAg) polypeptides required for the assembly of replication-competent HBV nucleocapsids. This observation highlights a potential cooperative capsid assembly process required for viral replication to occur. In conclusion, the current study provides a suggested model for the potential coupling of FOXA pioneer transcription factor-mediated loss of repressive HBV DNA methylation to viral transcriptional activation in which PGC1 transcriptional coactivators could play a role. These observations provide mechanistic insights into HBV gene regulation and also suggest potential routes for resolution of chronic HBV infection via modulating FOXA and PGC1 levels or activities.
Notlar:
School code: 0799
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(687461.1) | 687461-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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