Mice Deficient in APOBEC2 and APOBEC3

Mikl, Marie C.; Watt, Ian N.; Lu, Mason; Reik, Wolf; Davies, Sarah L.; Neuberger, Michael S.; Rada, Cristina

doi:10.1128/mcb.25.16.7270-7277.2005

Cited by 110 publications

(113 citation statements)

References 53 publications

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“…It is possible that these proteins, like other Apobecs, catalytically edit RNAs, but it is also possible that they perform some function that is independent of a deaminase activity. Indeed, some have questioned whether Apobec2 proteins are catalytically active and whether they bind polynucleotides (36)(37)(38)(39). Further work is needed to shed light on the mechanism of these proteins.…”

Section: Discussionmentioning

confidence: 99%

Analysis of DNA methylation reveals a partial reprogramming of the Müller glia genome during retina regeneration

Powell

Grant

Cornblath

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

113

138

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Upon retinal injury, zebrafish Müller glia (MG) transition from a quiescent supportive cell to a progenitor cell (MGPC). This event is accompanied by the induction of key transcription and pluripotency factors. Because somatic cell reprogramming during induced pluripotent stem cell generation is accompanied by changes in DNA methylation, especially in pluripotency factor gene promoters, we were interested in determining whether DNA methylation changes also underlie MG reprogramming following retinal injury. Consistent with this idea, we found that genes encoding components of the DNA methylation/demethylation machinery were induced in MGPCs and that manipulating MGPC DNA methylation with 5-aza-2′-deoxycytidine altered their properties. A comprehensive analysis of the DNA methylation landscape as MG reprogram to MGPCs revealed that demethylation predominates at early times, whereas levels of de novo methylation increase at later times. We found that these changes in DNA methylation were largely independent of Apobec2 protein expression. A correlation between promoter DNA demethylation and injurydependent gene induction was noted. In contrast to induced pluripotent stem cell formation, we found that pluripotency factor gene promoters were already hypomethylated in quiescent MG and remained unchanged in MGPCs. Interestingly, these pluripotency factor promoters were also found to be hypomethylated in mouse MG. Our data identify a dynamic DNA methylation landscape as zebrafish MG transition to an MGPC and suggest that DNA methylation changes will complement other regulatory mechanisms to ensure gene expression programs controlling MG reprogramming are appropriately activated during retina regeneration.repair | multipotent | Ascl1 | bisulfite sequencing | DNA sequencing I nduced pluripotent stem cells (iPSCs) can be generated through the forced expression of pluripotency factor genes, such as Oct4, Klf4, Sox2, c-Myc, Lin28, and Nanog, which are normally expressed in embryonic stem cells (ESCs) (1, 2). Pluripotency factor gene expression in ESCs and iPSCs is associated with chromatin that is in an "open" accessible state, whereas their repression in somatic cells is associated with less accessible, condensed chromatin (3). DNA methylation has a significant impact on chromatin structure (3). DNA demethylation of pluripotency factor promoter regions is correlated with increased expression during iPSC formation (4, 5). Similar epigenetic changes are seen in other cellular reprogramming events such as nuclear transfer (6), heterokaryon formation (7), and carcinogenesis (8).Tissue regeneration provides another avenue to study cellular reprogramming. Unlike mammals, zebrafish can regenerate multiple tissues, including the retina. During zebrafish retina regeneration, Müller glia (MG) reprogram to generate progenitor cells (MGPCs) capable of replacing all lost neural cell types (9-12). The role that MG play during this regenerative event can be roughly divided into three phases: the replication-independent transition of MG to...

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Section: Discussionmentioning

confidence: 99%

Analysis of DNA methylation reveals a partial reprogramming of the Müller glia genome during retina regeneration

Powell

Grant

Cornblath

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

113

138

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“…The B6-BAFF-R Ϫ/Ϫ mice homozygously carry a targeted disruption of the BAFF-R gene (44). The APOBEC3-deficient mice on a B6 background (B6-mA3 Ϫ/Ϫ ) have been described previously (26,49). Mice 7 to 10 weeks old were used throughout the present study.…”

Section: Methodsmentioning

confidence: 99%

Persistence of Viremia and Production of Neutralizing Antibodies Differentially Regulated by PolymorphicAPOBEC3andBAFF-RLoci in Friend Virus-Infected Mice

Tsuji-Kawahara¹,

Chikaishi²,

Takeda³

et al. 2010

J Virol

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Several host genes control retroviral replication and pathogenesis through the regulation of immune responses to viral antigens. The Rfv3 gene influences the persistence of viremia and production of virusneutralizing antibodies in mice infected with Friend mouse retrovirus complex (FV). This locus has been mapped within a narrow segment of mouse chromosome 15 harboring the APOBEC3 and BAFF-R loci, both of which show functional polymorphisms among different strains of mice. The exon 5-lacking product of the APOBEC3 allele expressed in FV-resistant C57BL/6 (B6) mice directly restricts viral replication, and mice lacking the B6-derived APOBEC3 exhibit exaggerated pathology and reduced production of neutralizing antibodies. However, the mechanisms by which the polymorphisms at the APOBEC3 locus affect the production of neutralizing antibodies remain unclear. Here we show that the APOBEC3 genotypes do not directly affect the B-cell repertoire, and mice lacking B6-derived APOBEC3 still produce FV-neutralizing antibodies in the presence of primed T helper cells. Instead, higher viral loads at a very early stage of FV infection caused by either a lack of the B6-derived APOBEC3 or a lack of the wild-type BAFF-R resulted in slower production of neutralizing antibodies. Indeed, B cells were hyperactivated soon after infection in the APOBEC3-or BAFF-R-deficient mice. In contrast to mice deficient in the B6-derived APOBEC3, which cleared viremia by 4 weeks after FV infection, mice lacking the functional BAFF-R allele exhibited sustained viremia, indicating that the polymorphisms at the BAFF-R locus may better explain the Rfv3-defining phenotype of persistent viremia.Several host genetic factors control retroviral replication and pathogenesis through the regulation of immune responses to viral antigens. The recovery from Friend virus 3 gene (Rfv3) was identified as a host gene locus that affects the persistence of viremia and development of virus-specific antibody (Ab) responses upon Friend virus (FV) infection (5). FV is the pathogenic retrovirus complex composed of replication-competent Friend murine leukemia virus (F-MuLV) and the defective spleen focus-forming virus (SFFV). The product of the SFFV env gene, gp55, forms a complex with the erythropoietin receptor and the short form of the hematopoietic-cell-specific receptor tyrosine kinase (STK), and this interaction induces the growth and terminal differentiation of erythroid progenitor cells, causing increased hematocrit values and massive splenomegaly. The resultant increase in targets of FV integration consequently causes the emergence of mono-or oligoclonal erythroleukemia through insertional activation of transcription factors or disruption of a tumor suppressor gene (15,29,34). Mice of the C57BL background possess mutations in the intron of the Stk gene and lack expression of the short-form STK, resulting in resistance to SFFV-induced splenomegaly (37).This host factor was first described as polymorphisms at the Fv2 locus, with the resistance allele found in C57BL m...

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“…A3-deficient (mA3 Ϫ/Ϫ ) mice (mA3-knockout [KO] mice) were backcrossed 12 times to a C57BL/6 mouse background. These mice have the A3 gene disrupted by the insertion of a neomycin resistance cassette in exon 3 (51). C57BL/6 (mA3 wild-type [WT]) and mA3-KO mice were maintained in the barrier unit of the University of Ottawa Animal Care Facility.…”

Section: Methodsmentioning

confidence: 99%

N -Linked Glycosylation Protects Gammaretroviruses against Deamination by APOBEC3 Proteins

Gerpe

Renner

Bélanger

et al. 2015

J Virol

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Retroviruses are pathogens with rapid infection cycles that can be a source of disease, genome instability, and tumor development in their hosts. Host intrinsic restriction factors, such as APOBEC3 (A3) proteins, are constitutively expressed and dedicated to interfering with the replication cycle of retroviruses. To survive, propagate, and persist, retroviruses must counteract these restriction factors, often by way of virus genome-encoded accessory proteins. Glycosylated Gag, also called glycosylated Pr80 Gag (gPr80), is a gammaretrovirus genome-encoded protein that inhibits the antiretroviral activity of mouse A3 (mA3). Here we show that gPr80 exerts two distinct inhibitory effects on mA3: one that antagonizes deamination-independent restriction and another one that inhibits its deaminase activity. More specifically, we find that the number of N-glycosylated residues in gPr80 inversely correlates with the sensitivity of a gammaretrovirus to deamination by mouse A3 and also, surprisingly, by human A3G. Finally, our work highlights that retroviruses which have successfully integrated into the mouse germ line generally express a gPr80 with fewer glycosylated sites than exogenous retroviruses. This observation supports the suggestion that modulation of A3 deamination intensity could be a desirable attribute for retroviruses to increase genetic diversification and avoid immune detection. Overall, we present here the first description of how gammaretroviruses employ posttranslational modification to antagonize and modulate the activity of a host genome-encoded retroviral restriction factor. IMPORTANCEAPOBEC3 proteins are host factors that have a major role in protecting humans and other mammals against retroviruses. These enzymes hinder their replication and intensely mutate their DNA, thereby inactivating viral progeny and the spread of infection. Here we describe a newly recognized way in which some retroviruses protect themselves against the mutator activity of APOBEC3 proteins. We show that gammaretroviruses expressing an accessory protein called glycosylated Gag, or gPr80, use the host's posttranslational machinery and, more specifically, N-linked glycosylation as a way to modulate their sensitivity to mutations by APOBEC3 proteins. By carefully controlling the amount of mutations caused by APOBEC3 proteins, gammaretroviruses can find a balance that helps them evolve and persist.

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Mice Deficient in APOBEC2 and APOBEC3

Cited by 110 publications

References 53 publications

Analysis of DNA methylation reveals a partial reprogramming of the Müller glia genome during retina regeneration

Analysis of DNA methylation reveals a partial reprogramming of the Müller glia genome during retina regeneration

Persistence of Viremia and Production of Neutralizing Antibodies Differentially Regulated by PolymorphicAPOBEC3andBAFF-RLoci in Friend Virus-Infected Mice

N -Linked Glycosylation Protects Gammaretroviruses against Deamination by APOBEC3 Proteins

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