Zinc-binding Domain-dependent, Deaminase-independent Actions of Apolipoprotein B mRNA-editing Enzyme, Catalytic Polypeptide 2 (Apobec2), Mediate Its Effect on Zebrafish Retina Regeneration

Powell, Curtis; Cornblath, Eli J.; Goldman, Daniel

doi:10.1074/jbc.m114.603043

Cited by 22 publications

(21 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, Zhou et al [31] demonstrated that Pou6f2 i s present in the developing and adult retinal ganglion cells. This gene product is also associated with the regeneration of neurons in zebrafish [57].…”

Section: Discussionmentioning

confidence: 99%

Genomic Locus Modulating Corneal Thickness in the Mouse IdentifiesPOU6F2as a Potential Risk of Developing Glaucoma

King

Struebing

Liu

et al. 2017

Preprint

View full text Add to dashboard Cite

Purpose: Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG.Methods: The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60-100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to identify quantitative trait loci (QTLs) modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human primary open-angle glaucoma (POGA) genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.Results: This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10−6 for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/2J model of glaucoma than most RGCs.Conclusions: Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells and these RGCs are sensitive to injury.Authors SummaryGlaucoma is a complex group of diseases with several known causal mutations and many known risk factors. One well-known risk factor for developing primary open angle glaucoma is the thickness of the central cornea. The present study leverages a unique blend of systems biology methods using BXD recombinant inbred mice and genome-wide association studies from humans to define a putative molecular link between a phenotypic risk factor (central corneal thickness) and glaucoma. We identified a transcription factor, POU6F2, that is found in the developing retinal ganglion cells and cornea. POU6F2 is also present in a subpopulation of retinal ganglion cells and in stem cells of the cornea. Functional studies reveal that POU6F2 is associated the central corneal thickness and with susceptibility of retinal ganglion cells to injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Genomic Locus Modulating Corneal Thickness in the Mouse IdentifiesPOU6F2as a Potential Risk of Developing Glaucoma

King

Struebing

Liu

et al. 2017

Preprint

View full text Add to dashboard Cite

show abstract

“…Apobec2 has been implicated in DNA demethylation (18), a process essential for normal myoblast differentiation and fusion into myotubes (50), as well as for normal development in zebrafish and Xenopus (14–17). Our results confirmed the localization of mouse Apobec2 in the sarcomeric Z-lines in adult muscle tissue and in primary cultured myotubes, as has been reported for zebrafish Apob2b (13).…”

Section: Discussionmentioning

confidence: 99%

“…Muscle defects associated with Apobec2 deficiency have been also documented in zebrafish by using morpholino oligonucleotide–mediated knockdown of the Apobec2 proteins (Apo2a and Apo2b), which demonstrated myopathy in the somitic musculature (evidenced by the presence of cell-free spaces, long myofibers, and impaired heart function) (13). Recent studies have suggested that Apobec2 might also play important roles in the regulation of left-right axis specification in Xenopus (14) and retinal regeneration of zebrafish glial cells (15–17). The exact molecular mechanism of Apobec2 action remains unclear.…”

mentioning

confidence: 99%

“…Muscle defects associated with Apobec2 deficiency have been also documented in zebrafish by using morpholino oligonucleotide-mediated knockdown of the Apobec2 proteins (Apo2a and Apo2b), which demonstrated myopathy in the somitic musculature (evidenced by the presence of cell-free spaces, long ABBREVIATIONS: APOBEC, apolipoprotein B mRNA editing enzyme catalytic polypeptide; DHE, dihydroethidium; EDL, extensor digitorum longus; LC, light chain; mtDNA, mitochondrial DNA; MyHC, myosin heavy chain; mTOR, mechanistic target of rapamycin; NADH-TR, nicotinamide adenine dinucleotide tetrazolium reductase; PGC-1a, proliferatoractivated receptor g coactivator 1-a; PINK1, phosphatase and tensin homolog-induced putative kinase 1; TCA, tricarboxylic acid cycle; ROS, reactive oxygen species; TA, tibialis anterior; WT, wild type myofibers, and impaired heart function) (13). Recent studies have suggested that Apobec2 might also play important roles in the regulation of left-right axis specification in Xenopus (14) and retinal regeneration of zebrafish glial cells (15)(16)(17). The exact molecular mechanism of Apobec2 action remains unclear.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Apobec2 deficiency causes mitochondrial defects and mitophagy in skeletal muscle

et al. 2018

View full text Add to dashboard Cite

Apobec2 is a member of the activation-induced deaminase/apolipoprotein B mRNA editing enzyme catalytic polypeptide cytidine deaminase family expressed in differentiated skeletal and cardiac muscle. We previously reported that Apobec2 deficiency in mice leads to a shift in muscle fiber type, myopathy, and diminished muscle mass. However, the mechanisms of myopathy caused by Apobec2 deficiency and its physiologic functions are unclear. Here we show that, although Apobec2 localizes to the sarcomeric Z-lines in mouse tissue and cultured myotubes, the sarcomeric structure is not affected in Apobec2-deficient muscle. In contrast, electron microscopy reveals enlarged mitochondria and mitochondria engulfed by autophagic vacuoles, suggesting that Apobec2 deficiency causes mitochondrial defects leading to increased mitophagy in skeletal muscle. Indeed, Apobec2 deficiency results in increased reactive oxygen species generation and depolarized mitochondria, leading to mitophagy as a defensive response. Furthermore, the exercise capacity of Apobec2−/− mice is impaired, implying Apobec2 deficiency results in ongoing muscle dysfunction. The presence of rimmed vacuoles in myofibers from 10-mo-old mice suggests that the chronic muscle damage impairs normal autophagy. We conclude that Apobec2 deficiency causes mitochondrial defects that increase muscle mitophagy, leading to myopathy and atrophy. Our findings demonstrate that Apobec2 is required for mitochondrial homeostasis to maintain normal skeletal muscle function.—Sato, Y., Ohtsubo, H., Nihei, N., Kaneko, T., Sato, Y., Adachi, S.-I., Kondo, S., Nakamura, M., Mizunoya, W., Iida, H., Tatsumi, R., Rada, C., Yoshizawa, F. Apobec2 deficiency causes mitochondrial defects and mitophagy in skeletal muscle.

show abstract

“…Based on its homology with the other AID/APOBEC family members, it has been hypothesized that APOBEC2 may be involved in RNA editing (W. Liao et al, 1999;Okuyama et al, 2012) or DNA demethylation (Guo et al, 2011;Powell et al, 2012;Rai et al, 2008). It has also been hypothesized that it has lost its deaminase activity altogether and may act biologically by a novel mechanism (Powell et al, 2014). However, there is currently a lack of knowledge on the direct physiological targets of APOBEC2, and its mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

APOBEC2 is a Transcriptional Repressor required for proper Myoblast Differentiation

Lorenzo

Molla

Ibarra³

et al. 2020

Preprint

View full text Add to dashboard Cite

APOBEC2 is a member of the prolific activation induced cytidine deaminase/ apolipoprotein B editing complex (AID/APOBEC) family of DNA or RNA editors. This family of nucleic acid editors has diverse molecular roles ranging from antibody diversification to RNA transcript editing. However, even though APOBEC2 is an evolutionarily conserved zinc-dependent cytidine deaminase, it neither has an established molecular substrate nor function. In this work, we use the C2C12 skeletal myoblast differentiation model to confirm that APOBEC2 is upregulated during differentiation and is critical to proper differentiation. Furthermore, we show that APOBEC2 has none of the attributed molecular functions of the AID/APOBEC family, such as mRNA editing, DNA demethylation, and DNA mutation. Unexpectedly, we reveal that APOBEC2 binds chromatin at promoter regions of actively transcribed genes, and binding correlates with transcriptional repression of non-myogenesis related gene pathways. APOBEC2 occupied regions co-occur with sequence motifs for several transcription factors such as Specificity Protein/Krüppel-like Factor (SP/KLF), and we demonstrate in vitro that APOBEC2 binds directly and co-operatively to double stranded DNA containing a SP1 binding site. Finally, protein-proximity data show that APOBEC2 directly interacts with histone deacetylase (HDAC) transcriptional co-repressor complexes. Taken together, these data suggest a role for APOBEC2 as a transcriptional repressor for muscle differentiation, a novel role that is unique among AID/APOBEC family members.

show abstract

Zinc-binding Domain-dependent, Deaminase-independent Actions of Apolipoprotein B mRNA-editing Enzyme, Catalytic Polypeptide 2 (Apobec2), Mediate Its Effect on Zebrafish Retina Regeneration

Cited by 22 publications

References 43 publications

Genomic Locus Modulating Corneal Thickness in the Mouse IdentifiesPOU6F2as a Potential Risk of Developing Glaucoma

Genomic Locus Modulating Corneal Thickness in the Mouse IdentifiesPOU6F2as a Potential Risk of Developing Glaucoma

Apobec2 deficiency causes mitochondrial defects and mitophagy in skeletal muscle

APOBEC2 is a Transcriptional Repressor required for proper Myoblast Differentiation

Contact Info

Product

Resources

About