Gene structure and expression of the mouse APOBEC-1 complementation factor: multiple transcriptional initiation sites and a spliced variant with a premature stop translation codon

Dür, Stefan; Krause, Kristina; Pluntke, Nina; Greeve, Jobst

doi:10.1016/j.bbaexp.2004.07.006

Cited by 11 publications

(6 citation statements)

References 45 publications

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“…S3). Staining in the liver was strong in both cytoplasm and nucleus at P0 and P21 but was largely circumscribed within nucleus of hepatocytes in adults, in accordance with previous studies (76,78). Similarly, weak expression of A1CF in muscle (76) was confirmed at all time points in our study (Fig.…”

Section: A1cfsupporting

confidence: 81%

“…A1CF transcripts also were detected in gonads of adult humans (77). Here, the presence of A1cf transcripts was confirmed in 129/Sv muscle and liver (76) at birth [postnatal day 0 (P0)], P21, and P71 (Fig. S2).…”

Section: A1cfmentioning

confidence: 53%

“…Surprisingly, however, A1cf Expression of A1cf in Developing and Mature 129/Sv Gonads. A1CF is highly expressed in the kidney, liver, and small intestine of adult mice and humans and also in heart, spinal cord, and lung of mouse embryos at embryonic day 12.5 (E12.5) (57,76,77). A1CF transcripts also were detected in gonads of adult humans (77).…”

Section: A1cfmentioning

confidence: 94%

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Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias

Carouge

Blanc

Knoblaugh

et al. 2016

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

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Testicular tumors, the most common cancer in young men, arise from abnormalities in germ cells during fetal development. Unconventional inheritance for testicular germ cell tumor (TGCT) risk both in humans and mice implicates epigenetic mechanisms. Apolipoprotein B mRNA-editing enzyme complex 1 (APOBEC1) cytidine deaminase and Deadend-1, which are involved in C-to-U RNA editing and microRNA-dependent mRNA silencing, respectively, are potent epigenetic modifiers of TGCT susceptibility in the genetically predisposed 129/Sv inbred mouse strain. Here, we show that partial loss of either APOBEC1 complementation factor (A1CF), the RNA-binding cofactor of APOBEC1 in RNA editing, or Argonaute 2 (AGO2), a key factor in the biogenesis of certain noncoding RNAs, modulates risk for TGCTs and testicular abnormalities in both parent-of-origin and conventional genetic manners. In addition, non-Mendelian inheritance was found among progeny of A1cf and Ago2 mutant intercrosses but not in backcrosses and without fetal loss. Together these findings suggest nonrandom union of gametes rather than meiotic drive or preferential lethality. Finally, this survey also suggested that A1CF contributes to long-term reproductive performance. These results directly implicate the RNA-binding proteins A1CF and AGO2 in the epigenetic control of germ-cell fate, urogenital development, and gamete functions.he germline is the only cell lineage that transmits genetic and epigenetic information across generations. Early in mammalian development, primordial germ cells (PGCs) escape a somatic fate to become unipotent precursors of gametes, the highly specialized cells that give rise to the totipotent zygote upon fertilization (1). Various molecular mechanisms regulate pluripotency by modulating gene expression and protein activity throughout development (2). Failure of pluripotency control can lead to infertility, carcinoma in situ, gamete dysfunctions, and unusual modes of inheritance. Carcinoma in situ anomalously express markers of pluripotency and can give rise to testicular germ cell tumors (TGCTs) (3-7). Studying the genetics, epigenetics, and biology of germ cells (GCs) and TGCTs can provide unique insights about GC development, pluripotency control, tumorigenesis, and unconventional inheritance.TGCTs are the third most heritable cancer and are the most common cancers in young men 15-35 y old (8). Genome-wide association studies (GWAS) in humans identified susceptibility loci such as KIT ligand (KITL), Sprouty 4 (SPRY4), Bcl2 antagonist killer (BAK1), Doublesex-and Mab3-related transcription factor (DMRT1), Deleted in azoospermia RNA-binding protein (DAZL), PRDM transcriptional regulator (PRDM14), the telomerase reverse transcriptase TERT, and its cofactor AFT7IP (9-15). Individually and collectively, however, these susceptibility genes account for only a modest portion of inherited risk. Many genes and inherited factors remain to be discovered, their functions in normal development characterized, and the ways that dysfunction leads to TGCTs inve...

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Section: A1cfsupporting

confidence: 81%

Section: A1cfmentioning

confidence: 53%

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Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias

Carouge

Blanc

Knoblaugh

et al. 2016

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

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“…The tissue-specific distribution of apoB mRNA editing reflects the tissue- and cell-specific distribution of apobec-1, which is expressed in enterocytes and subepithelial cells throughout the luminal gastrointestinal tract (68, 76). ACF is predominantly expressed in the liver, kidney, and intestine, but low levels are found in almost all tissues in humans, rats, and mice (39, 48, 82). Apobec-1 and ACF shuttle between nuclear and cytoplasmic compartments (19, 34), but whether ACF and apobec-1 shuttle independently or together has yet to be resolved.…”

Section: Lipoprotein Assembly Vectorial Transport and Secretionmentioning

confidence: 99%

Role of the Gut in Lipid Homeostasis

Abumrad

Davidson

2012

Physiological Reviews

293

245

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Intestinal lipid transport plays a central role in fat homeostasis. Here we review the pathways regulating intestinal absorption and delivery of dietary and biliary lipid substrates, principally long-chain fatty acid, cholesterol, and other sterols. We discuss the regulation and functions of CD36 in fatty acid absorption, NPC1L1 in cholesterol absorption, as well as other lipid transporters including FATP4 and SRB1. We discuss the pathways of intestinal sterol efflux via ABCG5/G8 and ABCA1 as well as the role of the small intestine in high-density lipoprotein (HDL) biogenesis and reverse cholesterol transport. We review the pathways and genetic regulation of chylomicron assembly, the role of dominant restriction points such as microsomal triglyceride transfer protein and apolipoprotein B, and the role of CD36, l-FABP, and other proteins in formation of the prechylomicron complex. We will summarize current concepts of regulated lipoprotein secretion (including HDL and chylomicron pathways) and include lessons learned from families with genetic mutations in dominant pathways (i.e., abetalipoproteinemia, chylomicron retention disease, and familial hypobetalipoproteinemia). Finally, we will provide an integrative view of intestinal lipid homeostasis through recent findings on the role of lipid flux and fatty acid signaling via diverse receptor pathways in regulating absorption and production of satiety factors.

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“…As such, A1cf is expressed in the same tissues as APOBEC1, but A1cf also is expressed in a number of tissues in which APOBEC1 appears to be absent, suggesting that A1cf may subserve additional, as yet undefined, roles (Mehta et al, 2000). Functional elements within the murine A1cf promoter have been mapped, and small deletions within the sequence appear to inactivate promoter activity, at least in tissue culture (Dur et al, 2004); thus, the complete ablation of the promoter sequence (in CM-MCM Tg/Tg mice) would be expected to significantly disrupt gene expression, altering the abundance of the A1cf mRNA. Moreover, even if A1cf transcription were to be driven by an unidentified promoter, the primary RNA product would lack exon 1, and part of intron 1/2.…”

Section: Resultsmentioning

confidence: 99%

Chromosomal mapping of the αMHC-MerCreMer transgene in mice reveals a large genomic deletion

Harkins

Whitton

2016

Transgenic Res

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Transgenic mice expressing a tamoxifen-inducible Cre recombinase specifically in cardiomyocytes were generated in 2001 and are in widespread use, having been employed in >150 published studies. However, several groups recently have reported that tamoxifen administration to these mice can have off-target effects that include cardiac dysfunction, fibrosis, and death. For this reason, among others, we considered it important to better characterize the transgene (termed herein, CM-MCM) and its chromosomal location(s). Cytogenetic analysis positioned the CM-MCM transgene within the C band of chromosome 19, and more precise mapping, using genome walking and DNA sequencing, showed that transgene insertion is in the C1 region. Using the genome walking data, we have developed PCR assays that not only identify mice that carry the transgene, but also distinguish homozygous animals (CM-MCMTg/Tg) from hemizygous (CM-MCMTg/0), permitting the rapid assessment of transgene zygosity and, thereby, helping to minimize off-target tamoxifen-induced effects. Substantial rearrangement / duplication of transgene elements is present, and transgene integration was accompanied by the deletion of a 19,500 bp fragment of genomic DNA that contains the promoter, exon 1 and part of intron 1 of the APOBEC1 complementation factor (A1cf) gene, as well as several elements that are predicted to regulate chromosomal architecture. A1cf protein expression is ablated by the deletion and, therefore, homozygous mice are functionally A1cf knockout. The implications of this unexpected finding are discussed.

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Gene structure and expression of the mouse APOBEC-1 complementation factor: multiple transcriptional initiation sites and a spliced variant with a premature stop translation codon

Cited by 11 publications

References 45 publications

Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias

Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias

Role of the Gut in Lipid Homeostasis

Chromosomal mapping of the αMHC-MerCreMer transgene in mice reveals a large genomic deletion

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