Control of mRNA stability contributes to low levels of nuclear poly(A) binding protein 1 (PABPN1) in skeletal muscle
© Apponi et al.; licensee BioMed Central Ltd. 2013
Received: 30 May 2013
Accepted: 28 August 2013
Published: 1 October 2013
The nuclear poly(A) binding protein 1 (PABPN1) is a ubiquitously expressed proteinthat plays critical roles at multiple steps in post-transcriptional regulation ofgene expression. Short expansions of the polyalanine tract in the N-terminus ofPABPN1 lead to oculopharyngeal muscular dystrophy (OPMD), which is an adult onsetdisease characterized by eyelid drooping, difficulty in swallowing, and weaknessin the proximal limb muscles. Why alanine-expanded PABPN1 leads to muscle-specificpathology is unknown. Given the general function of PABPN1 in RNA metabolism,intrinsic characteristics of skeletal muscle may make this tissue susceptible tothe effects of mutant PABPN1.
To begin to understand the muscle specificity of OPMD, we investigated thesteady-state levels of PABPN1 in different tissues of humans and mice.Additionally, we analyzed the levels of PABPN1 during muscle regeneration afterinjury in mice. Furthermore, we assessed the dynamics of PABPN1 mRNA decay inskeletal muscle compared to kidney.
Here, we show that the steady-state levels of both PABPN1 mRNA and protein aredrastically lower in mouse and human skeletal muscle, particularly those impactedin OPMD, compared to other tissues. In contrast, PABPN1 levels are increasedduring muscle regeneration, suggesting a greater requirement for PABPN1 functionduring tissue repair. Further analysis indicates that modulation of PABPN1expression is likely due to post-transcriptional mechanisms acting at the level ofmRNA stability.
Our results demonstrate that PABPN1 steady-state levels and likely control ofexpression differ significantly in skeletal muscle as compared to other tissues,which could have important implications for understanding the muscle-specificnature of OPMD.
KeywordsPABPN1 OPMD Skeletal muscle Muscular dystrophy Polyalanine expansion
RNA-binding proteins regulate all steps of RNA biogenesis and play a key role inpost-transcriptional regulation of gene expression . Key players among these RNA-binding proteins are the poly(A)-bindingproteins, which modulate 3′-end formation of mRNA transcripts . The nuclear poly (A)-binding protein 1 (PABPN1) is a ubiquitously expressedprotein in eukaryotes that binds with high affinity to polyadenosine RNA . PABPN1 has critical roles at multiple steps in post-transcriptionalregulation of gene expression. The best characterized role of PABPN1 is in mRNApolyadenylation, where PABPN1 stimulates poly(A) synthesis by direct interaction withthe nascent mRNA poly(A) tail and the poly(A) polymerase [3, 4]. In a subsequent regulatory step, PABPN1 decreases poly(A) polymeraseelongation activity following addition of 250 adenine residues, thereby dictating thelength of the poly(A) tail added to mRNA transcripts . Moreover, PABPN1 is also involved in regulation of alternative cleavage andpolyadenylation by suppressing weak proximal polyadenylation signals , which can influence both gene expression and the structure of the proteinproduced . Finally, PABPN1 has been implicated in the polyadenylation-dependent pathwayof RNA decay, which targets non-protein coding genes such as the long non-coding RNAs(lncRNAs) . Thus, PABPN1 modulates a number of processes that are critical forcontrolling gene expression.
In addition to playing a key role in RNA metabolism, PABPN1 is of significant clinicalinterest as mutations in the PABPN1 gene lead to oculopharyngeal musculardystrophy (OPMD) . This disease is caused by a small GCN trinucleotide expansion in the codingregion of PABPN1, resulting in the expansion of a stretch of 10 alanines to 12to 17 alanines in the PABPN1 N-terminus. OPMD is a late onset, autosomal dominantdisease characterized primarily by progressive eyelid drooping (ptosis) and difficultiesin swallowing . Additional weakness is noted in proximal limb, facial and other extraocularmuscles [10–12]. Disease progression is variable between patients and complications includechoking, regurgitation, aspiration and pneumonia. The pathologic hallmark of the diseaseis the presence of nuclear aggregates of PABPN1 in muscle [13, 14]. Given the ubiquitous expression and general function of PABPN1 in RNAmetabolism , how mutations of this post-transcriptional regulatory factor cause amuscle-specific disease is unclear. PABPN1 is essential for both mRNA biogenesis as wellas proliferation and differentiation of myogenic precursor cells, suggesting a criticalrole in muscle regeneration and maintenance . Skeletal muscle is highly specialized for contraction and has uniquecharacteristics compared to other tissues, such as being highly regenerative andcomprised of multinucleated post-mitotic cells, which suggests that intrinsiccharacteristics of this tissue may make it more vulnerable to the effects of mutantPABPN1 than other tissues that are not affected in OPMD.
To begin to understand the muscle specificity of OPMD, we investigated the steady-statelevels of the PABPN1 protein in different tissues. We find that the steady-state levelsof PABPN1 are drastically lower in skeletal muscle compared to other tissues.Strikingly, craniofacial muscles, which are affected in OPMD, show the lowest levels ofPABPN1. We also found that PABPN1 is upregulated during muscle repair after injury.Studies of mRNA stability indicate that regulation of PABPN1 expression is likely due todistinct post-transcriptional mechanisms in different tissues. Taken together, ourresults demonstrate that PABPN1 steady-state levels and likely control of expressiondiffer significantly in skeletal muscle as compared to other tissues, which could haveimportant implications for understanding the muscle-specific nature of OPMD.
Animals and primary muscle cell culture
Experiments involving animals were performed in accordance with approved guidelinesand ethical approval from Emory University’s Institutional Animal Care and UseCommittee. Adult male C57BL/6 mice between 2 to 6 months of age were used inexperiments. To induce regeneration, gastrocnemius muscles of male mice were injectedwith 40 μl of 1.2% BaCl2 and collected 2, 5 and 14 days after injury. Primary myoblasts werederived from the hindlimb muscles of mice and cultured to >99% purity as previouslydescribed . Cells were maintained in growth media (GM: Ham’s F10, 20% fetalbovine serum, 5 ng/ml basic fibroblast growth factor (bFGF), 100 U/ml penicillin G,100 mg/ml streptomycin) in a humidified 5% CO2 incubator at 37°C oncollagen-coated dishes. For histologic analyses, serial 10 μm sections werecollected along the length of the muscle and stained with hematoxylin and eosin.Images were obtained using Axiovert 200 M microscope with a 0.30 NA 10× or20× Plan-Neofluar objective (Carl Zeiss MicroImaging, Inc., Oberkochen, Germany)and camera (QImaging, Surrey, Canada) with OpenLab 5.5.2 (PerkinElmer, Waltham,MA).
Tissues were homogenized in radioimmunoprecipitation assay (RIPA)-2 buffer (50 mMTris-HCl pH 8.0, 150 mM NaCl, 1% NP-40, 0.5% deoxycholic acid, 0.1% SDS) withprotease inhibitors (Complete Mini Tablets, Roche, Pleasanton, CA). Equal amounts oftotal protein were resolved by SDS-PAGE, transferred to nitrocellulose and thedesired protein was detected by immunoblotting with appropriate antibodies andenhanced chemiluminescence. PABPN1 levels in human tissues were analyzed usingINSTA-blot (IMGENEX, San Diego, CA) membranes. The primary antibodies andconcentrations used were as follows: anti-PABPN1 antibody 1:5,000 , anti-Histone H3 1:1,000 (Abcam, Cambridge, MA), anti-heat shock protein90 (HSP90) 1:1,000 (Santa Cruz Biotechnology, Dallas, TX) and anti-tubulin 1:5,000(Sigma-Aldrich, St. Louis, MO). Anti-mouse or anti-rabbit IgG 1:5,000 (JacksonImmunoResearch, West Grove, PA) were used as secondary antibodies.
Northern blot analysis
Total RNA from tissues, primary cell cultures and fluorescence-activated cell sorting(FACS)-sorted cells was isolated using TRIzol (Invitrogen, Carlsbad, CA) according tothe manufacturer’s protocol. Northern blotting was performed as describedpreviously by Ausubel et al. . DNA probes were generated by polymerase chain reaction (PCR) using customprimers (PABPN1-F 5′-CCCAGGCAATGCTGGCCCAGTGATCATGTCTC-3′ and PABPN1-R5′-CTAGCCCGGCCCCTGTAGATTCGACCCCGGGGC-3′, c-Myc-F5′-GAACTTCACCAACAGGAACTATGACCTCG-3′ and c-Myc-R5′-GGTGTCTCCTCATGCAGCACTAGG-3′), primers from SA Biosciences, Valencia,CA (peroxisome proliferator-activated receptor gamma coactivator 1α(PGC1α); PPM03360E, glyceraldehyde 3-phosphate dehydrogenase (GAPDH); PPM02946E)or by Ambion, Austin, TX (QuantumRNA Classic II 18S). PCR products were labeled with[α-32P]dCTP using a random primer DNA labeling system (Invitrogen,Carlsbad, CA).
Mononucleated cells were enzymatically isolated from gastrocnemius muscles 3 daysafter BaCl2 injury and fluorescently labeled with antibodies to CD31 andCD45 (PE), Sca-1 (PE-Cy7), and alpha-7-integrin (AlexaFluor 649). Propidium iodidestaining was used to gate out dead cells from the sort. Myoblasts(CD31 - /CD45 - /Sca-1 - /alpha-7-integrin + /PI - )and non-myogenic cells(CD31 + /CD45 + /Sca-1 + /alpha-7-integrin - /PI - )were collected using a FACSAria II (Becton-Dickinson, Franklin Lakes, NJ). Isolatedcells were then processed for RNA extraction.
Quantitative reverse transcription (RT)-PCR
cDNA synthesis from 100 ng RNA was performed using M-MLV reverse transcriptase(Invitrogen, Carlsbad, CA). mRNA levels were determined by real-time PCR using the iQSYBR Green (Bio-Rad, Hercules, CA) and iCycler iQ Real-Time Detection System andsoftware (Bio-Rad, Hercules, CA). The relative levels of PABPN1 were determined bythe ΔΔCt method and normalized to the housekeeping gene HPRT1. Primers werefrom SA Bioscences, Valencia, CA (PABPN1: PPM25445A, HPRT1: PPM03559E).
To analyze mRNA stability in vivo, mice were injected intraperitoneally withactinomycin D (Sigma-Aldrich, St. Louis, MO) at 2.5 μg/g and quadriceps musclesand kidney were collected 1, 2, 4 and 6 h later. To measure mRNA stability in primarymyoblasts in vitro, 5 μg/ml actinomycin D was added to the growthmedium and cells were harvested 0.5, 1, 2 and 4 h later. Total RNA was extracted fromtissues or cells and analyzed by northern blot and half-lives were determined bydensitometry.
5′ and 3′ RACE
In order to determine the 5′ and 3′UTRs of PABPN1 transcripts, we usedthe 5′ and 3′ rapid amplification of cDNA ends (RACE) system (Invitrogen,Carlsbad, CA), respectively. Total RNA from either muscle or testis was used as atemplate according to the manufacturer’s instructions. PCR products were clonedinto the pCR2.1 vector (TOPO TA cloning, Invitrogen, Carlsbad, CA) and sequenced byBeckman Coulter Genomics, Danvers, MA.
Statistical analysis to determine significance between two groups was performed usinga Student’s t test. One-way analysis of variance (ANOVA) was used forcomparisons between multiple groups as appropriate. All statistical analyses wereperformed using GraphPad Prism 5.0 for Macintosh (GraphPad Software). Differenceswere considered to be statistically significant at P <0.05.
PABPN1 levels are lower in skeletal muscle compared to other tissues
PABPN1 levels are increased during muscle regeneration
PABPN1 mRNA is unstable in skeletal muscle
Nuclear poly(A) binding protein 1 (PABPN1) mRNA is unstable in muscle tissuebut stable in cultured myoblasts
As shown earlier (Figure 3C), PABPN1 levels are modulatedduring muscle regeneration and myoblasts contribute in part to the increased levelsof PABPN1 during this process. We next investigated if the increase in PABPN1 levelsin myoblasts is accompanied by a corresponding increase in PABPN1 mRNA stability.Similar to myoblasts directly isolated from injured muscle, we found that culturedprimary mouse myoblasts displayed higher levels of PABPN1 mRNA compared to uninjuredmuscle tissue (Figure 4B). Consistent with this finding,steady-state levels of PABPN1 protein were also higher in cultured myoblasts comparedto muscle tissue (Figure 4C). We analyzed the stabilityof PABPN1 transcripts in cultured myoblasts. As observed in skeletal muscle tissue,the 2.1 kb PABPN1 transcript was the predominant transcript in myoblasts (data notshown). However, in contrast to muscle tissue, the 2.1 kb PABPN1 transcript wasextremely stable in myoblasts (Figure 4D,E; Table 1). As expected, c-Myc mRNA, a known unstable transcript inmyoblasts , had a short half-life compared to the much longer half-life for GAPDHmRNA, a known stable transcript (Table 1). These resultsindicate that the high levels of PABPN1 in cultured myoblasts, and likely inmyoblasts present during muscle regeneration, is due at least in part to the increasein PABPN1 mRNA stability in those cells compared to muscle tissue. Taken together,our results suggest that PABPN1 expression in different tissues or during muscleregeneration is regulated by a post-transcriptional mechanism that modulatestranscript stability.
Studying PABPN1 specifically in skeletal muscle is critical for defining the mechanismswhich make this tissue uniquely susceptible to the mutation causing OPMD. Here, wereport that steady-state levels of PABPN1 mRNA and protein are low in skeletal muscleand that expression of PABPN1 in this tissue is controlled, at least in part, bypost-transcriptional regulation of RNA levels. We also demonstrate that PABPN1 levelsare modulated during muscle repair providing further support for regulation of PABPN1expression in this tissue.
PABPN1 is not the only ubiquitous protein with a general function in basic cellularprocesses whose expression level is variable among tissues [28, 29]. For example, the expression of histone H3A, transcription elongation factorA1 (TCEA1) and heterogeneous nuclear ribonucleoprotein (hnRNP) C is relatively constantamong different tissues, whereas levels of GAPDH, β-actin and histone H2A are amongthe most variable within tissues . These differences in expression levels are most likely related to intrinsicproperties of individual tissues and reflect differences in metabolic activity andcellular structure.
The extremely low levels of PABPN1 in skeletal muscle compared to other tissues mayindicate a low requirement for this factor in basal muscle metabolism and maintenance.Skeletal muscle is distinctly characterized by multinucleated, post-mitotic cells with avery specialized function and low complexity transcriptome [30, 31]. In skeletal muscle, a small number of genes contribute to a large fractionof the total mRNA pool, with the ten most expressed genes in muscle accounting for 20%to 40% of the total mRNA . The most abundant transcripts in skeletal muscle encode proteins involved incontraction, glucose metabolism, ATP production and ribosomal proteins [30, 31], consistent with the role of this tissue in movement and metabolism. Suchtranscripts encoding proteins involved in general cellular functions are usually stablewith low turnover [27, 32]. Therefore, the low complexity of the skeletal muscle transcriptomeassociated with low turnover of a significant fraction of its transcripts may explainwhy skeletal muscle has low requirements for a protein involved in mRNA metabolism suchas PABPN1.
Our data indicate the low levels of PABPN1 in skeletal muscle are, at least in part,determined at the level of regulation of PABPN1 transcript stability. Regulation of mRNAdecay rate is a key factor in determining the expression pattern of many genes allowingrapid adaptation to changing cellular requirements [33, 34]. PABPN1 levels increase significantly during skeletal muscle regenerationsuggesting a greater requirement for PABPN1 in myoblasts and non-myogenic cells such asinflammatory cells, which may be due to their highly proliferative status and to a morecomplex transcriptome compared to uninjured muscle tissue. As the increased levels ofPABPN1 in regenerating muscle correlate with an increased transcript stability inmyoblasts and subsequent increase in the steady-state levels of PABPN1 transcript, wesuggest that skeletal muscle employs a post-transcriptional mechanism to control PABPN1levels according to the tissue requirements.
mRNA decay rates are modulated by an interplay of specific stabilizing or destabilizingfactors with the transcript, such as RNA-binding proteins and/or miRNAs and theirassociated enzymes . One of the most studied post-transcriptional pathways is orchestrated by avariety of RNA-binding proteins that interact with AU-rich elements (ARE) within the3′UTR of mRNAs [33, 36] and many unstable mRNAs expressed in muscle contain AU-rich elements in their3′UTRs . As the main 2.1 kb PABPN1 transcript expressed in skeletal muscle harbors anARE in the 3′UTR, we speculate this pathway is a strong candidate for the controlof PABPN1 levels in skeletal muscle.
Our results demonstrate that PABPN1 steady-state levels and likely control of expressiondiffer significantly in skeletal muscle as compared to other tissues, which could haveimportant implications for understanding the muscle-specific nature of OPMD. We suggestthe low levels of PABPN1 observed in skeletal muscle may be an important aspect of thistissue that underlies OPMD pathology. Further studies are necessary to better comprehendthe mechanisms and implications of the regulation of PABPN1 expression in skeletalmuscle, which could open avenues for potential therapeutic approaches for OPMD.
Heat shockprotein 90
Oculopharyngeal muscular dystrophy
Nuclear poly(A)-bindingprotein 1
Peroxisome proliferator-activated receptor gamma, coactivator1α
- qRT PCR:
Quantitative real-time polymerase chain reaction
Rapidamplification of cDNA ends
We thank Matthew Randolph for assistance with flow cytometry experiments. This workwas supported by the Muscular Dystrophy Association (MDA157523, MDA68022), and by theNational Institutes of Health (NS059340, AR061987).
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