Transcript shortening via alternative polyadenylation promotes gene expression during fracture healing
Abstract Maturation of the 3′ end of almost all eukaryotic messenger RNAs (mRNAs) requires cleavage and polyadenylation. Most mammalian mRNAs are polyadenylated at different sites within the last exon, generating alternative polyadenylation (APA) isoforms that have the same coding region but distinc...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-01-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-022-00236-7 |
| _version_ | 1797958826691919872 |
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| author | Deepak Kumar Khajuria Irena Nowak Ming Leung Vengadeshprabhu Karuppagounder Yuka Imamura Christopher C. Norbury Fadia Kamal Reyad A. Elbarbary |
| author_facet | Deepak Kumar Khajuria Irena Nowak Ming Leung Vengadeshprabhu Karuppagounder Yuka Imamura Christopher C. Norbury Fadia Kamal Reyad A. Elbarbary |
| author_sort | Deepak Kumar Khajuria |
| collection | DOAJ |
| description | Abstract Maturation of the 3′ end of almost all eukaryotic messenger RNAs (mRNAs) requires cleavage and polyadenylation. Most mammalian mRNAs are polyadenylated at different sites within the last exon, generating alternative polyadenylation (APA) isoforms that have the same coding region but distinct 3′ untranslated regions (UTRs). The 3′UTR contains motifs that regulate mRNA metabolism; thus, changing the 3′UTR length via APA can significantly affect gene expression. Endochondral ossification is a central process in bone healing, but the impact of APA on gene expression during this process is unknown. Here, we report the widespread occurrence of APA, which impacts multiple pathways that are known to participate in bone healing. Importantly, the progression of endochondral ossification involves global 3′UTR shortening, which is coupled with an increased abundance of shortened transcripts relative to other transcripts; these results highlight the role of APA in promoting gene expression during endochondral bone formation. Our mechanistic studies of transcripts that undergo APA in the fracture callus revealed an intricate regulatory network in which APA enhances the expression of the collagen, type I, alpha 1 (Col1a1) and Col1a2 genes, which encode the 2 subunits of the abundantly expressed protein collagen 1. APA exerts this effect by shortening the 3′UTRs of the Col1a1 and Col1a2 mRNAs, thus removing the binding sites of miR-29a-3p, which would otherwise strongly promote the degradation of both transcripts. Taken together, our study is the first to characterize the crucial roles of APA in regulating the 3′UTR landscape and modulating gene expression during fracture healing. |
| first_indexed | 2024-04-11T00:24:20Z |
| format | Article |
| id | doaj.art-ace99c2b6c1c40069a695cef1d9a662b |
| institution | Directory Open Access Journal |
| issn | 2095-6231 |
| language | English |
| last_indexed | 2024-04-11T00:24:20Z |
| publishDate | 2023-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj.art-ace99c2b6c1c40069a695cef1d9a662b2023-01-08T12:06:51ZengNature Publishing GroupBone Research2095-62312023-01-0111111510.1038/s41413-022-00236-7Transcript shortening via alternative polyadenylation promotes gene expression during fracture healingDeepak Kumar Khajuria0Irena Nowak1Ming Leung2Vengadeshprabhu Karuppagounder3Yuka Imamura4Christopher C. Norbury5Fadia Kamal6Reyad A. Elbarbary7Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of MedicineDepartment of Orthopaedics and Rehabilitation, The Pennsylvania State University College of MedicineInstitute for Personalized Medicine, Penn State College of MedicineDepartment of Orthopaedics and Rehabilitation, The Pennsylvania State University College of MedicineInstitute for Personalized Medicine, Penn State College of MedicineDepartment of Microbiology and Immunology, The Pennsylvania State University College of MedicineDepartment of Orthopaedics and Rehabilitation, The Pennsylvania State University College of MedicineDepartment of Orthopaedics and Rehabilitation, The Pennsylvania State University College of MedicineAbstract Maturation of the 3′ end of almost all eukaryotic messenger RNAs (mRNAs) requires cleavage and polyadenylation. Most mammalian mRNAs are polyadenylated at different sites within the last exon, generating alternative polyadenylation (APA) isoforms that have the same coding region but distinct 3′ untranslated regions (UTRs). The 3′UTR contains motifs that regulate mRNA metabolism; thus, changing the 3′UTR length via APA can significantly affect gene expression. Endochondral ossification is a central process in bone healing, but the impact of APA on gene expression during this process is unknown. Here, we report the widespread occurrence of APA, which impacts multiple pathways that are known to participate in bone healing. Importantly, the progression of endochondral ossification involves global 3′UTR shortening, which is coupled with an increased abundance of shortened transcripts relative to other transcripts; these results highlight the role of APA in promoting gene expression during endochondral bone formation. Our mechanistic studies of transcripts that undergo APA in the fracture callus revealed an intricate regulatory network in which APA enhances the expression of the collagen, type I, alpha 1 (Col1a1) and Col1a2 genes, which encode the 2 subunits of the abundantly expressed protein collagen 1. APA exerts this effect by shortening the 3′UTRs of the Col1a1 and Col1a2 mRNAs, thus removing the binding sites of miR-29a-3p, which would otherwise strongly promote the degradation of both transcripts. Taken together, our study is the first to characterize the crucial roles of APA in regulating the 3′UTR landscape and modulating gene expression during fracture healing.https://doi.org/10.1038/s41413-022-00236-7 |
| spellingShingle | Deepak Kumar Khajuria Irena Nowak Ming Leung Vengadeshprabhu Karuppagounder Yuka Imamura Christopher C. Norbury Fadia Kamal Reyad A. Elbarbary Transcript shortening via alternative polyadenylation promotes gene expression during fracture healing Bone Research |
| title | Transcript shortening via alternative polyadenylation promotes gene expression during fracture healing |
| title_full | Transcript shortening via alternative polyadenylation promotes gene expression during fracture healing |
| title_fullStr | Transcript shortening via alternative polyadenylation promotes gene expression during fracture healing |
| title_full_unstemmed | Transcript shortening via alternative polyadenylation promotes gene expression during fracture healing |
| title_short | Transcript shortening via alternative polyadenylation promotes gene expression during fracture healing |
| title_sort | transcript shortening via alternative polyadenylation promotes gene expression during fracture healing |
| url | https://doi.org/10.1038/s41413-022-00236-7 |
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