Comprehensive RNA-sequencing analysis in serum and muscle reveals novel small RNA signatures with biomarker potential for DMD
Extracellular small RNAs (sRNAs), including microRNAs (miRNAs), are promising biomarkers for diseases such as Duchenne muscular dystrophy (DMD), although their biological relevance is largely unknown. To investigate the relationship between intracellular and extracellular sRNA levels on a global sca...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2018
|
| _version_ | 1797068355503390720 |
|---|---|
| author | Coenen-Stass, AML Sork, H Gatto, S Godfrey, C Bhomra, A Krjutškov, K Hart, JR Westholm, JO O'Donovan, L Roos, A Lochmüller, H Puri, PL Andaloussi, S Wood, MJA Roberts, TC |
| author_facet | Coenen-Stass, AML Sork, H Gatto, S Godfrey, C Bhomra, A Krjutškov, K Hart, JR Westholm, JO O'Donovan, L Roos, A Lochmüller, H Puri, PL Andaloussi, S Wood, MJA Roberts, TC |
| author_sort | Coenen-Stass, AML |
| collection | OXFORD |
| description | Extracellular small RNAs (sRNAs), including microRNAs (miRNAs), are promising biomarkers for diseases such as Duchenne muscular dystrophy (DMD), although their biological relevance is largely unknown. To investigate the relationship between intracellular and extracellular sRNA levels on a global scale, we performed sRNA sequencing in four muscle types and serum from wild-type, dystrophic mdx, and mdx mice in which dystrophin protein expression was restored by exon skipping. Differentially abundant sRNAs were identified in serum (mapping to miRNA, small nuclear RNA [snRNA], and PIWI-interacting RNA [piRNA] loci). One novel candidate biomarker, miR-483, was increased in both mdx serum and muscle, and also elevated in DMD patient sera. Dystrophin restoration induced global shifts in miRNA (including miR-483) and snRNA-fragment abundance toward wild-type levels. Specific serum piRNA-like sRNAs also responded to exon skipping therapy. Absolute miRNA expression in muscle was positively correlated with abundance in the circulation, although multiple highly expressed miRNAs in muscle were not elevated in mdx serum, suggesting that both passive and selective release mechanisms contribute to serum miRNA levels. In conclusion, this study has revealed new insights into the sRNA biology of dystrophin deficiency and identified novel DMD biomarkers. |
| first_indexed | 2024-03-06T22:09:34Z |
| format | Journal article |
| id | oxford-uuid:5157ce00-a4dc-4099-90d3-8d71d84390f8 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:09:34Z |
| publishDate | 2018 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:5157ce00-a4dc-4099-90d3-8d71d84390f82022-03-26T16:18:57ZComprehensive RNA-sequencing analysis in serum and muscle reveals novel small RNA signatures with biomarker potential for DMDJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5157ce00-a4dc-4099-90d3-8d71d84390f8EnglishSymplectic Elements at OxfordElsevier2018Coenen-Stass, AMLSork, HGatto, SGodfrey, CBhomra, AKrjutškov, KHart, JRWestholm, JOO'Donovan, LRoos, ALochmüller, HPuri, PLAndaloussi, SWood, MJARoberts, TCExtracellular small RNAs (sRNAs), including microRNAs (miRNAs), are promising biomarkers for diseases such as Duchenne muscular dystrophy (DMD), although their biological relevance is largely unknown. To investigate the relationship between intracellular and extracellular sRNA levels on a global scale, we performed sRNA sequencing in four muscle types and serum from wild-type, dystrophic mdx, and mdx mice in which dystrophin protein expression was restored by exon skipping. Differentially abundant sRNAs were identified in serum (mapping to miRNA, small nuclear RNA [snRNA], and PIWI-interacting RNA [piRNA] loci). One novel candidate biomarker, miR-483, was increased in both mdx serum and muscle, and also elevated in DMD patient sera. Dystrophin restoration induced global shifts in miRNA (including miR-483) and snRNA-fragment abundance toward wild-type levels. Specific serum piRNA-like sRNAs also responded to exon skipping therapy. Absolute miRNA expression in muscle was positively correlated with abundance in the circulation, although multiple highly expressed miRNAs in muscle were not elevated in mdx serum, suggesting that both passive and selective release mechanisms contribute to serum miRNA levels. In conclusion, this study has revealed new insights into the sRNA biology of dystrophin deficiency and identified novel DMD biomarkers. |
| spellingShingle | Coenen-Stass, AML Sork, H Gatto, S Godfrey, C Bhomra, A Krjutškov, K Hart, JR Westholm, JO O'Donovan, L Roos, A Lochmüller, H Puri, PL Andaloussi, S Wood, MJA Roberts, TC Comprehensive RNA-sequencing analysis in serum and muscle reveals novel small RNA signatures with biomarker potential for DMD |
| title | Comprehensive RNA-sequencing analysis in serum and muscle reveals novel small RNA signatures with biomarker potential for DMD |
| title_full | Comprehensive RNA-sequencing analysis in serum and muscle reveals novel small RNA signatures with biomarker potential for DMD |
| title_fullStr | Comprehensive RNA-sequencing analysis in serum and muscle reveals novel small RNA signatures with biomarker potential for DMD |
| title_full_unstemmed | Comprehensive RNA-sequencing analysis in serum and muscle reveals novel small RNA signatures with biomarker potential for DMD |
| title_short | Comprehensive RNA-sequencing analysis in serum and muscle reveals novel small RNA signatures with biomarker potential for DMD |
| title_sort | comprehensive rna sequencing analysis in serum and muscle reveals novel small rna signatures with biomarker potential for dmd |
| work_keys_str_mv | AT coenenstassaml comprehensivernasequencinganalysisinserumandmusclerevealsnovelsmallrnasignatureswithbiomarkerpotentialfordmd AT sorkh comprehensivernasequencinganalysisinserumandmusclerevealsnovelsmallrnasignatureswithbiomarkerpotentialfordmd AT gattos comprehensivernasequencinganalysisinserumandmusclerevealsnovelsmallrnasignatureswithbiomarkerpotentialfordmd AT godfreyc comprehensivernasequencinganalysisinserumandmusclerevealsnovelsmallrnasignatureswithbiomarkerpotentialfordmd AT bhomraa comprehensivernasequencinganalysisinserumandmusclerevealsnovelsmallrnasignatureswithbiomarkerpotentialfordmd AT krjutskovk comprehensivernasequencinganalysisinserumandmusclerevealsnovelsmallrnasignatureswithbiomarkerpotentialfordmd AT hartjr comprehensivernasequencinganalysisinserumandmusclerevealsnovelsmallrnasignatureswithbiomarkerpotentialfordmd AT westholmjo comprehensivernasequencinganalysisinserumandmusclerevealsnovelsmallrnasignatureswithbiomarkerpotentialfordmd AT odonovanl comprehensivernasequencinganalysisinserumandmusclerevealsnovelsmallrnasignatureswithbiomarkerpotentialfordmd AT roosa comprehensivernasequencinganalysisinserumandmusclerevealsnovelsmallrnasignatureswithbiomarkerpotentialfordmd AT lochmullerh comprehensivernasequencinganalysisinserumandmusclerevealsnovelsmallrnasignatureswithbiomarkerpotentialfordmd AT puripl comprehensivernasequencinganalysisinserumandmusclerevealsnovelsmallrnasignatureswithbiomarkerpotentialfordmd AT andaloussis comprehensivernasequencinganalysisinserumandmusclerevealsnovelsmallrnasignatureswithbiomarkerpotentialfordmd AT woodmja comprehensivernasequencinganalysisinserumandmusclerevealsnovelsmallrnasignatureswithbiomarkerpotentialfordmd AT robertstc comprehensivernasequencinganalysisinserumandmusclerevealsnovelsmallrnasignatureswithbiomarkerpotentialfordmd |