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Primary respiratory chain disease causes tissue-specific dysregulation of the global transcriptome and nutrient-sensing signaling network.

Zhang Z, Tsukikawa M, Peng M, Polyak E, Nakamaru-Ogiso E, Ostrovsky J, McCormack S, Place E, Clarke C, Reiner G, McCormick E, Rappaport E, Haas R, Baur JA, Falk MJ - PLoS ONE (2013)

Bottom Line: Global transcriptional and post-transcriptional dysregulation was also found to occur in a highly tissue-specific fashion.In parallel with these transcriptional effects, RC disease dysregulated the integrated nutrient-sensing signaling network involving FOXO, PPAR, sirtuins, AMPK, and mTORC1, which collectively sense nutrient availability and regulate cellular growth.Remarkably, treating RC mutant fibroblasts with nicotinic acid to enhance sirtuin and PPAR activity also normalized mTORC1 and AMPK signaling, restored NADH/NAD(+) redox balance, and improved cellular respiratory capacity.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. Mechanism(s) by which RC dysfunction causes global cellular sequelae are poorly understood. To identify a common cellular response to RC disease, integrated gene, pathway, and systems biology analyses were performed in human primary RC disease skeletal muscle and fibroblast transcriptomes. Significant changes were evident in muscle across diverse RC complex and genetic etiologies that were consistent with prior reports in other primary RC disease models and involved dysregulation of genes involved in RNA processing, protein translation, transport, and degradation, and muscle structure. Global transcriptional and post-transcriptional dysregulation was also found to occur in a highly tissue-specific fashion. In particular, RC disease muscle had decreased transcription of cytosolic ribosomal proteins suggestive of reduced anabolic processes, increased transcription of mitochondrial ribosomal proteins, shorter 5'-UTRs that likely improve translational efficiency, and stabilization of 3'-UTRs containing AU-rich elements. RC disease fibroblasts showed a strikingly similar pattern of global transcriptome dysregulation in a reverse direction. In parallel with these transcriptional effects, RC disease dysregulated the integrated nutrient-sensing signaling network involving FOXO, PPAR, sirtuins, AMPK, and mTORC1, which collectively sense nutrient availability and regulate cellular growth. Altered activities of central nodes in the nutrient-sensing signaling network were validated by phosphokinase immunoblot analysis in RC inhibited cells. Remarkably, treating RC mutant fibroblasts with nicotinic acid to enhance sirtuin and PPAR activity also normalized mTORC1 and AMPK signaling, restored NADH/NAD(+) redox balance, and improved cellular respiratory capacity. These data specifically highlight a common pathogenesis extending across different molecular and biochemical etiologies of individual RC disorders that involves global transcriptome modifications. We further identify the integrated nutrient-sensing signaling network as a common cellular response that mediates, and may be amenable to targeted therapies for, tissue-specific sequelae of primary mitochondrial RC disease.

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Differential UTR expression in RC disease.(A) Association between AU-rich elements and 3′-UTR changes in RC disease. All genes were split into five exclusive groups based on the presence and type of AU-rich elements (ARE) in their 3′-UTRs. Genes in muscle without ARE had little change of their 3′-UTR, while those with long ARE motifs showed the most significant average increase. The reverse trend of lesser magnitude occurred in RC disease FCLs. Only effective probesets having expression significantly higher than background were analyzed. (B) PAPD4 encodes the GDL-2 protein that acts as a cytoplasmic poly(A) polymerase, and was dysregulated by RC disease in a fashion consistent with its overall 3′-UTR changes in both cell types. (C) DHX36, also known as RHAU, enhances RNA decay by binding to AU-rich elements (AREs) in 3′-UTRs. Interestingly, DHX36 dysregulation in RC disease positively correlated to changes in 3′-UTRs containing AREs, which likely reflects its novel role in the regulation of RNA structure and synthesis. (D) Position-specific differential expression of 3′-UTRs in RC disease. Probes mapped to 3′-UTRs were assigned to 1% intervals from the 5′ to 3′ ends. Since 3′-UTR degradation starts from the 3′-end, the increasing difference from the 3′ to 5′ indicates a gradually decreased pace of 3′-UTR degradation occurs in RC disease. (E) Relative 5′-UTR change in RC disease is dependent on the baseline absolute abundance of 5′-UTR in muscle. Significantly changed 5′-UTRs (p<0.05) are highlighted in red, with the green line generated by Lowess smoothing. This plot demonstrates the nearly unanimous downregulation in RC disease of 5′-UTRs with the highest baseline transcription levels. See also Fig. S12 in File S3.
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pone-0069282-g007: Differential UTR expression in RC disease.(A) Association between AU-rich elements and 3′-UTR changes in RC disease. All genes were split into five exclusive groups based on the presence and type of AU-rich elements (ARE) in their 3′-UTRs. Genes in muscle without ARE had little change of their 3′-UTR, while those with long ARE motifs showed the most significant average increase. The reverse trend of lesser magnitude occurred in RC disease FCLs. Only effective probesets having expression significantly higher than background were analyzed. (B) PAPD4 encodes the GDL-2 protein that acts as a cytoplasmic poly(A) polymerase, and was dysregulated by RC disease in a fashion consistent with its overall 3′-UTR changes in both cell types. (C) DHX36, also known as RHAU, enhances RNA decay by binding to AU-rich elements (AREs) in 3′-UTRs. Interestingly, DHX36 dysregulation in RC disease positively correlated to changes in 3′-UTRs containing AREs, which likely reflects its novel role in the regulation of RNA structure and synthesis. (D) Position-specific differential expression of 3′-UTRs in RC disease. Probes mapped to 3′-UTRs were assigned to 1% intervals from the 5′ to 3′ ends. Since 3′-UTR degradation starts from the 3′-end, the increasing difference from the 3′ to 5′ indicates a gradually decreased pace of 3′-UTR degradation occurs in RC disease. (E) Relative 5′-UTR change in RC disease is dependent on the baseline absolute abundance of 5′-UTR in muscle. Significantly changed 5′-UTRs (p<0.05) are highlighted in red, with the green line generated by Lowess smoothing. This plot demonstrates the nearly unanimous downregulation in RC disease of 5′-UTRs with the highest baseline transcription levels. See also Fig. S12 in File S3.

Mentions: 3′-UTR stability is regulated by binding of regulatory proteins to AU-rich elements (AREs) located in the 3′-UTRs [50]. All AREs include a core motif, AUUUA, but often exhibit a more specific form such as WWWAUUUAWWW, where W is an A or U. Our analyses identified a strong association between the presence of AREs and the 3′-UTR changes induced by RC disease, particularly in muscle. ARE-containing gene lists were downloaded from the AREsite database [51] and classified into 5 mutually-exclusive groups based on the complexity of ARE motifs, from the basic AUUUA pentamer to the most complex 13mer (File S1). The average 3′-UTR changes of these gene groups in RC disease muscle (Fig. 7A) revealed: (1) genes without a 3′-UTR ARE had almost no change; (2) genes having the basic AUUUA motif were increased by an average of approximately 8% (p = 7.7×10−73); and (3) genes having extended ARE motifs were more significantly increased by an average of more than 16% (p = 2.6×10−174). The inverse pattern, albeit less pronounced, was evident in RC disease FCLs (p = 1.1×10−11 and 2.7×10−22, respectively). Collectively, these results suggest that the 3′-UTR changes observed in RC disease are predominantly caused by a disturbance of ARE-based 3′-UTR regulation.


Primary respiratory chain disease causes tissue-specific dysregulation of the global transcriptome and nutrient-sensing signaling network.

Zhang Z, Tsukikawa M, Peng M, Polyak E, Nakamaru-Ogiso E, Ostrovsky J, McCormack S, Place E, Clarke C, Reiner G, McCormick E, Rappaport E, Haas R, Baur JA, Falk MJ - PLoS ONE (2013)

Differential UTR expression in RC disease.(A) Association between AU-rich elements and 3′-UTR changes in RC disease. All genes were split into five exclusive groups based on the presence and type of AU-rich elements (ARE) in their 3′-UTRs. Genes in muscle without ARE had little change of their 3′-UTR, while those with long ARE motifs showed the most significant average increase. The reverse trend of lesser magnitude occurred in RC disease FCLs. Only effective probesets having expression significantly higher than background were analyzed. (B) PAPD4 encodes the GDL-2 protein that acts as a cytoplasmic poly(A) polymerase, and was dysregulated by RC disease in a fashion consistent with its overall 3′-UTR changes in both cell types. (C) DHX36, also known as RHAU, enhances RNA decay by binding to AU-rich elements (AREs) in 3′-UTRs. Interestingly, DHX36 dysregulation in RC disease positively correlated to changes in 3′-UTRs containing AREs, which likely reflects its novel role in the regulation of RNA structure and synthesis. (D) Position-specific differential expression of 3′-UTRs in RC disease. Probes mapped to 3′-UTRs were assigned to 1% intervals from the 5′ to 3′ ends. Since 3′-UTR degradation starts from the 3′-end, the increasing difference from the 3′ to 5′ indicates a gradually decreased pace of 3′-UTR degradation occurs in RC disease. (E) Relative 5′-UTR change in RC disease is dependent on the baseline absolute abundance of 5′-UTR in muscle. Significantly changed 5′-UTRs (p<0.05) are highlighted in red, with the green line generated by Lowess smoothing. This plot demonstrates the nearly unanimous downregulation in RC disease of 5′-UTRs with the highest baseline transcription levels. See also Fig. S12 in File S3.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3722174&req=5

pone-0069282-g007: Differential UTR expression in RC disease.(A) Association between AU-rich elements and 3′-UTR changes in RC disease. All genes were split into five exclusive groups based on the presence and type of AU-rich elements (ARE) in their 3′-UTRs. Genes in muscle without ARE had little change of their 3′-UTR, while those with long ARE motifs showed the most significant average increase. The reverse trend of lesser magnitude occurred in RC disease FCLs. Only effective probesets having expression significantly higher than background were analyzed. (B) PAPD4 encodes the GDL-2 protein that acts as a cytoplasmic poly(A) polymerase, and was dysregulated by RC disease in a fashion consistent with its overall 3′-UTR changes in both cell types. (C) DHX36, also known as RHAU, enhances RNA decay by binding to AU-rich elements (AREs) in 3′-UTRs. Interestingly, DHX36 dysregulation in RC disease positively correlated to changes in 3′-UTRs containing AREs, which likely reflects its novel role in the regulation of RNA structure and synthesis. (D) Position-specific differential expression of 3′-UTRs in RC disease. Probes mapped to 3′-UTRs were assigned to 1% intervals from the 5′ to 3′ ends. Since 3′-UTR degradation starts from the 3′-end, the increasing difference from the 3′ to 5′ indicates a gradually decreased pace of 3′-UTR degradation occurs in RC disease. (E) Relative 5′-UTR change in RC disease is dependent on the baseline absolute abundance of 5′-UTR in muscle. Significantly changed 5′-UTRs (p<0.05) are highlighted in red, with the green line generated by Lowess smoothing. This plot demonstrates the nearly unanimous downregulation in RC disease of 5′-UTRs with the highest baseline transcription levels. See also Fig. S12 in File S3.
Mentions: 3′-UTR stability is regulated by binding of regulatory proteins to AU-rich elements (AREs) located in the 3′-UTRs [50]. All AREs include a core motif, AUUUA, but often exhibit a more specific form such as WWWAUUUAWWW, where W is an A or U. Our analyses identified a strong association between the presence of AREs and the 3′-UTR changes induced by RC disease, particularly in muscle. ARE-containing gene lists were downloaded from the AREsite database [51] and classified into 5 mutually-exclusive groups based on the complexity of ARE motifs, from the basic AUUUA pentamer to the most complex 13mer (File S1). The average 3′-UTR changes of these gene groups in RC disease muscle (Fig. 7A) revealed: (1) genes without a 3′-UTR ARE had almost no change; (2) genes having the basic AUUUA motif were increased by an average of approximately 8% (p = 7.7×10−73); and (3) genes having extended ARE motifs were more significantly increased by an average of more than 16% (p = 2.6×10−174). The inverse pattern, albeit less pronounced, was evident in RC disease FCLs (p = 1.1×10−11 and 2.7×10−22, respectively). Collectively, these results suggest that the 3′-UTR changes observed in RC disease are predominantly caused by a disturbance of ARE-based 3′-UTR regulation.

Bottom Line: Global transcriptional and post-transcriptional dysregulation was also found to occur in a highly tissue-specific fashion.In parallel with these transcriptional effects, RC disease dysregulated the integrated nutrient-sensing signaling network involving FOXO, PPAR, sirtuins, AMPK, and mTORC1, which collectively sense nutrient availability and regulate cellular growth.Remarkably, treating RC mutant fibroblasts with nicotinic acid to enhance sirtuin and PPAR activity also normalized mTORC1 and AMPK signaling, restored NADH/NAD(+) redox balance, and improved cellular respiratory capacity.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. Mechanism(s) by which RC dysfunction causes global cellular sequelae are poorly understood. To identify a common cellular response to RC disease, integrated gene, pathway, and systems biology analyses were performed in human primary RC disease skeletal muscle and fibroblast transcriptomes. Significant changes were evident in muscle across diverse RC complex and genetic etiologies that were consistent with prior reports in other primary RC disease models and involved dysregulation of genes involved in RNA processing, protein translation, transport, and degradation, and muscle structure. Global transcriptional and post-transcriptional dysregulation was also found to occur in a highly tissue-specific fashion. In particular, RC disease muscle had decreased transcription of cytosolic ribosomal proteins suggestive of reduced anabolic processes, increased transcription of mitochondrial ribosomal proteins, shorter 5'-UTRs that likely improve translational efficiency, and stabilization of 3'-UTRs containing AU-rich elements. RC disease fibroblasts showed a strikingly similar pattern of global transcriptome dysregulation in a reverse direction. In parallel with these transcriptional effects, RC disease dysregulated the integrated nutrient-sensing signaling network involving FOXO, PPAR, sirtuins, AMPK, and mTORC1, which collectively sense nutrient availability and regulate cellular growth. Altered activities of central nodes in the nutrient-sensing signaling network were validated by phosphokinase immunoblot analysis in RC inhibited cells. Remarkably, treating RC mutant fibroblasts with nicotinic acid to enhance sirtuin and PPAR activity also normalized mTORC1 and AMPK signaling, restored NADH/NAD(+) redox balance, and improved cellular respiratory capacity. These data specifically highlight a common pathogenesis extending across different molecular and biochemical etiologies of individual RC disorders that involves global transcriptome modifications. We further identify the integrated nutrient-sensing signaling network as a common cellular response that mediates, and may be amenable to targeted therapies for, tissue-specific sequelae of primary mitochondrial RC disease.

Show MeSH
Related in: MedlinePlus