Identification of HSP90 as Potential Biomarker of Biliary Atresia Using Two-Dimensional Electrophoresis and Mass Spectrometry

Dong, Rui; Deng, Panmo; Huang, Yanlei; Shen, Chun; Xue, Ping; Zheng, Shan

doi:10.1371/journal.pone.0068602

Cited by 14 publications

(13 citation statements)

References 40 publications

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“…Mass spectrometry experiments to identify differentially expressed proteins in 20 BA liver biopsies compared to 12 non-BA, neonatal cholestasis livers found that heat shock protein 90 (HSP90) was significantly down-regulated in BA livers, and was the most significantly altered protein. This suggests that HSP90 could serve as a potential biomarker for BA 48 . We therefore hypothesized that a gene-environment interaction may explain isolated BA where a predisposing genetic factor exists and an external insult triggers the initiation of the disease.…”

Section: Discussionmentioning

confidence: 91%

Exome Sequencing in Individuals with Isolated Biliary Atresia

Rajagoapalan

Tsai

Grochowski

et al. 2019

Preprint

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Biliary atresia (BA) is a severe pediatric liver disease resulting in necroinflammatory obliteration of the extrahepatic biliary tree. BA presents within the first few months of life as either an isolated finding or with additional syndromic features. The etiology of isolated BA is unknown, with evidence for infectious, environmental, and genetic risk factors described. However, to date, there are no definitive causal genes identified for isolated BA in humans, and the question of whether single gene defects play a major role remains open. We performed exome-sequencing in 100 North American patients of European descent with isolated BA (including 30 parent-child trios) and considered several experimental designs to identify potentially deleterious protein-altering variants that may be involved in the disease. In a case-only analysis, we did not identify genes with variants shared among more than two probands, and burden tests of rare variants using a case-case control design did not yield significant results. In the trio analysis of 30 simplex families (patient and parent trios), we identified 66 de novo variants in 66 genes including a nonsense variant, p.(Cys30Ter), in the gene STIP1. STIP1 is a co-chaperone for the heat-shock protein, HSP90AA1, and has been shown to have diverse functions in yeast, flies and mammals, including stress-response. Conclusion: Our results do not support the hypothesis that a simple genetic model is responsible for the majority of cases of isolated BA. Our finding of a de novo mutation in a candidate gene for BA (STIP1) linked to evolutionarily conserved stress responses suggests further exploration of how genetic susceptibility and environmental exposure interact to cause BA is warranted.

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Section: Discussionmentioning

confidence: 91%

Exome Sequencing in Individuals with Isolated Biliary Atresia

Rajagoapalan

Tsai

Grochowski

et al. 2019

Preprint

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“…Transcriptome analyses revealed that genes involved in protein folding were up-regulated at M2 when the most dramatic metamorphic events occurred. Hsp90 was identified as a candidate key factor during liver metamorphosis because of its involvement in protein folding [ 31 ], metamorphosis in invertebrates [ 15 , 18 ], and human biliary atresia [ 32 ]. Increased hsp90 mRNA expression coincided with the onset (M1), gall bladder disappearance (M3), and final stages (M6-M7) of metamorphosis (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, we found that HSP90 blocker geldanamycin facilitated and hsp90 siRNA treatment synchronized gall bladder degeneration during liver metamorphosis in the sea lamprey. Coincidentally, proteomic analyses comparing BA and non-BA neonatal cholestasis patients showed that HSP90 was the most significant biomarker that was down-regulated in BA patients [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Hsp90 and hepatobiliary transformation during sea lamprey metamorphosis

et al. 2015

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BackgroundBiliary atresia (BA) is a human infant disease with inflammatory fibrous obstructions in the bile ducts and is the most common cause for pediatric liver transplantation. In contrast, the sea lamprey undergoes developmental BA with transient cholestasis and fibrosis during metamorphosis, but emerges as a fecund adult. Therefore, sea lamprey liver metamorphosis may serve as an etiological model for human BA and provide pivotal information for hepatobiliary transformation and possible therapeutics.ResultsWe hypothesized that liver metamorphosis in sea lamprey is due to transcriptional reprogramming that dictates cellular remodeling during metamorphosis. We determined global gene expressions in liver at several metamorphic landmark stages by integrating mRNA-Seq and gene ontology analyses, and validated the results with real-time quantitative PCR, histological and immunohistochemical staining. These analyses revealed that gene expressions of protein folding chaperones, membrane transporters and extracellular matrices were altered and shifted during liver metamorphosis. HSP90, important in protein folding and invertebrate metamorphosis, was identified as a candidate key factor during liver metamorphosis in sea lamprey. Blocking HSP90 with geldanamycin facilitated liver metamorphosis and decreased the gene expressions of the rate limiting enzyme for cholesterol biosynthesis, HMGCoA reductase (hmgcr), and bile acid biosynthesis, cyp7a1. Injection of hsp90 siRNA for 4 days altered gene expressions of met, hmgcr, cyp27a1, and slc10a1. Bile acid concentrations were increased while bile duct and gall bladder degeneration was facilitated and synchronized after hsp90 siRNA injection.ConclusionsHSP90 appears to play crucial roles in hepatobiliary transformation during sea lamprey metamorphosis. Sea lamprey is a useful animal model to study postembryonic development and mechanisms for hsp90-induced hepatobiliary transformation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12861-015-0097-2) contains supplementary material, which is available to authorized users.

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“…STIP1 is a chaperone that assists in the transfer of proteins from HSP70 to HSP90, which are an integral part of the heat shock response pathway. Mass spectrometry experiments to identify differentially expressed proteins in 20 BA liver biopsies compared to 12 non-BA, neonatal cholestasis livers found that HSP90 was significantly down-regulated in BA livers, and was the most significantly altered protein 50 . REV1 encodes a protein similar to the S. cerevisiae mutagenesis protein Rev1 and is known to be involved in DNA repair.…”

Section: Discussionmentioning

confidence: 99%

Exome Sequencing in Individuals with Isolated Biliary Atresia

Rajagopalan

Tsai

Grochowski

et al. 2020

Sci Rep

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Biliary atresia (BA) is a severe pediatric liver disease resulting in necroinflammatory obliteration of the extrahepatic biliary tree. BA presents within the first few months of life as either an isolated finding or with additional syndromic features. The etiology of isolated BA is unknown, with evidence for infectious, environmental, and genetic risk factors described. However, to date, there are no definitive causal genes identified for isolated BA in humans, and the question of whether single gene defects play a major role remains open. We performed exome-sequencing in 101 North American patients of European descent with isolated BA (including 30 parent-child trios) and considered several experimental designs to identify potentially deleterious protein-altering variants that may be involved in the disease. In a case-only analysis, we did not identify genes with variants shared among more than two probands, and burden tests of rare variants using a case-case control design did not yield significant results. In the trio analysis of 30 simplex families (patient and parent trios), we identified 66 de novo variants in 66 genes including potentially deleterious variants in STIP1 and REV1. STIP1 is a co-chaperone for the heat-shock protein, HSP90, and has been shown to have diverse functions in yeast, flies and mammals, including stress-responses. REV1 is known to be a key player in DNA repair pathway and to interact with HSP90. In conclusion, our results do not support the hypothesis that a simple genetic model is responsible for the majority of cases of isolated BA. Our finding of de novo variants in genes linked to evolutionarily conserved stress responses (STIP1 and REV1) suggests that exploration of how genetic susceptibility and environmental exposure may interact to cause BA is warranted.

show abstract

Identification of HSP90 as Potential Biomarker of Biliary Atresia Using Two-Dimensional Electrophoresis and Mass Spectrometry

Cited by 14 publications

References 40 publications

Exome Sequencing in Individuals with Isolated Biliary Atresia

Exome Sequencing in Individuals with Isolated Biliary Atresia

Hsp90 and hepatobiliary transformation during sea lamprey metamorphosis

Exome Sequencing in Individuals with Isolated Biliary Atresia

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