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Identification of an epigenetic signature of early mouse liver regeneration that is disrupted by Zn-HDAC inhibition.

Huang, Jiansheng; Schriefer, Andrew E; Yang, Wei; Cliften, Paul F; Rudnick, David A

2014-11-01

Liver regeneration has been well studied with hope of discovering strategies to improve liver disease outcomes. Nevertheless, the signals that initiate such regeneration remain incompletely defined, and translation of mechanism-based pro-regenerative interventions into new treatments for hepatic diseases has not yet been achieved. We previously reported the isoform-specific regulation and essential function of zinc-dependent histone deacetylases (Zn-HDACs) during mouse liver regeneration . Those data suggest that epigenetically regulated anti-proliferative genes are deacetylated and transcriptionally suppressed by Zn-HDAC activity or that pro-regenerative factors are acetylated and induced by such activity in response to partial hepatectomy (PH). To investigate these possibilities, we conducted genome-wide interrogation of the liver histone acetylome during early PH-induced liver regeneration in mice using acetyL-histone chromatin immunoprecipitation and next generation DNA sequencing. We also compared the findings of that study to those seen during the impaired regenerative response that occurs with Zn-HDAC inhibition. The results reveal an epigenetic signature of early liver regeneration that includes both hyperacetylation of pro-regenerative factors and deacetylation of anti-proliferative and pro-apoptotic genes. Our data also show that administration of an anti-regenerative regimen of the Zn-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) not only disrupts gene-specific pro-regenerative changes in liver histone deacetylation but also reverses PH-induced effects on histone hyperacetylation. Taken together, these studies offer new insight into and suggest novel hypotheses about the epigenetic mechanisms that regulate liver regeneration .

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Liver regeneration has been well studied with hope of discovering strategies to improve liver disease outcomes. Nevertheless, the signals that initiate such regeneration remain incompletely defined, and translation of mechanism-based pro-regenerative interventions into new treatments for hepatic diseases has not yet been achieved. We previously reported the isoform-specific regulation and essential function of zinc-dependent histone deacetylases (Zn-HDACs) during mouse liver regeneration . Those data suggest that epigenetically regulated anti-proliferative genes are deacetylated and transcriptionally suppressed by Zn-HDAC activity or that pro-regenerative factors are acetylated and induced by such activity in response to partial hepatectomy (PH). To investigate these possibilities, we conducted genome-wide interrogation of the liver histone acetylome during early PH-induced liver regeneration in mice using acetyL-histone chromatin immunoprecipitation and next generation DNA sequencing. We also compared the findings of that study to those seen during the impaired regenerative response that occurs with Zn-HDAC inhibition. The results reveal an epigenetic signature of early liver regeneration that includes both hyperacetylation of pro-regenerative factors and deacetylation of anti-proliferative and pro-apoptotic genes. Our data also show that administration of an anti-regenerative regimen of the Zn-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) not only disrupts gene-specific pro-regenerative changes in liver histone deacetylation but also reverses PH-induced effects on histone hyperacetylation. Taken together, these studies offer new insight into and suggest novel hypotheses about the epigenetic mechanisms that regulate liver regeneration . PMID:25482284

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Oxford Studies in Metaethics: 11

Russ Shafer-Landau

Print publication date: 2016

Print ISBN-13: 9780198784647

Published to Oxford Scholarship Online: September 2016

DOI: 10.1093/acprof:oso/9780198784647.001.0001

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PRINTED FROM OXFORD SCHOLARSHIP ONLINE (www.oxfordscholarship.com). (c) Copyright Oxford University Press, 2018. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a monograph in OSO for personal use (for details see AMELIA Classic heels red Best Sale Cheap Online Excellent For Sale Clearance 2018 Discount Find Great Discount Brand New Unisex 8pHn80YM
).date: 06 July 2018

DOI:10.1093/acprof:oso/9780198784647.003.0002

According to ethical intuitionists, basic moral propositions are self-evident. Robert Audi has made significant progress articulating and defending this view, claiming that an adequate understanding of a self-evident proposition justifies rather than compels belief. It is argued here that understanding a proposition cannot justify belief in it, and that intuition, suitably understood, provides the right sort of justification. An alternative account is offered of self-evidence based on intuition rather than understanding, and it is concluded that once we have an adequate understanding of a self-evident proposition, we can see that it does no distinctive epistemic work. It merely reports that intuition is doing some significant epistemic work. Since the very idea of self-evident moral propositions is so controversial, and self-evidence does no significant epistemic work, ethical intuitionists should drop this notion from their moral epistemology. All they need are intuitive propositions and our intuition of these.

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