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The transcriptional activator Ino2p dissociates from the yeast INM1 promoter in induction.

ABSTRACT: Mood stabilizers lithium and valproates are widely used in the treatment of bipolar disorder. It has been shown that these drugs can affect the inositol monophosphatase activity and thus the inositol de novo biosynthesis. However, the molecular mechanism of this action has thus far been vague. As such, characterizing the regulation of the gene encoding inositol monophosphatase at the molecular level can help to understand the bipolar disorder. As the model organism, the inositol monophosphatase is encoded by INM1 in Saccharomyces cerevisiae. In this study, we showed, using real-time reverse transcriptase polymerase chain reaction analysis, that INM1 is expressed in the presence of inositol, suggesting that the presence of inositol is required for INM1 transcriptional activation. We also demonstrated, using chromatin immunoprecipitation, that Ino2p is present at the promoter under uninduced conditions. Upon induction, Ino2p dissociates from the INM1 promoter. Furthermore, chromatin remodelers Ino80p and Snf2p are recruited to INM1 promoter upon induction as well as histone acetylases Gcn5p and Esa1p. Altogether, we have provided the evidence which describes how the transcriptional activator and coactivators participate in INM1 activation.

SUBMITTER: Zhang L

PROVIDER: S-EPMC4248251 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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The transcriptional activator Ino2p dissociates from the yeast INM1 promoter in induction.

Zhang Lingzhi L Di Jing J

DNA and cell biology 20141201 12

Mood stabilizers lithium and valproates are widely used in the treatment of bipolar disorder. It has been shown that these drugs can affect the inositol monophosphatase activity and thus the inositol de novo biosynthesis. However, the molecular mechanism of this action has thus far been vague. As such, characterizing the regulation of the gene encoding inositol monophosphatase at the molecular level can help to understand the bipolar disorder. As the model organism, the inositol monophosphatase ...[more]

PMID: 25211324

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Project description:RationaleEndoplasmic reticulum (ER) stress dysregulates ER proteostasis, which activates the transcription factor, ATF6 (activating transcription factor 6α), an inducer of genes that enhance protein folding and restore ER proteostasis. Because of increased protein synthesis, it is possible that protein folding and ER proteostasis are challenged during cardiac myocyte growth. However, it is not known whether ATF6 is activated, and if so, what its function is during hypertrophic growth of cardiac myocytes.ObjectiveTo examine the activity and function of ATF6 during cardiac hypertrophy.Methods and resultsWe found that ER stress and ATF6 were activated and ATF6 target genes were induced in mice subjected to an acute model of transverse aortic constriction, or to free-wheel exercise, both of which promote adaptive cardiac myocyte hypertrophy with preserved cardiac function. Cardiac myocyte-specific deletion of Atf6 (ATF6 cKO [conditional knockout]) blunted transverse aortic constriction and exercise-induced cardiac myocyte hypertrophy and impaired cardiac function, demonstrating a role for ATF6 in compensatory myocyte growth. Transcript profiling and chromatin immunoprecipitation identified RHEB (Ras homologue enriched in brain) as an ATF6 target gene in the heart. RHEB is an activator of mTORC1 (mammalian/mechanistic target of rapamycin complex 1), a major inducer of protein synthesis and subsequent cell growth. Both transverse aortic constriction and exercise upregulated RHEB, activated mTORC1, and induced cardiac hypertrophy in wild type mouse hearts but not in ATF6 cKO hearts. Mechanistically, knockdown of ATF6 in neonatal rat ventricular myocytes blocked phenylephrine- and IGF1 (insulin-like growth factor 1)-mediated RHEB induction, mTORC1 activation, and myocyte growth, all of which were restored by ectopic RHEB expression. Moreover, adeno-associated virus 9- RHEB restored cardiac growth to ATF6 cKO mice subjected to transverse aortic constriction. Finally, ATF6 induced RHEB in response to growth factors, but not in response to other activators of ATF6 that do not induce growth, indicating that ATF6 target gene induction is stress specific.ConclusionsCompensatory cardiac hypertrophy activates ER stress and ATF6, which induces RHEB and activates mTORC1. Thus, ATF6 is a previously unrecognized link between growth stimuli and mTORC1-mediated cardiac growth.

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The transcriptional activator Ino2p dissociates from the yeast INM1 promoter in induction.

Publications

The transcriptional activator Ino2p dissociates from the yeast INM1 promoter in induction.

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