Cardiac hypertrophy and histone deacetylase–dependent transcriptional repression mediated by the atypical homeodomain protein Hop

Kook, Hyun; Lepore, John J.; Gitler, Aaron D.; Lü, Min; Yung, Wendy Wing-Man; Mackay, Joel P.; Zhou, Rong; Ferrari, Victor A.; Gruber, Peter J.; Epstein, Jonathan A.

doi:10.1172/jci19137

Cited by 295 publications

(124 citation statements)

References 44 publications

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“…Another transcription factor that was differentially expressed in our experiment was Hod, an unusual homeodomain protein that modulates cardiac growth and development [44,45]. Hod functions by interacting with serum response factor (SRF) to inhibit activation of SRF-dependent transcription [46]. Inactivation of Hod in transgenic mouse models confirm that an absence of Hod results in an imbalance between proliferation and differentiation of cardiomyocytes, culminating in impaired cardiac development [44,45].…”

Section: Discussionmentioning

confidence: 97%

Changes in skeletal muscle gene expression following clenbuterol administration

2006

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Background: Beta-adrenergic receptor agonists (BA) induce skeletal muscle hypertrophy, yet specific mechanisms that lead to this effect are not well understood. The objective of this research was to identify novel genes and physiological pathways that potentially facilitate BA induced skeletal muscle growth. The Affymetrix platform was utilized to identify gene expression changes in mouse skeletal muscle 24 hours and 10 days after administration of the BA clenbuterol.

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Section: Discussionmentioning

confidence: 97%

Changes in skeletal muscle gene expression following clenbuterol administration

2006

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“…For example, cardiac hypertrophy is blocked for 2 weeks by the hydroxamate, TSA, or the aliphatic acid valproate, indicating that these compounds are well tolerated. 58 In addition to TSA, the pan-HDAC inhibitor scriptaid attenuated cardiac hypertrophy in both short-term (3 week) and long-term (9 week) studies in mice models, and was well tolerated with chronic administration not adversely impacting survival. 59 There is a tremendous push for isoform-selective small molecule HDAC inhibitors to further improve safety profiles based on the identification of HDAC isoforms implicated in heart failure.…”

Section: Discussionmentioning

confidence: 99%

HDAC inhibition attenuates cardiac hypertrophy by acetylation and deacetylation of target genes

Ooi¹,

Tuano

Rafehi³

et al. 2015

Epigenetics

120

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Pharmacological histone deacetylase (HDAC) inhibitors attenuate pathological cardiac remodeling and hypertrophic gene expression; yet, the direct histone targets remain poorly characterized. Since the inhibition of HDAC activity is associated with suppressing hypertrophy, we hypothesized histone acetylation would target genes implicated in cardiac remodeling. Trichostatin A (TSA) regulates cardiac gene expression and attenuates transverse aortic constriction (TAC) induced hypertrophy. We used chromatin immunoprecipitation (ChIP) coupled with massive parallel sequencing (ChIP-seq) to map, for the first time, genome-wide histone acetylation changes in a preclinical model of pathological cardiac hypertrophy and attenuation of pathogenesis with TSA. Pressure overload-induced cardiac hypertrophy was associated with histone acetylation of genes implicated in cardiac contraction, collagen deposition, inflammation, and extracellular matrix identified by ChIP-seq. Gene set enrichment analysis identified NF-kappa B (NF-kB) transcription factor activation with load induced hypertrophy. Increased histone acetylation was observed on the promoters of NFkB target genes (Icam1, Vcam1, Il21r, Il6ra, Ticam2, Cxcl10) consistent with gene activation in the hypertrophied heart. Surprisingly, TSA attenuated pressure overload-induced cardiac hypertrophy and the suppression of NFkB target genes by broad histone deacetylation. Our results suggest a mechanism for cardioprotection subject to histone deacetylation as a previously unknown target, implicating the importance of inflammation by pharmacological HDAC inhibition. The results of this study provides a framework for HDAC inhibitor function in the heart and argues the long held views of acetylation is subject to more flexibility than previously thought.

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“…Two genes ( HOPX, GUCY1A3 ) in this signature, which have previously been incorporated into AML prognostic models 16, 37 , are notable for their distinctive pattern of expression and histone modification in self-renewing cells 39 . HOPX is an unusual homeodomain protein known to directly recruit histone deacetylase activity without directly binding DNA 40 , and to be directly repressed in vivo in malignant cells in response to administration of the histone deacetylase inhibitor panobinostat 41 . The latter is currently being studied in clinical trials for patients with AML.…”

Section: Commentmentioning

confidence: 99%

Association of a Leukemic Stem Cell Gene Expression Signature With Clinical Outcomes in Acute Myeloid Leukemia

Gentles

Plevritis²,

Majeti³

et al. 2010

JAMA

370

317

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CUTE MYELOID LEUKEMIA(AML) is an aggressive malignancy of the bone marrow characterized by accumulation of early myeloid blood cells that fail to mature and differentiate. The course of the disease is marked by poor prognosis, frequent relapse, and high disease-related mortality. 1,2 Recent clinical investigation has focused on the identification of prognostic subgroups in adult AML with the goal of guiding patients into risk-adapted therapies. Such investigation determined that cytogenetic abnormalities are prognostic, some favorable and others unfavorable, 3,4 yet up to 50% of patients have normal karyotype AML with a wide range of clinical outcomes. In these patients, the presence of specific molecular mutations can provide prognostic information, including internal tandem duplications within the FLT3 gene, partial tandem duplication of the MLL gene, mislocalizing mutations of the NPM1 gene, mutations in the CEBPA and RAS genes, and increased expression of the BAALC and ERG genes. 5,6 However, these parameters and others such as patient age are only partially successful at capturing risk of relapse and patient outcomes following treatment.A growing body of evidence suggests that specific cancer cell subpopu-Context In many cancers, specific subpopulations of cells appear to be uniquely capable of initiating and maintaining tumors. The strongest support for this cancer stem cell model comes from transplantation assays in immunodeficient mice, which indicate that human acute myeloid leukemia (AML) is driven by self-renewing leukemic stem cells (LSCs). This model has significant implications for the development of novel therapies, but its clinical relevance has yet to be determined.Objective To identify an LSC gene expression signature and test its association with clinical outcomes in AML. Design, Setting, and PatientsRetrospective study of global gene expression (microarray) profiles of LSC-enriched subpopulations from primary AML and normal patient samples, which were obtained at a US medical center between April 2005 and July 2007, and validation data sets of global transcriptional profiles of AML tumors from 4 independent cohorts (n=1047). Main Outcome MeasuresIdentification of genes discriminating LSC-enriched populations from other subpopulations in AML tumors; and association of LSCspecific genes with overall, event-free, and relapse-free survival and with therapeutic response.Results Expression levels of 52 genes distinguished LSC-enriched populations from other subpopulations in cell-sorted AML samples. An LSC score summarizing expression of these genes in bulk primary AML tumor samples was associated with clinical outcomes in the 4 independent patient cohorts. High LSC scores were associated with worse overall, event-free, and relapse-free survival among patients with either normal karyotypes or chromosomal abnormalities. For the largest cohort of patients with normal karyotypes (n=163), the LSC score was significantly associated with overall survival as a continuous variable (hazard ratio [HR], 1.15; ...

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Cardiac hypertrophy and histone deacetylase–dependent transcriptional repression mediated by the atypical homeodomain protein Hop

Cited by 295 publications

References 44 publications

Changes in skeletal muscle gene expression following clenbuterol administration

Changes in skeletal muscle gene expression following clenbuterol administration

HDAC inhibition attenuates cardiac hypertrophy by acetylation and deacetylation of target genes

Association of a Leukemic Stem Cell Gene Expression Signature With Clinical Outcomes in Acute Myeloid Leukemia

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