Histone deacetylases (HDACs) are epigenetic regulators that regulate the histone tail, chromatin conformation, protein-DNA interaction, and even transcription. HDACs are also post-transcriptional modifiers that regulate the protein acetylation implicated in several pathophysiologic states. HDAC inhibitors have been highlighted as a novel category of anti-cancer drugs. To date, four HDAC inhibitors, Vorinostat, Romidepsin, Panobinostat, and Belinostat, have been approved by the United States Food and Drug Administration. Principally, these HDAC inhibitors are used for hematologic cancers in clinic with less severe side effects. Clinical trials are continuously expanding to address other types of cancer and also nonmalignant diseases. HDAC inhibition also results in beneficial outcomes in various types of neurodegenerative diseases, inflammation disorders, and cardiovascular diseases. In this review, we will briefly discuss 1) the roles of HDACs in the acquisition of a cancer's phenotype and the general outcome of the HDAC inhibitors in cancer, 2) the functional relevance of HDACs in cardiovascular diseases and the possible therapeutic implications of HDAC inhibitors in cardiovascular disease.

Development of localized inflammatory environments by M1 macrophages in the cardiac infarction region exacerbates heart failure after myocardial infarction (MI). Therefore, the regulation of inflammation by M1 macrophages and their timely polarization toward regenerative M2 macrophages suggest an immunotherapy. Particularly, controlling cellular generation of reactive oxygen species (ROS), which cause M1 differentiation, and developing M2 macrophage phenotypes in macrophages propose a therapeutic approach. Previously, stem or dendritic cells were used in MI for their anti-inflammatory and cardioprotective potentials and showed inflammation modulation and M2 macrophage progression for cardiac repair. However, cell-based therapeutics are limited due to invasive cell isolation, time-consuming cell expansion, labor-intensive and costly ex vivo cell manipulation, and low grafting efficiency. Here, we report that graphene oxide (GO) can serve as an antioxidant and attenuate inflammation and inflammatory polarization of macrophages via reduction in intracellular ROS. In addition, GO functions as a carrier for interleukin-4 plasmid DNA (IL-4 pDNA) that propagates M2 macrophages. We synthesized a macrophage-targeting/polarizing GO complex (MGC) and demonstrated that MGC decreased ROS in immune-stimulated macrophages. Furthermore, DNA-functionalized MGC (MGC/IL-4 pDNA) polarized M1 to M2 macrophages and enhanced the secretion of cardiac repair-favorable cytokines. Accordingly, injection of MGC/IL-4 pDNA into mouse MI models attenuated inflammation, elicited early polarization toward M2 macrophages, mitigated fibrosis, and improved heart function. Taken together, the present study highlights a biological application of GO in timely modulation of the immune environment in MI for cardiac repair. Current therapy using off-the-shelf material GO may overcome the shortcomings of cell therapies for MI.

Histone lysine methylation, as one of the most important factors in transcriptional regulation, is associated with a various physiological conditions. Using a bioinformatics search, we identified and subsequently cloned mouse SET domain containing 3 (SETD3) with SET (Su(var)3-9, Enhancer-of-zeste and Trithorax) and Rubis-subs-bind domains. SETD3 is a novel histone H3K4 and H3K36 methyltransferase with transcriptional activation activity. SETD3 is expressed abundantly in muscular tissues and, when overexpressed, activates transcription of muscle-related genes, myogenin, muscle creatine kinase (MCK), and myogenic factor 6 (Myf6), thereby inducing muscle cell differentiation. Conversely, knockdown of SETD3 by shRNA significantly retards muscle cell differentiation. In this study, SETD3 was recruited to the myogenin gene promoter along with MyoD where it activated transcription. Together, these data indicate that SETD3 is a H3K4/K36 methyltransferase and plays an important role in the transcriptional regulation of muscle cell differentiation.The conformational structure or molecular charge of the histone core complex can be modified via methylation of the lysine/arginine residue in the histone tail, which affects gene expression and heterochromatin formation (1). Arginine methylation is mediated by PRDM family proteins, which are characterized by the presence of a PR (PRD1-BF1 and RIZ homology) domain at their N terminus, whereas lysine is methylated by histone methyltransferase (HMTase), 4 which commonly harbors the SET (Su(var)3-9, Enhancer-of-zeste and Trithorax) domain (2). By forming complexes with a broad variety of transcription factors, HMTases perform an important role in the regulation of gene expression, stem cell renewal, reproductive organ maturation, and tumorigenesis in mammals (2-5).Additionally, HMTases have been confirmed as crucial to myofibril organization (6), intestinal and pancreatic differentiation (7), and neurogenesis (8) in zebrafish.Muscle differentiation requires sequences of harmonized steps after the commitment of mesodermal progenitor cells to the muscular lineage (9). Under the regulation of diverse modifiers, myoblasts fuse with other neighboring myoblasts to generate multinucleated myotubes (10). During differentiation, the cell cycle is withdrawn and muscle-specific transcription factors activated. Mesodermal precursor cells with muscular lineages are differentiated into skeletal muscle or smooth muscle via the interplay of muscle-specific factors, including MyoD, myogenin, myogenic factor 5 (Myf5), muscle regulatory factor 4 (MRF4), and myocyte enhancer factor-2 (MEF2) (10).Histone modification enzymes have been implicated in muscle cell differentiation through the regulation of musclespecific gene expression (11,12). Chromatin modification enzymes such as histone acetyltransferases, deacetylases (HDACs), and chromatin remodeling factors have recently been reported to regulate MyoD activity during muscle differentiation. For example, the histone acetyltransferases p300 and p300/C...

f Histone lysine methylation and demethylation are considered critical steps in transcriptional regulation. In this report, we performed chromatin immunoprecipitation with microarray technology (ChIP-chip) analysis to examine the genome-wide occupancy of H3K9-me2 during all-trans-retinoic acid (ATRA)-induced differentiation of HL-60 promyelocytic leukemia cells. Using this approach, we found that KDM3B, which contains a JmjC domain, was downregulated during differentiation through the recruitment of a corepressor complex. Furthermore, KDM3B displayed histone H3K9-me1/2 demethylase activity and induced leukemogenic oncogene lmo2 expression via a synergistic interaction with CBP. Here, we found that KDM3B repressed leukemia cell differentiation and was upregulated in blood cells from acute lymphoblastic leukemia (ALL)-type leukemia patients. The combined results of this study provide evidence that the H3K9-me1/2 demethylase KDM3B might play a role in leukemogenesis via activation of lmo2 through interdependent actions with the histone acetyltransferase (HAT) complex containing CBP.

Abstract-Diverse cardiac diseases induce cardiac hypertrophy, which leads to dilatation and heart failure. We previously reported that hypertrophy can be blocked by class I histone deacetylase (HDAC) inhibitor, which prompted us to investigate the regulatory mechanism of class I HDACs. Cardiac hypertrophy was introduced by aortic banding, by infusion of isoproterenol or angiotensin II, or by swimming. Hypertrophic stimuli transiently elevated the activity of histone deacetylase-2 (Hdac2), a class I HDAC. In cardiomyocytes, forced expression of Hdac2 simulated hypertrophy in an Akt-dependent manner, whereas enzymatically inert Hdac2 H141A failed to do so. Hypertrophic stimuli induced the expression of heat shock protein (Hsp)70. The induced Hsp70 physically associated with and activated Hdac2. Hsp70 overexpression produced a hypertrophic phenotype, which was blocked either by siHdac2 or by a dominant negative Hsp70⌬ABD. In Hsp70.1 Ϫ/Ϫ mice, cardiac hypertrophy and Hdac2 activation were significantly blunted. Heat shock either to cardiomyocytes or to mice activated Hdac2 and induced hypertrophy. However, heat shock-induced Hdac2 activation was blunted in the cardiomyocytes isolated from Hsp70.1 Ϫ/Ϫ mice. These results suggest that the induction of Hsp70 in response to diverse hypertrophic stresses and the ensuing activation of HDAC2 trigger cardiac hypertrophy, emphasizing HSP70/HDAC2 as a novel mechanism regulating hypertrophy. Key Words: cardiac hypertrophy Ⅲ class I histone deacetylases Ⅲ histone deacetylase 2 Ⅲ heat shock protein 70 Ⅲ Hsp70.1 Ϫ/Ϫ mice C ardiac hypertrophy is a response, either adaptive or maladaptive, to pressure or volume overload, mutations, or loss of contractile mass. Hypertrophic growth accompanies many forms of heart disease, including ischemic diseases, myocardial infarction, hypertension, aortic stenosis, and valvular dysfunctions. Although the initial hypertrophic responses seem to be an adaptation to those stimuli, the sustained stress may lead to cardiomyopathy and heart failure, a major cause of human morbidity and mortality. However, few interventions have proven effective in blocking the hypertrophy or in preventing the transition to congestive heart failure.Cardiomyocyte hypertrophy is characterized by an increase in individual myocyte size, enhanced protein synthesis, and heightened organization of the sarcomere, 1 which are regulated by activation of heart-specific transcription factors such as GATA4, MEF2, and immediate early genes like c-jun and c-fos. 2 The subsequent reactivation of the fetal gene program and repression of adult cardiac genes are closely related to the deterioration of heart function in hypertrophy.Recently, modulation of gene transcription by altering chromatin structure, especially by adding or removing acetyl groups to histone tails, has been implicated in diverse human pathologies, including cardiac hypertrophy. 3 Histone deacetylases (HDACs), which remove the acetyl group, repress downstream gene expression. Although HDACs are divided into 4 familie...