Accumulative evidence suggests that more than 20 neuron-specific genes are regulated by a transcriptional cis-regulatory element known as the neural restrictive silencer (NRS). A trans-acting repressor that binds the NRS, NRSF [also designated RE1-silencing transcription factor (REST)] has been cloned, but the mechanism by which it represses transcription is unknown. Here we show evidence that NRSF represses transcription of its target genes by recruiting mSin3 and histone deacetylase. Transfection experiments using a series of NRSF deletion constructs revealed the presence of two repression domains, RD-1 and RD-2, within the Nand C-terminal regions, respectively. A yeast two-hybrid screen using the RD-1 region as a bait identified a short form of mSin3B. In vitro pull-down assays and in vivo immunoprecipitation-Western analyses revealed a specific interaction between NRSF-RD1 and mSin3 PAH1-PAH2 domains. Furthermore, NRSF and mSin3 formed a complex with histone deacetylase 1, suggesting that NRSFmediated repression involves histone deacetylation. When the deacetylation of histones was inhibited by tricostatin A in nonneuronal cells, mRNAs encoding several neuronal-specific genes such as SCG10, NMDAR1, and choline acetyltransferase became detectable. These results indicate that NRSF recruits mSin3 and histone deacetylase 1 to silence neural-specific genes and suggest further that repression of histone deacetylation is crucial for transcriptional activation of neural-specific genes during neuronal terminal differentiation.

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Circadian clock genes are regulated through a transcriptional-translational feedback loop. Alterations of the chromatin structure by histone acetyltransferases and histone deacetylases (HDACs) are commonly implicated in the regulation of gene transcription. However, little is known about the transcriptional regulation of mammalian clock genes by chromatin modification. Here, we show that the state of acetylated histones fluctuated in parallel with the rhythm of mouse Per1 (mPer1) or mPer2 expression in fibroblast cells and liver. Mouse CRY1 (mCRY1) repressed transcription with HDACs and mSin3B, which was relieved by the HDAC inhibitor trichostatin A (TSA). In turn, TSA induced endogenous mPer1 expression as well as the acetylation of histones H3 and H4, which interacted with the mPer1 promoter region in fibroblast cells. Moreover, a light pulse stimulated rapid histone acetylation associated with the promoters of mPer1 or mPer2 in the suprachiasmatic nucleus (SCN) and the binding of phospho-CREB in the CRE of mPer1. We also showed that TSA administration into the lateral ventricle induced mPer1 and mPer2 expression in the SCN. Taken together, these data indicate that the rhythmic transcription and light induction of clock genes are regulated by histone acetylation and deacetylation.Most organisms have physiological and behavioral rhythms, so-called circadian rhythms, having an intrinsic period of approximately 24 h. The circadian clock is an endogenous oscillator that controls daily physiological and behavioral rhythms. In mammals, molecular oscillators exist in the suprachiasmatic nucleus (SCN) of the brain, a master clock (19,21,31), and also in peripheral tissues (24,48). Even in fibroblast cell lines, clock genes are induced rhythmically under certain conditions (1, 5, 47). The core circadian system consists of an interacting transcriptional-translational feedback loop of clock genes in an individual cell (11, 31). A negative feedback loop involves the regulation of two period genes (Per1 and -2) and two cryptochrome genes (Cry1 and -2) (22, 33). The rhythmic transcription is driven by the basic helix-loop-helix-PAS protein (CLOCK-BMAL1) complex, which binds the E-box on the mPer1 and mPer2 genes (14). This CLOCK-BMAL1-mediated transcription is, in turn, repressed by the translated products of clock genes, such as the mPER and mCRY protein complex, which translocate to the nucleus (14,17,22,33).On the other hand, rapid inductions of mPer1 and mPer2 are also involved in phase resetting of the circadian rhythm (3,4,34). A light pulse during subjective night induced rapid increases in mPer1 and mPer2 expression in the SCN and caused a behavioral phase shift. Thus, mPer1 and mPer2 are considered to work both in the generation of circadian rhythm and in light entrainment.It has recently become clear that histone modification plays an important role when genes are transcribed in the nucleus and basic domains in the histone N-terminal are modified, such as by phosphorylation, acetylation, methylation, or ubiquityla...

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Background— Fatal arrhythmia is commonly observed in cardiac sarcoidosis, but clinical effects of a systematic treatment approach are still uncertain. This study sought to describe both clinical and electrophysiological characteristics and outcomes of systematic treatment approach to ventricular tachycardia (VT) associated with cardiac sarcoidosis. Methods and Results— We enrolled 37 consecutive patients (11 men; age, 56±11 years) with a diagnosis of sustained VT associated with cardiac sarcoidosis. Clinical effects of a systematic treatment approach including medical therapy (both steroid and antiarrhythmic agents), in association with radiofrequency catheter ablation, were evaluated. All patients received antiarrhythmic agents, and 34 received steroid therapy. During a 39-month follow-up, 23 (62%) patients were free from any VT episodes with medical therapy. Multivariable Cox regression analyses revealed that the absence of gallium-67 myocardial uptake was an independent predictor for VT recurrence (hazard ratio, 7.51; 95% confidence interval, 1.65–34.26; P <0.01). Fourteen patients who experienced VT recurrences even while on drug therapy underwent radiofrequency catheter ablation. Electrophysiological study revealed that the mechanisms of VTs could be classified into 2 subgroups: Purkinje-related or scar-related VT. The QRS duration of VT was narrower in Purkinje-related than in scar-related VTs (157±23 versus 183±22 ms; P <0.05). After a 33-month follow-up subsequent to the radiofrequency catheter ablation, 6 of 14 patients experienced VT recurrence. The number of VTs sustained during electrophysiological study was higher in the patients with VT recurrence than in those without (3.7±1.4 versus 1.9±0.8; P <0.01). Conclusions— A systematic treatment approach to cardiac sarcoidosis with VT successfully suppressed VT recurrences in the majority of patients studied.

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Background-Recent evidence has linked early repolarization (ER) to idiopathic ventricular fibrillation (VF) in patients without structural heart disease. However, no studies have clarified whether or not there is an association between ER and the VF occurrences after the onset of an acute myocardial infarction (AMI). Methods and Results-This study retrospectively included 220 consecutive patients with an AMI (57 female; mean age, 69±11 years) in whom the 12-lead ECGs before the AMI onset could be evaluated. The patients were classified on the basis of a VF occurrence within 48 hours after the AMI onset. Early repolarization was defined as an elevation of the QRS-ST junction of >0.1 mV from baseline in at least 2 inferior or lateral leads, manifested as QRS slurring or notching.

BackgroundOur study aimed to investigate both the clinical implications of late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) and the relation of LGE to clinical findings in patients with Takotsubo cardiomyopathy (TTC).MethodsWe evaluated 20 consecutive patients (2 men, 18 women; median age, 77 years; interquartile range [IQR] 67-82 years) who were admitted to our hospital with the diagnosis of TTC. CMR was performed within 1 week after admission, and follow-up studies were conducted 1.5 and 6 months later.ResultsIn 8 patients, CMR imaging during the sub-acute phase revealed LGE in the area matched with wall motion impairment. Cardiogenic shock was more frequently observed in patients with LGE than in those without LGE (38% vs 0%, p = 0.049). The patients with LGE needed a longer duration for ECG normalization and recovery of wall motion than did those without LGE (median 205 days, IQR [152-363] vs 68 days, [43-145], p = 0.005; 15 days, [10-185] vs 7 days, [4-13], p = 0.030, respectively). In 5 of these 8 patients, LGE disappeared within 45-180 days (170, IQR [56-180]) of onset. The patients with LGE remaining in the chronic phase had higher peak creatine kinase levels than did those without LGE (median 307 IU/L, IQR [264-460] vs 202 IU/L, [120-218], p = 0.017).ConclusionLGE by CMR in the sub-acute phase may be associated with the severity and prolonged recovery to normal of clinical findings in TTC.