Esophageal emergencies: another important cause of acute chest pain.

A variety of esophageal pathologies can present emergently with a chief complaint of acute chest pain. Computed tomography (CT) is often the first line of imaging in esophageal emergencies and provides useful information-even without an initial suspicion-when used in conjunction with other imaging modalities such as esophagography and direct visualization. We review various urgent and emergent esophageal disease entities which may manifest as acute chest pain, with an emphasis on CT and ancillary imaging appearances, while discussing management according to their emergency. Radiologists should be familiar with the imaging findings of these esophageal emergencies in order to provide an accurate diagnosis and recommend timely and appropriate management.

Unperturbed expression bias of imprinted genes in schizophrenia.

How gene expression correlates with schizophrenia across individuals is beginning to be examined through analyses of RNA-seq from postmortem brains of individuals with disease and control brains. Here we focus on variation in allele-specific expression, following up on the CommonMind Consortium (CMC) RNA-seq experiments of nearly 600 human dorsolateral prefrontal cortex (DLPFC) samples. Analyzing the extent of allelic expression bias-a hallmark of imprinting-we find that the number of imprinted human genes is consistent with lower estimates (≈0.5% of all genes), and thus contradicts much higher estimates. Moreover, the handful of putatively imprinted genes are all in close genomic proximity to known imprinted genes. Joint analysis of the imprinted genes across hundreds of individuals allowed us to establish how allelic bias depends on various factors. We find that age and genetic ancestry have gene-specific, differential effect on allelic bias. In contrast, allelic bias appears to be independent of schizophrenia.

Genome-wide increase in histone H2A ubiquitylation in a mouse model of Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder with selective vulnerability of striatal neurons and involves extensive transcriptional dysregulation early in the disease process. Previous work in cell and mouse models has shown that histone modifications are altered in HD. Specifically, monoubiquitylated histone H2A (uH2A) is present at the promoters of downregulated genes which led to the hypothesis that uH2A plays a role in transcriptional silencing in HD. OBJECTIVE: To broaden our view of uH2A function in transcription in HD, we examined genome-wide binding sites of uH2A in 12-week old striatal tissue from R6/2 transgenic HD mouse model. METHODS: We used chromatin immunoprecipitation followed by genomic promoter microarray hybridization (ChIP-chip) and then interrogated how these binding sites correlate with transcribed genes. RESULTS: Our analysis reveals that, while uH2A levels are globally increased at the genome in the transgenic (TG) striatum, uH2A localization at a gene did not strongly correlate with the absence of its transcript. Furthermore, analysis of differential ubiquitylation in wild-type (WT) and TG striata did not reveal the expected enrichment of uH2A at genes with decreased expression in the TG striatum. CONCLUSIONS: This first description of genome-wide localization of uH2A in an HD model reveals that monoubiquitylation of histone H2A may not function at the level of the individual gene but may rather influence transcription through global chromatin structure.

Genome-wide histone acetylation is altered in a transgenic mouse model of Huntington's disease.

In Huntington's disease (HD; MIM ID #143100), a fatal neurodegenerative disorder, transcriptional dysregulation is a key pathogenic feature. Histone modifications are altered in multiple cellular and animal models of HD suggesting a potential mechanism for the observed changes in transcriptional levels. In particular, previous work has suggested an important link between decreased histone acetylation, particularly acetylated histone H3 (AcH3; H3K9K14ac), and downregulated gene expression. However, the question remains whether changes in histone modifications correlate with transcriptional abnormalities across the entire transcriptome. Using chromatin immunoprecipitation paired with microarray hybridization (ChIP-chip), we interrogated AcH3-gene interactions genome-wide in striata of 12-week old wild-type (WT) and transgenic (TG) R6/2 mice, an HD mouse model, and correlated these interactions with gene expression levels. At the level of the individual gene, we found decreases in the number of sites occupied by AcH3 in the TG striatum. In addition, the total number of genes bound by AcH3 was decreased. Surprisingly, the loss of AcH3 binding sites occurred within the coding regions of the genes rather than at the promoter region. We also found that the presence of AcH3 at any location within a gene strongly correlated with the presence of its transcript in both WT and TG striatum. In the TG striatum, treatment with histone deacetylase (HDAC) inhibitors increased global AcH3 levels with concomitant increases in transcript levels; however, AcH3 binding at select gene loci increased only slightly. This study demonstrates that histone H3 acetylation at lysine residues 9 and 14 and active gene expression are intimately tied in the rodent brain, and that this fundamental relationship remains unchanged in an HD mouse model despite genome-wide decreases in histone H3 acetylation.

A system for performing high throughput assays of synaptic function.

Unbiased, high-throughput screening has proven invaluable for dissecting complex biological processes. Application of this general approach to synaptic function would have a major impact on neuroscience research and drug discovery. However, existing techniques for studying synaptic physiology are labor intensive and low-throughput. Here, we describe a new high-throughput technology for performing assays of synaptic function in primary neurons cultured in microtiter plates. We show that this system can perform 96 synaptic vesicle cycling assays in parallel with high sensitivity, precision, uniformity, and reproducibility and can detect modulators of presynaptic function. By screening libraries of pharmacologically defined compounds on rat forebrain cultures, we have used this system to identify novel effects of compounds on specific aspects of presynaptic function. As a system for unbiased compound as well as genomic screening, this technology has significant applications for basic neuroscience research and for the discovery of novel, mechanism-based treatments for central nervous system disorders.

Cocaine-induced chromatin remodeling increases brain-derived neurotrophic factor transcription in the rat medial prefrontal cortex, which alters the reinforcing efficacy of cocaine.

Cocaine self-administration alters patterns of gene expression in the brain that may underlie cocaine-induced neuronal plasticity. In the present study, male Sprague Dawley rats were allowed to self-administer cocaine (0.25 mg/infusion) 2 h/d for 14 d, followed by 7 d of forced abstinence. Compared with yoked saline control rats, cocaine self-administration resulted in increased brain-derived neurotrophic factor (BDNF) protein levels in the rat medial prefrontal cortex (mPFC). To examine the functional relevance of this finding, cocaine self-administration maintained under a progressive ratio schedule of reinforcement was assessed after short hairpin RNA-induced suppression of BDNF expression in the mPFC. Decreased BDNF expression in the mPFC increased the cocaine self-administration breakpoint. Next, the effect of cocaine self-administration on specific BDNF exons was assessed; results revealed selectively increased BDNF exon IV-containing transcripts in the mPFC. Moreover, there were significant cocaine-induced increases in acetylated histone H3 (AcH3) and phospho-cAMP response element binding protein (pCREB) association with BDNF promoter IV. In contrast, there was decreased methyl-CpG-binding protein 2 (MeCP2) association with BDNF promoter IV in the mPFC of rats that previously self-administered cocaine. Together, these results indicate that cocaine-induced increases in BDNF promoter IV transcript in the mPFC are driven by increased binding of AcH3 and pCREB as well as decreased MeCP2 binding at this BDNF promoter. Collectively, these results indicate that cocaine self-administration remodels chromatin in the mPFC, resulting in increased expression of BDNF, which appears to represent a compensatory neuroadaptation that reduces the reinforcing efficacy of cocaine.

Altered histone monoubiquitylation mediated by mutant huntingtin induces transcriptional dysregulation.

Although transcriptional dysregulation is a critical pathogenic mechanism in Huntington's disease (HD), it is still not known how mutant huntingtin causes it. Here we show that alteration of histone monoubiquitylation is a key mechanism. Disrupted interaction of huntingtin with Bmi-1, a component of the hPRC1L E3 ubiquitin ligase complex, increases monoubiquityl histone H2A (uH2A) levels in a cell culture model of HD. Genes with expression that is repressed in transgenic R6/2 mouse brain have increased uH2A and decreased uH2B at their promoters, whereas actively transcribed genes show the opposite pattern. Reduction in uH2A reverses transcriptional repression and inhibits methylation of histone H3 at lysine 9 in cell culture. In contrast, reduction in uH2B induces transcriptional repression and inhibits methylation of histone H3 at lysine 4. This is the first report to demonstrate hPRC1L as a huntingtin-interacting histone modifying complex and a crucial role for histone monoubiquitylation in mammalian brain gene expression, which broadens our understanding of histone code. These findings also provide a rationale for targeting histone monoubiquitylation for therapy in HD.

Histones associated with downregulated genes are hypo-acetylated in Huntington's disease models.

Transcriptional dysregulation plays a major role in the pathology of Huntington's disease (HD). However, the mechanisms causing selective downregulation of genes remain unknown. Histones regulate chromatin structure and thereby control gene expression; recent studies have demonstrated a therapeutic role for histone deacetylase (HDAC) inhibitors in polyglutamine diseases. This study demonstrates that despite no change in overall acetylated histone levels, histone H3 is hypo-acetylated at promoters of downregulated genes in R6/2 mice, ST14a and STHdh cells, as demonstrated by in vivo chromatin immunoprecipitation. In addition, HDAC inhibitor treatment increases association of acetylated histones with downregulated genes and corrects mRNA abnormalities. In contrast, there is a decrease in mRNA levels in wild-type cells following treatment with a histone acetyltransferase inhibitor. Although changes in histone acetylation correlate with decreased gene expression, histone hypo-acetylation may be a late event, as no hypo-acetylation is observed in 4-week-old R6/2 mice. Nevertheless, treatment with HDAC inhibitors corrects mRNA abnormalities through modification of histone proteins and may prove to be of therapeutic value in HD.