CREBH Maintains Circadian Glucose Homeostasis by Regulating Hepatic Glycogenolysis and Gluconeogenesis.

Cyclic AMP-responsive element binding protein, hepatocyte specific (CREBH), is a liver-enriched, endoplasmic reticulum-tethered transcription factor known to regulate the hepatic acute-phase response and lipid homeostasis. In this study, we demonstrate that CREBH functions as a circadian transcriptional regulator that plays major roles in maintaining glucose homeostasis. The proteolytic cleavage and posttranslational acetylation modification of CREBH are regulated by the circadian clock.

CREBH Couples Circadian Clock With Hepatic Lipid Metabolism.

The circadian clock orchestrates diverse physiological processes critical for health and disease. CREB, hepatocyte specific (CREBH) is a liver-enriched, endoplasmic reticulum (ER)-tethered transcription factor known to regulate the hepatic acute phase response and energy homeostasis under stress conditions. We demonstrate that CREBH is regulated by the circadian clock and functions as a circadian regulator of hepatic lipid metabolism.

Identification of long noncoding RNAs dysregulated in the midbrain of human cocaine abusers.

Maintenance of the drug-addicted state is thought to involve changes in gene expression in different neuronal cell types and neural circuits. Midbrain dopamine (DA) neurons in particular mediate numerous responses to drugs of abuse. Long noncoding RNAs (lncRNAs) regulate CNS gene expression through a variety of mechanisms, but next to nothing is known about their role in drug abuse.

A molecular profile of cocaine abuse includes the differential expression of genes that regulate transcription, chromatin, and dopamine cell phenotype.

Chronic drug abuse, craving, and relapse are thought to be linked to long-lasting changes in neural gene expression arising through transcriptional and chromatin-related mechanisms. The key contributions of midbrain dopamine (DA)-synthesizing neurons throughout the addiction process provide a compelling rationale for determining the drug-induced molecular changes that occur in these cells. Yet our understanding of these processes remains rudimentary.

The neurobiology of tetrahydrobiopterin biosynthesis: a model for regulation of GTP cyclohydrolase I gene transcription within nigrostriatal dopamine neurons.

Within the brain, the reduced pteridine cofactor 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) is absolutely required for the synthesis of the monoamine (MA) neurotransmitters dopamine (DA), norepinephrine, epinephrine (E), and serotonin (5-HT), the novel gaseous neurotransmitter nitric oxide and the production of yet to be identified 1-O-alkylglycerol-derived lipids. GTP cyclohydrolase I (GTPCH) catalyzes the first and limiting step in the BH4 biosynthetic pathway, which is now thought to involve up to eight different proteins supporting six alternate de novo and two alternate salvage pathways. Gene expression analysis across different regions of the human brain shows the abundance of transcripts coding for all eight of these proteins to be highly correlated with each other and to be enriched within human MA neurons.

Layer-specific CREB target gene induction in human neocortical epilepsy.

Epilepsy is a disorder of recurrent seizures that affects 1% of the population. To understand why some areas of cerebral cortex produce seizures and others do not, we identified differentially expressed genes in human epileptic neocortex compared with nearby regions that did not produce seizures. The transcriptome that emerged strongly implicates MAPK signaling and CREB-dependent transcription, with 74% of differentially expressed genes containing a cAMP response element (CRE) in their proximal promoter, more than half of which are conserved.

Mining Affymetrix microarray data for long non-coding RNAs: altered expression in the nucleus accumbens of heroin abusers.

Although recent data suggest that some long non-coding RNAs (lncRNAs) exert widespread effects on gene expression and organelle formation, lncRNAs as a group constitute a sizable but poorly characterized fraction of the human transcriptome. We investigated whether some human lncRNA sequences were fortuitously represented on commonly used microarrays, then used this annotation to assess lncRNA expression in human brain. A computational and annotation pipeline was developed to identify lncRNA transcripts represented on Affymetrix U133 arrays.

GCH1 in early-onset Parkinson's disease.

Mutations in GTP-cyclohydrolase 1 (GCH1) cause autosomal dominant dopa-responsive dystonia (DRD), characterized by childhood-onset foot dystonia that later generalizes. DRD patients frequently present with associated Parkinsonism. Conversely, early-onset Parkinson's disease (EOPD) patients commonly display dystonia.

GCH1 expression in human cerebellum from healthy individuals is not gender dependent.

Dopa-responsive dystonia (DRD) is a familial childhood-onset disease characterized by fluctuating dystonia, associated with tremor and parkinsonism in some patients. In most families the disease displays autosomal dominant inheritance due to mutations in the GTP cyclohydrolase 1 gene (GCH1). Penetrance and symptom severity display strong female predominance for which gender-specific GCH1 expression has been hypothesized.

Identification of neuronal target genes for CCAAT/enhancer binding proteins.

CCAAT/Enhancer Binding Proteins (C/EBPs) play pivotal roles in the development and plasticity of the nervous system. Identification of the physiological targets of C/EBPs (C/EBP target genes) should therefore provide insight into the underlying biology of these processes. We used unbiased genome-wide mapping to identify 115 C/EBPbeta target genes in PC12 cells that include transcription factors, neurotransmitter receptors, ion channels, protein kinases and synaptic vesicle proteins.

Specificity proteins Sp1 and Sp3 interact with the rat GTP cyclohydrolase I proximal promoter to regulate transcription.

The role of the proximal promoter GC-box in regulating basal and cAMP-dependent GTP Cyclohydrolase I gene transcription was investigated using a variety of cell lines and techniques. These studies show that the GC-box is composed of a triad of cis-elements that in vitro bind specificity proteins Sp1 and Sp3. Sp1 and Sp3 were found associated with the native proximal promoter in PC12 cells but were not recruited to the promoter during cAMP-dependent transcription.

Protein kinase A-dependent recruitment of RNA polymerase II, C/EBP beta and NF-Y to the rat GTP cyclohydrolase I proximal promoter occurs without alterations in histone acetylation.

Cyclic-AMP stimulation of GTP cyclohydrolase I (GCH1) gene transcription was investigated in PC12 cells, the protein kinase A-deficient PC12 cell line 126-1B2 and C6 cells using transient transfection assays of proximal promoter reporter constructs and wild type or dominant negative proteins, chromatin immunoprecipitation and real-time quantitative PCR. These studies show that protein kinase A is necessary and sufficient for cAMP-dependent transcription conferred by both the cAMP regulatory element and the adjacent CCAAT-box. In intact cells these cis-elements were shown to bind cAMP response element binding protein, CCAAT-enhancer binding protein beta and nuclear factor-Y, with each protein controlling a different aspect of the cAMP response.

Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse.

Drug abuse is thought to induce long-term cellular and behavioral adaptations as a result of alterations in gene expression. Understanding the molecular consequences of addiction may contribute to the development of better treatment strategies. This study utilized high-throughput Affymetrix microarrays to identify gene expression changes in the post-mortem nucleus accumbens of chronic heroin abusers.

A yeast 2-hybrid analysis of human GTP cyclohydrolase I protein interactions.

The yeast 2-hybrid system was used to identify protein domains involved in the oligomerization of human guanosine 5'-triphosphate (GTP) Cyclohydrolase I (GCH1) and the interaction of GCH1 with its regulatory partner, GCH1 feedback regulatory protein (GFRP). When interpreted within the structural framework derived from crystallography, our results indicate that the GCH1 N-terminal alpha-helices are not the only domains involved in the formation of dimers from monomers and also suggest an important role for the C-terminal alpha-helix in the assembly of dimers to form decamers. Moreover, a previously unknown role of the extended N-terminal alpha-helix in the interaction of GCH1 and GFRP was revealed.

Gene expression profiling in the brains of human cocaine abusers.

Chronic cocaine abuse induces long-term neurochemical, structural and behavioural changes thought to result from altered gene expression within the nucleus accumbens and other brain regions playing a critical role in addiction. Recent methodological advances now allow the profiling of gene expression in human postmortem brain. In this article, we review studies in which we have used Affymetrix oligonucleotide microarrays to identify transcripts that are differentially expressed in the nucleus accumbens of cocaine abusers in comparison to well-matched control subjects.

N-myc regulates parkin expression.

Mutations in the parkin gene are common in early-onset and familial Parkinson's disease (PD), and the parkin protein interacts in the ubiquitin-proteasome system as an E3 ligase. However, the regulatory pathways that govern parkin expression are unknown. In this study, we showed that a phylogenetically conserved N-myc binding site in the bi-directional parkin promoter interacted with myc-family transcription factors in reporter assays, and N-myc bound to the parkin promoter in chromatin immunoprecipitation assays and repressed transcription activity.

Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin.

Chronic cocaine abuse induces long-term neural adaptations as a consequence of alterations in gene expression. This study was undertaken to identify those transcripts differentially regulated in the nucleus accumbens of human cocaine abusers. Affymetrix microarrays were used to measure transcript abundance in 10 cocaine abusers and 10 control subjects matched for age, race, sex, and brain pH.

Sister grouping of chimpanzees and humans as revealed by genome-wide phylogenetic analysis of brain gene expression profiles.

Gene expression profiles from the anterior cingulate cortex (ACC) of human, chimpanzee, gorilla, and macaque samples provide clues about genetic regulatory changes in human and other catarrhine primate brains. The ACC, a cerebral neocortical region, has human-specific histological features. Physiologically, an individual's ACC displays increased activity during that individual's performance of cognitive tasks.

Gene transfer of human guanosine 5'-triphosphate cyclohydrolase I restores vascular tetrahydrobiopterin level and endothelial function in low renin hypertension.

Background: We recently reported that arterial superoxide (O2-) is augmented by increased endothelin-1 (ET-1) in deoxycorticosterone acetate (DOCA)-salt hypertension, a model of low renin hypertension. Tetrahydrobiopterin (BH4), a potent reducing molecule with antioxidant properties and an essential cofactor for endothelial nitric oxide synthase, protects against O2--induced vascular dysfunction. However, the interaction between O2- and BH4 on endothelial function and the underlying mechanisms are unknown.

Functional association of the parkin gene promoter with idiopathic Parkinson's disease.

Loss-of-function mutations in the parkin gene were first identified in autosomal recessive juvenile parkinsonism (AR-JP). Subsequently, parkin mutations were found in many early-onset patients with Parkinson's disease (PD) (<45 years at onset). We hypothesized that parkin gene expression also may contribute to the age-associated risk of idiopathic PD (>50 years at onset).

Brain biopterin and tyrosine hydroxylase in asymptomatic dopa-responsive dystonia.

It is assumed that brain biopterin and dopamine loss should not be as severe in asymptomatic dopa-responsive dystonia caused by GCH1 mutations as it is in symptomatic dopa-responsive dystonia. However, the actual status of dopaminergic systems in asymptomatic cases is unknown. In the autopsied putamen of an asymptomatic GCH1 mutation carrier, we found that brain biopterin loss (-82%) paralleled that reported in dopa-responsive dystonia patients (-84%).