The Saccharomyces Genome Database (SGD) provides Internet access to the complete Saccharomyces cerevisiae genomic sequence, its genes and their products, the phenotypes of its mutants, and the literature supporting these data. The amount of information and the number of features provided by SGD have increased greatly following the release of the S.cerevisiae genomic sequence, which is currently the only complete sequence of a eukaryotic genome. SGD aids researchers by providing not only basic information, but also tools such as sequence similarity searching that lead to detailed information about features of the genome and relationships between genes. SGD presents information using a variety of user-friendly, dynamically created graphical displays illustrating physical, genetic and sequence feature maps. SGD can be accessed via the World Wide Web at http://genome-www.stanford.edu/Saccharomyces/
The entire DNA sequence of chromosome III of the yeast Saccharomyces cerevisiae has been determined. This is the first complete sequence analysis of an entire chromosome from any organism. The 315-kilobase sequence reveals 182 open reading frames for proteins longer than 100 amino acids, of which 37 correspond to known genes and 29 more show some similarity to sequences in databases. Of 55 new open reading frames analysed by gene disruption, three are essential genes; of 42 non-essential genes that were tested, 14 show some discernible effect on phenotype and the remaining 28 have no overt function.
The expression of some nuclear genes in Saccharomyces cerevisiae, such as the CIT2 gene, which encodes a glyoxylate cycle isoform of citrate synthase, is responsive to the functional state of mitochondria. Previous studies identified a basic helix-loop-helix-leucine zipper (bHLH/Zip) transcription factor encoded by the RTG1 gene that is required for both basal expression of the CIT2 gene and its increased expression in respiratorydeficient cells. Here, we describe the cloning and characterization of RTG3, a gene encoding a 54-kDa bHLH/ Zip protein that is also required for CIT2 expression. Rtg3p binds together with Rtg1p to two identical sites oriented as inverted repeats 28 bp apart in a regulatory upstream activation sequence element (UAS r ) in the CIT2 promoter. The core binding site for the Rtg1p-Rtg3p heterodimer is 5-GGTCAC-3, which differs from the canonical E-box site, CANNTG, to which most other bHLH proteins bind. We demonstrate that both of the Rtg1p-Rtg3p binding sites in the UAS r element are required in vivo and act synergistically for CIT2 expression. The basic region of Rtg3p conforms well to the basic region of most bHLH proteins, whereas the basic region of Rtg1p does not. These findings suggest that the Rtg1p-Rtg3p complex interacts in a novel way with its DNA target sites.Cells of the yeast Saccharomyces cerevisiae are able to monitor and respond to changes in mitochondrial function through accommodating changes in nuclear gene expression (26). We have referred to this process as retrograde regulation, which can be thought of as a stress response to mitochondrial dysfunctions (reviewed by Shyjan and Butow [36]). One example of retrograde regulation is the elevated expression of the CIT2 gene in response to various mitochondrial lesions (17). CIT2 encodes a peroxisomal isoform of citrate synthase (CS2) (15, 21) that functions in the glyoxylate cycle. CS2 has 83% sequence similarity with the tricarboxylic acid (TCA) cycle isoform of citrate synthase, CS1, encoded by the CIT1 gene. Various mitochondrial lesions, such as a block in the TCA cycle or the loss of mitochondrial DNA, result in a transcriptional activation of CIT2 anywhere from 2-to 30-fold. This activation is dependent, in part, on the kind mitochondrial defect (4, 17). We have suggested that the corresponding increases in CS2 activity could compensate for decreases in TCA cycle activity (17) through the known metabolic interactions between the glyoxylate and TCA cycles (38).We have identified two genes, RTG1 and RTG2, that are central to this novel signaling pathway (16). Each is required for basal as well as retrograde-regulated CIT2 expression. Surprisingly, both RTG1 and RTG2 are also essential for peroxisome proliferation (4, 13), which can be induced in yeast cells by the presence of oleic acid in the growth medium (14,37,40). RTG1 and RTG2 are also required for the oleic acid-dependent increase in expression of POX genes (encoding enzymes of the -oxidation pathway) and PMP27, which encodes a protein associated with peroxisoma...
Transcriptome analysis of human brain provides fundamental insight about development and disease, but largely relies on existing annotation. We sequenced transcriptomes of 72 prefrontal cortex samples across six life stages, and identified 50,650 differentially expression regions (DERs) associated with developmental and aging, agnostic of annotation. While many DERs annotated to non-exonic sequence (41.1%), most were similarly regulated in cytosolic mRNA extracted from independent samples. The DERs were developmentally conserved across 16 brain regions and within the developing mouse cortex, and were expressed in diverse cell and tissue types. The DERs were further enriched for active chromatin marks and clinical risk for neurodevelopmental disorders like schizophrenia. Lastly, we demonstrate quantitatively that these DERs associate with a changing neuronal phenotype related to differentiation and maturation. These data highlight conserved molecular signatures of transcriptional dynamics across brain development, some potential clinical relevance and the incomplete annotation of the human brain transcriptome.
Genome-wide association studies (GWASs) have reported many single nucleotide polymorphisms (SNPs) associated with psychiatric disorders, but knowledge is lacking regarding molecular mechanisms. Here we show that risk alleles spanning multiple genes across the 10q24.32 schizophrenia-related locus are associated in the human brain selectively with an increase in the expression of both BLOC-1 related complex subunit 7 (BORCS7) and a previously uncharacterized, human-specific arsenite methyltransferase (AS3MT) isoform (AS3MT(d2d3)), which lacks arsenite methyltransferase activity and is more abundant in individuals with schizophrenia than in controls. Conditional-expression analysis suggests that BORCS7 and AS3MT(d2d3) signals are largely independent. GWAS risk SNPs across this region are linked with a variable number tandem repeat (VNTR) polymorphism in the first exon of AS3MT that is associated with the expression of AS3MT(d2d3) in samples from both Caucasians and African Americans. The VNTR genotype predicts promoter activity in luciferase assays, as well as DNA methylation within the AS3MT gene. Both AS3MT(d2d3) and BORCS7 are expressed in adult human neurons and astrocytes, and they are upregulated during human stem cell differentiation toward neuronal fates. Our results provide a molecular explanation for the prominent 10q24.32 locus association, including a novel and evolutionarily recent protein that is involved in early brain development and confers risk for psychiatric illness.
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