Human and Mouse α-Synuclein Genes: Comparative Genomic Sequence Analysis and Identification of a Novel Gene Regulatory Element

Touchman, Jeffrey W.; Dehejia, Anindya; Chiba‐Falek, Ornit; Cabin, Deborah E.; Schwartz, Jody R.; Orrison, Bonnie M.; Polymeropoulos, Mihael H.; Nussbaum, Robert L.

doi:10.1101/gr.165801

Cited by 117 publications

(82 citation statements)

References 40 publications

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“…4 A) (31) with the translation start codon ATG encoded by exon-2. Intron-1 is 1,097 bp in size (31). To determine whether the GATA motifs in Snca were occupied by GATA-1, we conducted quantitative chromatin immunoprecipitation analysis (ChIP) in G1E-ER-GATA-1 cells.…”

Section: Gata-1 Specifically Occupies a Highly Restricted Region Withmentioning

confidence: 99%

GATA transcription factors directly regulate the Parkinson's disease-linked gene α-synuclein

Scherzer

Grass²,

Liao³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

242

227

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Increased ␣-synuclein gene (SNCA) dosage due to locus multiplication causes autosomal dominant Parkinson's disease (PD). Variation in SNCA expression may be critical in common, genetically complex PD but the underlying regulatory mechanism is unknown. We show that SNCA and the heme metabolism genes ALAS2, FECH, and BLVRB form a block of tightly correlated gene expression in 113 samples of human blood, where SNCA naturally abounds (validated P ‫؍‬ 1.6 ؋ 10 ؊11 , 1.8 ؋ 10 ؊10 , and 6.6 ؋ 10 ؊5 ). Genetic complementation analysis revealed that these four genes are co-induced by the transcription factor GATA-1. GATA-1 specifically occupies a conserved region within SNCA intron-1 and directly induces a 6.9-fold increase in ␣-synuclein. Endogenous GATA-2 is highly expressed in substantia nigra vulnerable to PD, occupies intron-1, and modulates SNCA expression in dopaminergic cells. This critical link between GATA factors and SNCA may enable therapies designed to lower ␣-synuclein production.␣-synuclein dosage ͉ GATA-1 ͉ GATA-2 ͉ gene expression ͉ microarray

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Section: Gata-1 Specifically Occupies a Highly Restricted Region Withmentioning

confidence: 99%

GATA transcription factors directly regulate the Parkinson's disease-linked gene α-synuclein

Scherzer

Grass²,

Liao³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

242

227

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“…Algorithms for identifying regulatory elements are not very effective; therefore, orthologous cross-species comparisons of noncoding regions is a strategy used to identify potential regulatory elements (Oeltjen et al 1997;Loots et al 2000;Touchman et al 2001). One such element, in a noncoding region of the mouse and human T-cell receptor J␣ region, was demonstrated to have enhancer activities (Kuo et al 1998).…”

Section: Conserved Noncoding Sequences (Cns) and Gene Regulationmentioning

confidence: 99%

Analysis of the Gene-Dense Major Histocompatibility Complex Class III Region and Its Comparison to Mouse

Xie

Rowen

Aguado³

et al. 2003

Genome Research

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In mammals, the Major Histocompatibility Complex class I and II gene clusters are separated by an ∼700-kb stretch of sequence called the MHC class III region, which has been associated with susceptibility to numerous diseases. To facilitate understanding of this medically important and architecturally interesting portion of the genome, we have sequenced and analyzed both the human and mouse class III regions. The cross-species comparison has facilitated the identification of 60 genes in human and 61 in mouse, including a potential RNA gene for which the introns are more conserved across species than the exons. Delineation of global organization, gene structure, alternative splice forms, protein similarities, and potential cis-regulatory elements leads to several conclusions: (1) The human MHC class III region is the most gene-dense region of the human genome: >14% of the sequence is coding, ∼72% of the region is transcribed, and there is an average of 8.5 genes per 100 kb. (2) Gene sizes, number of exons, and intergenic distances are for the most part similar in both species, implying that interspersed repeats have had little impact in disrupting the tight organization of this densely packed set of genes. (3) The region contains a heterogeneous mixture of genes, only a few of which have a clearly defined and proven function. Although many of the genes are of ancient origin, some appear to exist only in mammals and fish, implying they might be specific to vertebrates. (4) Conserved noncoding sequences are found primarily in or near the 5'-UTR or the first intron of genes, and seldom in the intergenic regions. Many of these conserved blocks are likely to be cis-regulatory elements.

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“…Cold Spring Harbor Laboratory Press on March 22, 2019 -Published by genome.cshlp.org Downloaded from regions, including regulatory elements (Duret and Bucher 1997;Hardison et al 1997;Hardison 2000;Miller 2000;Wasserman et al 2000;Cliften et al 2001;Pennacchio and Rubin 2001;Touchman et al 2001). With the recent completion of a working-draft sequence of the human genome (International Human Genome Sequencing Consortium 2001; Venter et al 2001), increasing attention is being given to the sequencing of other organisms (Green 2001).…”

Section: Sequence Of the Mouse Williams Syndrome Regionmentioning

confidence: 99%

Generation and Comparative Analysis of ∼3.3 Mb of Mouse Genomic Sequence Orthologous to the Region of Human Chromosome 7q11.23 Implicated in Williams Syndrome

DeSilva¹,

Elnitski²,

Idol³

et al. 2002

Genome Res.

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Williams syndrome is a complex developmental disorder that results from the heterozygous deletion of a ∼1.6-Mb segment of human chromosome 7q11.23. These deletions are mediated by large (∼300 kb) duplicated blocks of DNA of near-identical sequence. Previously, we showed that the orthologous region of the mouse genome is devoid of such duplicated segments. Here, we extend our studies to include the generation of ∼3.3 Mb of genomic sequence from the mouse Williams syndrome region, of which just over 1.4 Mb is finished to high accuracy. Comparative analyses of the mouse and human sequences within and immediately flanking the interval commonly deleted in Williams syndrome have facilitated the identification of nine previously unreported genes, provided detailed sequence-based information regarding 30 genes residing in the region, and revealed a number of potentially interesting conserved noncoding sequences. Finally, to facilitate comparative sequence analysis, we implemented several enhancements to the program PipMaker, including the addition of links from annotated features within a generated percent-identity plot to specific records in public databases. Taken together, the results reported here provide an important comparative sequence resource that should catalyze additional studies of Williams syndrome, including those that aim to characterize genes within the commonly deleted interval and to develop mouse models of the disorder.[The sequence data described in this paper have been submitted to GenBank under accession nos. AF267747, AF289666, AF289667, AF289664, AF289665, AC091250, AC079938, AC084109, AC024607, AC074359, AC024608, AC083858, AC083948, AC084162, AC087420, AC083890, AC080158, AC084402, AC083889, AC083857, and AC079872.]The past decade has brought spectacular advances in our understanding of the contiguous gene deletion disorder Williams syndrome (WS, also known as Williams-Beuren syndrome; OMIM 194050 [see http://www.ncbi.nlm.nih.gov/ Omim]). This complex and intriguing developmental disorder is associated with defects in multiple physiological systems, with the classic phenotypic features including cardiovascular disease, dysmorphic facial characteristics, infantile hypercalcemia, and unique cognitive and personality components (Burn 1986;Morris et al. 1988;Bellugi et al. 1990Bellugi et al. , 1999Lashkari et al. 1999;Mervis et al. 1999 A key turning point in elucidating the genetic basis of WS came in 1993 with the discovery that the disorder is associated with hemizygous microdeletions within human chromosome 7q11.23 that include the elastin gene (ELN; Ewart et al. 1993). Since that time, there have been numerous studies aiming to map this region of chromosome 7, identify the genes residing within the commonly deleted interval, and associate the phenotypic features of the disorder to the haploinsufficiency of specific genes. These efforts have been aided by a joint effort between our group and the Washington University Genome Sequencing Center (http://genome. wustl.edu/gsc) to map and sequence th...

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Human and Mouse α-Synuclein Genes: Comparative Genomic Sequence Analysis and Identification of a Novel Gene Regulatory Element

Cited by 117 publications

References 40 publications

GATA transcription factors directly regulate the Parkinson's disease-linked gene α-synuclein

GATA transcription factors directly regulate the Parkinson's disease-linked gene α-synuclein

Analysis of the Gene-Dense Major Histocompatibility Complex Class III Region and Its Comparison to Mouse

Generation and Comparative Analysis of ∼3.3 Mb of Mouse Genomic Sequence Orthologous to the Region of Human Chromosome 7q11.23 Implicated in Williams Syndrome

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