Thomas D Schneider | National Institutes of Health (original) (raw)
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Papers by Thomas D Schneider
Dictionary of Bioinformatics and Computational Biology, 2004
Nucleic Acids Research, 2001
Human Genetics, 2012
Beta-microseminoprotein (MSP)/MSMB is an immunoglobulin superfamily protein synthesized by prosta... more Beta-microseminoprotein (MSP)/MSMB is an immunoglobulin superfamily protein synthesized by prostate epithelial cells and secreted into seminal plasma. Variants in the promoter of the MSMB gene have been associated with the risk of prostate cancer (PCa) in several independent genome-wide association studies. Both MSMB and an adjacent gene, NCOA4, are subjected to transcriptional control via androgen response elements. The gene product of NCOA4 interacts directly with the androgen receptor as a co-activator to enhance AR transcriptional activity. Here, we provide evidence for the expression of full-length MSMB-NCOA4 fusion transcripts regulated by the MSMB promoter. The predominant MSMB-NCOA4 transcript arises by fusion of the 5'UTR and exons 1-2 of the MSMB pre-mRNA, with exons 2-10 of the NCOA4 pre-mRNA, producing a stable fusion protein, comprising the essential domains of NCOA4. Analysis of the splice sites of this transcript shows an unusually strong splice acceptor at NCOA4 exon 2 and the presence of Alu repeats flanking the exons potentially involved in the splicing event. Transfection experiments using deletion clones of the promoter coupled with luciferase reporter assays define a core MSMB promoter element located between -27 and -236 of the gene, and a negative regulatory element immediately upstream of the start codon. Computational network analysis reveals that the MSMB gene is functionally connected to NCOA4 and the androgen receptor signaling pathway. The data provide an example of how GWAS-associated variants may have multiple genetic and epigenetic effects.
Journal of bacteriology, Jan 16, 2018
DNA polymerases (DNAPs) recognize 3' recessed termini on duplex DNA and carry out nucleotide ... more DNA polymerases (DNAPs) recognize 3' recessed termini on duplex DNA and carry out nucleotide catalysis. Unlike promoter-specific RNA polymerases (RNAPs), no sequence specificity is required for binding or initiation of catalysis. Despite this, previous results indicate that viral reverse transcriptases bind much more tightly to DNA primers that mimic the polypurine tract. In the current report, primer sequences that bind with high affinity toand Klenow polymerases were identified using a modified Selective Evolution of Ligands by Exponential Enrichment (SELEX) approach. Two-specific primers that bound ∼10 (Taq1) and over 100 (Taq2) times more stably than controls towere identified.contained 8 nucleotides (5' -CACTAAAG-3') that matched the phage T3 RNAP "core" promoter. Both primers dramatically outcompeted primers with similar binding thermodynamics in PCR reactions. Similarly, exonuclease minus Klenow polymerase also selected a high affinity primer that contai...
Frontiers in molecular biosciences, 2016
The regulatory protein, GalR, is known for controlling transcription of genes related to D-galact... more The regulatory protein, GalR, is known for controlling transcription of genes related to D-galactose metabolism in Escherichia coli. Here, using a combination of experimental and bioinformatic approaches, we identify novel GalR binding sites upstream of several genes whose function is not directly related to D-galactose metabolism. Moreover, we do not observe regulation of these genes by GalR under standard growth conditions. Thus, our data indicate a broader regulatory role for GalR, and suggest that regulation by GalR is modulated by other factors. Surprisingly, we detect regulation of 158 transcripts by GalR, with few regulated genes being associated with a nearby GalR binding site. Based on our earlier observation of long-range interactions between distally bound GalR dimers, we propose that GalR indirectly regulates the transcription of many genes by inducing large-scale restructuring of the chromosome.
J Mol Biol, 2001
During translational initiation in prokaryotes, the 3' end of the 16S rRNA binds to a reg... more During translational initiation in prokaryotes, the 3' end of the 16S rRNA binds to a region just upstream of the initiation codon. The relationship between this Shine-Dalgarno (SD) region and the binding of ribosomes to translation start-points has been well studied, but a unified mathematical connection between the SD, the initiation codon and the spacing between them has been lacking. Using information theory, we constructed a model that treats these three components uniformly by assigning to the SD and the initiation region (IR) conservations in bits of information, and by assigning to the spacing an uncertainty, also in bits. To build the model, we first aligned the SD region by maximizing the information content there. The ease of this process confirmed the existence of the SD pattern within a set of 4122 reviewed and revised Escherichia coli gene starts. This large data set allowed us to show graphically, by sequence logos, that the spacing between the SD and the initiation region affects both the SD site conservation and its pattern. We used the aligned SD, the spacing, and the initiation region to model ribosome binding and to identify gene starts that do not conform to the ribosome binding site model. A total of 569 experimentally proven starts are more conserved (have higher information content) than the full set of revised starts, which probably reflects an experimental bias against the detection of gene products that have inefficient ribosome binding sites. Models were refined cyclically by removing non-conforming weak sites. After this procedure, models derived from either the original or the revised gene start annotation were similar. Therefore, this information theory-based technique provides a method for easily constructing biologically sensible ribosome binding site models. Such models should be useful for refining gene-start predictions of any sequenced bacterial genome.
Applied Bioinformatics, Feb 1, 2002
Nucleic Acids Research, Aug 26, 1986
Progress in Nucleic Acid Research and Molecular Biology, 1997
... See the world wide web site http:/mww-lmmb.ncifcrf.gov/-toms/paper/primer for a short primer ... more ... See the world wide web site http:/mww-lmmb.ncifcrf.gov/-toms/paper/primer for a short primer on information theory that explains how this formula works. Other useful references are Shannon's original papers (29) and the book by Pierce (30). ...
J Dermatological Sci, 1998
Nucleic Acids Research, 2007
Information theory was used to build a promoter model that accounts for the � 10, the � 35 and th... more Information theory was used to build a promoter model that accounts for the � 10, the � 35 and the uncertainty of the gap between them on a common scale. Helical face assignment indicated that base � 7, rather than � 11, of the � 10 may be flipping to initiate transcription. We found that the sequence conservation of s70
Dictionary of Bioinformatics and Computational Biology, 2004
Dictionary of Bioinformatics and Computational Biology, 2004
Dictionary of Bioinformatics and Computational Biology, 2004
Nucleic Acids Research, 2001
Human Genetics, 2012
Beta-microseminoprotein (MSP)/MSMB is an immunoglobulin superfamily protein synthesized by prosta... more Beta-microseminoprotein (MSP)/MSMB is an immunoglobulin superfamily protein synthesized by prostate epithelial cells and secreted into seminal plasma. Variants in the promoter of the MSMB gene have been associated with the risk of prostate cancer (PCa) in several independent genome-wide association studies. Both MSMB and an adjacent gene, NCOA4, are subjected to transcriptional control via androgen response elements. The gene product of NCOA4 interacts directly with the androgen receptor as a co-activator to enhance AR transcriptional activity. Here, we provide evidence for the expression of full-length MSMB-NCOA4 fusion transcripts regulated by the MSMB promoter. The predominant MSMB-NCOA4 transcript arises by fusion of the 5'UTR and exons 1-2 of the MSMB pre-mRNA, with exons 2-10 of the NCOA4 pre-mRNA, producing a stable fusion protein, comprising the essential domains of NCOA4. Analysis of the splice sites of this transcript shows an unusually strong splice acceptor at NCOA4 exon 2 and the presence of Alu repeats flanking the exons potentially involved in the splicing event. Transfection experiments using deletion clones of the promoter coupled with luciferase reporter assays define a core MSMB promoter element located between -27 and -236 of the gene, and a negative regulatory element immediately upstream of the start codon. Computational network analysis reveals that the MSMB gene is functionally connected to NCOA4 and the androgen receptor signaling pathway. The data provide an example of how GWAS-associated variants may have multiple genetic and epigenetic effects.
Journal of bacteriology, Jan 16, 2018
DNA polymerases (DNAPs) recognize 3' recessed termini on duplex DNA and carry out nucleotide ... more DNA polymerases (DNAPs) recognize 3' recessed termini on duplex DNA and carry out nucleotide catalysis. Unlike promoter-specific RNA polymerases (RNAPs), no sequence specificity is required for binding or initiation of catalysis. Despite this, previous results indicate that viral reverse transcriptases bind much more tightly to DNA primers that mimic the polypurine tract. In the current report, primer sequences that bind with high affinity toand Klenow polymerases were identified using a modified Selective Evolution of Ligands by Exponential Enrichment (SELEX) approach. Two-specific primers that bound ∼10 (Taq1) and over 100 (Taq2) times more stably than controls towere identified.contained 8 nucleotides (5' -CACTAAAG-3') that matched the phage T3 RNAP "core" promoter. Both primers dramatically outcompeted primers with similar binding thermodynamics in PCR reactions. Similarly, exonuclease minus Klenow polymerase also selected a high affinity primer that contai...
Frontiers in molecular biosciences, 2016
The regulatory protein, GalR, is known for controlling transcription of genes related to D-galact... more The regulatory protein, GalR, is known for controlling transcription of genes related to D-galactose metabolism in Escherichia coli. Here, using a combination of experimental and bioinformatic approaches, we identify novel GalR binding sites upstream of several genes whose function is not directly related to D-galactose metabolism. Moreover, we do not observe regulation of these genes by GalR under standard growth conditions. Thus, our data indicate a broader regulatory role for GalR, and suggest that regulation by GalR is modulated by other factors. Surprisingly, we detect regulation of 158 transcripts by GalR, with few regulated genes being associated with a nearby GalR binding site. Based on our earlier observation of long-range interactions between distally bound GalR dimers, we propose that GalR indirectly regulates the transcription of many genes by inducing large-scale restructuring of the chromosome.
J Mol Biol, 2001
During translational initiation in prokaryotes, the 3' end of the 16S rRNA binds to a reg... more During translational initiation in prokaryotes, the 3' end of the 16S rRNA binds to a region just upstream of the initiation codon. The relationship between this Shine-Dalgarno (SD) region and the binding of ribosomes to translation start-points has been well studied, but a unified mathematical connection between the SD, the initiation codon and the spacing between them has been lacking. Using information theory, we constructed a model that treats these three components uniformly by assigning to the SD and the initiation region (IR) conservations in bits of information, and by assigning to the spacing an uncertainty, also in bits. To build the model, we first aligned the SD region by maximizing the information content there. The ease of this process confirmed the existence of the SD pattern within a set of 4122 reviewed and revised Escherichia coli gene starts. This large data set allowed us to show graphically, by sequence logos, that the spacing between the SD and the initiation region affects both the SD site conservation and its pattern. We used the aligned SD, the spacing, and the initiation region to model ribosome binding and to identify gene starts that do not conform to the ribosome binding site model. A total of 569 experimentally proven starts are more conserved (have higher information content) than the full set of revised starts, which probably reflects an experimental bias against the detection of gene products that have inefficient ribosome binding sites. Models were refined cyclically by removing non-conforming weak sites. After this procedure, models derived from either the original or the revised gene start annotation were similar. Therefore, this information theory-based technique provides a method for easily constructing biologically sensible ribosome binding site models. Such models should be useful for refining gene-start predictions of any sequenced bacterial genome.
Applied Bioinformatics, Feb 1, 2002
Nucleic Acids Research, Aug 26, 1986
Progress in Nucleic Acid Research and Molecular Biology, 1997
... See the world wide web site http:/mww-lmmb.ncifcrf.gov/-toms/paper/primer for a short primer ... more ... See the world wide web site http:/mww-lmmb.ncifcrf.gov/-toms/paper/primer for a short primer on information theory that explains how this formula works. Other useful references are Shannon's original papers (29) and the book by Pierce (30). ...
J Dermatological Sci, 1998
Nucleic Acids Research, 2007
Information theory was used to build a promoter model that accounts for the � 10, the � 35 and th... more Information theory was used to build a promoter model that accounts for the � 10, the � 35 and the uncertainty of the gap between them on a common scale. Helical face assignment indicated that base � 7, rather than � 11, of the � 10 may be flipping to initiate transcription. We found that the sequence conservation of s70
Dictionary of Bioinformatics and Computational Biology, 2004
Dictionary of Bioinformatics and Computational Biology, 2004