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Finding subtypes of transcription factor motif pairs with distinct regulatory roles.

Bais AS, Kaminski N, Benos PV - Nucleic Acids Res. (2011)

Bottom Line: DNA sequences bound by a transcription factor (TF) are presumed to contain sequence elements that reflect its DNA binding preferences and its downstream-regulatory effects.We present DiSCo (Discovery of Subtypes and Cofactors), a novel approach for identifying variants of dyad motifs (and their respective target sequence sets) that are instrumental for differential downstream regulation.Using both simulated and experimental datasets, we demonstrate how current motif discovery can be successfully leveraged to address this question.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational and Systems Biology, Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine and Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA 15260, USA.

ABSTRACT
DNA sequences bound by a transcription factor (TF) are presumed to contain sequence elements that reflect its DNA binding preferences and its downstream-regulatory effects. Experimentally identified TF binding sites (TFBSs) are usually similar enough to be summarized by a 'consensus' motif, representative of the TF DNA binding specificity. Studies have shown that groups of nucleotide TFBS variants (subtypes) can contribute to distinct modes of downstream regulation by the TF via differential recruitment of cofactors. A TF(A) may bind to TFBS subtypes a(1) or a(2) depending on whether it associates with cofactors TF(B) or TF(C), respectively. While some approaches can discover motif pairs (dyads), none address the problem of identifying 'variants' of dyads. TFs are key components of multiple regulatory pathways targeting different sets of genes perhaps with different binding preferences. Identifying the discriminating TF-DNA associations that lead to the differential downstream regulation is thus essential. We present DiSCo (Discovery of Subtypes and Cofactors), a novel approach for identifying variants of dyad motifs (and their respective target sequence sets) that are instrumental for differential downstream regulation. Using both simulated and experimental datasets, we demonstrate how current motif discovery can be successfully leveraged to address this question.

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Dyad-dependent modes of regulation. A TF A with DNA binding specificity a may bind subtypes, a1 and a2, of binding sites depending on whether they co-occur with binding sites b and c of cofactors B and C, respectively. Alternatively, a TF that binds as a dimer may bind dyads a1:b or a2:c depending on the sets of downstream targets and/or vice versa. Finally, two distinct TFs with highly similar but distinct binding sites a1 and a2, may recognize and bind their respective TFBSs by associating with corresponding cofactors B and C, respectively. Logos represent the consensus motifs of the TFs and d is the maximum inter-site distance.
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Figure 1: Dyad-dependent modes of regulation. A TF A with DNA binding specificity a may bind subtypes, a1 and a2, of binding sites depending on whether they co-occur with binding sites b and c of cofactors B and C, respectively. Alternatively, a TF that binds as a dimer may bind dyads a1:b or a2:c depending on the sets of downstream targets and/or vice versa. Finally, two distinct TFs with highly similar but distinct binding sites a1 and a2, may recognize and bind their respective TFBSs by associating with corresponding cofactors B and C, respectively. Logos represent the consensus motifs of the TFs and d is the maximum inter-site distance.

Mentions: The precise nucleotide sequence of a TFBS plays an important role, not only in attracting the corresponding TF, but also in the recruitment of its cofactors and hence in the mode of regulation of its targets. A TF A may bind to TFBSs of subtype a1 or a2 and target different genes depending on whether it associates with cofactor B or C, respectively (Figure 1). For example, in Escherichia coli, the cyclic AMP receptor protein (CRP) binds a 22-bp consensus motif CRP-N to regulate roughly 100 genes involved in the response to sugar starvation in the cell (17). In Haemophilus influenzae, CRP recognizes the typical CRP-N sites, but it also recognizes and binds to a CRP-N variant, the non-canonical CRP-S motif (18,19). The CRP-S sites are found in the promoters of genes involved in ‘competence’, a process by which cells can take up DNA from the environment, and which require the presence of both CRP and another protein, Sxy, for transcriptional activation. A similar functional CRP-S regulon has also been identified in E. coli (13,20), suggesting possibly a similar mechanism. Hence, the protein CRP recognizes two highly similar but distinct motifs, subtypes CRP-N and CRP-S, in the presence or absence of Sxy thus regulating different sets of downstream genes. Single nucleotide changes too have been associated with the choice of cofactors and the set of target genes as in the case of the glucocorticoid receptor (16,21), NF-κB (22), Pit-1 (23), Foxa2 (24), etc. In the following, we use the term ‘subtypes’ of TFBSs to refer to groups of highly similar but distinct nucleotide variants of the canonical binding motif of a TF.Figure 1.


Finding subtypes of transcription factor motif pairs with distinct regulatory roles.

Bais AS, Kaminski N, Benos PV - Nucleic Acids Res. (2011)

Dyad-dependent modes of regulation. A TF A with DNA binding specificity a may bind subtypes, a1 and a2, of binding sites depending on whether they co-occur with binding sites b and c of cofactors B and C, respectively. Alternatively, a TF that binds as a dimer may bind dyads a1:b or a2:c depending on the sets of downstream targets and/or vice versa. Finally, two distinct TFs with highly similar but distinct binding sites a1 and a2, may recognize and bind their respective TFBSs by associating with corresponding cofactors B and C, respectively. Logos represent the consensus motifs of the TFs and d is the maximum inter-site distance.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3113591&req=5

Figure 1: Dyad-dependent modes of regulation. A TF A with DNA binding specificity a may bind subtypes, a1 and a2, of binding sites depending on whether they co-occur with binding sites b and c of cofactors B and C, respectively. Alternatively, a TF that binds as a dimer may bind dyads a1:b or a2:c depending on the sets of downstream targets and/or vice versa. Finally, two distinct TFs with highly similar but distinct binding sites a1 and a2, may recognize and bind their respective TFBSs by associating with corresponding cofactors B and C, respectively. Logos represent the consensus motifs of the TFs and d is the maximum inter-site distance.
Mentions: The precise nucleotide sequence of a TFBS plays an important role, not only in attracting the corresponding TF, but also in the recruitment of its cofactors and hence in the mode of regulation of its targets. A TF A may bind to TFBSs of subtype a1 or a2 and target different genes depending on whether it associates with cofactor B or C, respectively (Figure 1). For example, in Escherichia coli, the cyclic AMP receptor protein (CRP) binds a 22-bp consensus motif CRP-N to regulate roughly 100 genes involved in the response to sugar starvation in the cell (17). In Haemophilus influenzae, CRP recognizes the typical CRP-N sites, but it also recognizes and binds to a CRP-N variant, the non-canonical CRP-S motif (18,19). The CRP-S sites are found in the promoters of genes involved in ‘competence’, a process by which cells can take up DNA from the environment, and which require the presence of both CRP and another protein, Sxy, for transcriptional activation. A similar functional CRP-S regulon has also been identified in E. coli (13,20), suggesting possibly a similar mechanism. Hence, the protein CRP recognizes two highly similar but distinct motifs, subtypes CRP-N and CRP-S, in the presence or absence of Sxy thus regulating different sets of downstream genes. Single nucleotide changes too have been associated with the choice of cofactors and the set of target genes as in the case of the glucocorticoid receptor (16,21), NF-κB (22), Pit-1 (23), Foxa2 (24), etc. In the following, we use the term ‘subtypes’ of TFBSs to refer to groups of highly similar but distinct nucleotide variants of the canonical binding motif of a TF.Figure 1.

Bottom Line: DNA sequences bound by a transcription factor (TF) are presumed to contain sequence elements that reflect its DNA binding preferences and its downstream-regulatory effects.We present DiSCo (Discovery of Subtypes and Cofactors), a novel approach for identifying variants of dyad motifs (and their respective target sequence sets) that are instrumental for differential downstream regulation.Using both simulated and experimental datasets, we demonstrate how current motif discovery can be successfully leveraged to address this question.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational and Systems Biology, Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine and Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA 15260, USA.

ABSTRACT
DNA sequences bound by a transcription factor (TF) are presumed to contain sequence elements that reflect its DNA binding preferences and its downstream-regulatory effects. Experimentally identified TF binding sites (TFBSs) are usually similar enough to be summarized by a 'consensus' motif, representative of the TF DNA binding specificity. Studies have shown that groups of nucleotide TFBS variants (subtypes) can contribute to distinct modes of downstream regulation by the TF via differential recruitment of cofactors. A TF(A) may bind to TFBS subtypes a(1) or a(2) depending on whether it associates with cofactors TF(B) or TF(C), respectively. While some approaches can discover motif pairs (dyads), none address the problem of identifying 'variants' of dyads. TFs are key components of multiple regulatory pathways targeting different sets of genes perhaps with different binding preferences. Identifying the discriminating TF-DNA associations that lead to the differential downstream regulation is thus essential. We present DiSCo (Discovery of Subtypes and Cofactors), a novel approach for identifying variants of dyad motifs (and their respective target sequence sets) that are instrumental for differential downstream regulation. Using both simulated and experimental datasets, we demonstrate how current motif discovery can be successfully leveraged to address this question.

Show MeSH