Limits...
Loregic: a method to characterize the cooperative logic of regulatory factors.

Wang D, Yan KK, Sisu C, Cheng C, Rozowsky J, Meyerson W, Gerstein MB - PLoS Comput. Biol. (2015)

Bottom Line: We validate it with known yeast transcription-factor knockout experiments.Furthermore, we show that MYC, a well-known oncogenic driving TF, can be modeled as acting independently from other TFs (e.g., using OR gates) but antagonistically with repressing miRNAs.Finally, we inter-relate Loregic's gate logic with other aspects of regulation, such as indirect binding via protein-protein interactions, feed-forward loop motifs and global regulatory hierarchy.

View Article: PubMed Central - PubMed

Affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.

ABSTRACT
The topology of the gene-regulatory network has been extensively analyzed. Now, given the large amount of available functional genomic data, it is possible to go beyond this and systematically study regulatory circuits in terms of logic elements. To this end, we present Loregic, a computational method integrating gene expression and regulatory network data, to characterize the cooperativity of regulatory factors. Loregic uses all 16 possible two-input-one-output logic gates (e.g. AND or XOR) to describe triplets of two factors regulating a common target. We attempt to find the gate that best matches each triplet's observed gene expression pattern across many conditions. We make Loregic available as a general-purpose tool (github.com/gersteinlab/loregic). We validate it with known yeast transcription-factor knockout experiments. Next, using human ENCODE ChIP-Seq and TCGA RNA-Seq data, we are able to demonstrate how Loregic characterizes complex circuits involving both proximally and distally regulating transcription factors (TFs) and also miRNAs. Furthermore, we show that MYC, a well-known oncogenic driving TF, can be modeled as acting independently from other TFs (e.g., using OR gates) but antagonistically with repressing miRNAs. Finally, we inter-relate Loregic's gate logic with other aspects of regulation, such as indirect binding via protein-protein interactions, feed-forward loop motifs and global regulatory hierarchy.

No MeSH data available.


Related in: MedlinePlus

Promoter motifs for AND-consistent yeast triplets with directly and indirectly bound TFs.We present two example yeast triplets, (RF1 is the TF YEL009C, RF2 is the TF YER040W, T is the gene YDL066W) at top and (RF1 is the TF YNL216W, RF2 is the TF YNL167C, T is the gene YHR033W) at bottom, both of which are consistent with the AND gate by Loregic. Both TFs in the top triplet have motifs in the target promoter region, but only one TF, YNL216W, in the bottom triplet has a motif in the target promoter region. The other TF, YNL167C, cooperates with YNL216W in an AND logical relation via protein-protein interaction.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4401777&req=5

pcbi.1004132.g006: Promoter motifs for AND-consistent yeast triplets with directly and indirectly bound TFs.We present two example yeast triplets, (RF1 is the TF YEL009C, RF2 is the TF YER040W, T is the gene YDL066W) at top and (RF1 is the TF YNL216W, RF2 is the TF YNL167C, T is the gene YHR033W) at bottom, both of which are consistent with the AND gate by Loregic. Both TFs in the top triplet have motifs in the target promoter region, but only one TF, YNL216W, in the bottom triplet has a motif in the target promoter region. The other TF, YNL167C, cooperates with YNL216W in an AND logical relation via protein-protein interaction.

Mentions: Classification of logic-gate-consistent triplets with indirectly bound TFs. TFs can regulate target genes without binding directly to regulatory regions by instead forming protein-protein interactions with already bound TFs [2]. We suggest that evaluating the cooperative logic of TF pairs along with the analysis of promoter motifs can give insights regarding this type of TF-binding activity. We studied TF promoter motifs in target promoter regions (1,000 bps in yeast and 5,000 bps in human upstream of the transcription start site) [35–38]. In a number of cases even when the logic gate assessment predicted cooperation between the two TFs, we could not find a binding motif for one of these TFs (i.e., a Position Weight Matrix) in the target gene’s promoter region. This suggests that the motif-missing TF is only involved with the target gene indirectly—perhaps through a protein-protein interaction (specifically for this assessment, we define a TF binding motif are missing if we couldn’t find any matches in target promoter sequences for TF motifs with at least 80% Position Weight Matrix (PWM) similarity using matchPWM(…, min.score = “80%”) in [39]. Out of 948 yeast TF-TF-target triplets consistent with “T = RF1*RF2” (AND gate) (Fig. 6), 348 have one TF whose motif is not present in the target’s promoter region. The same holds true for 364 out of 1,100 for “T = RF1*~RF2” and 377 out of 1,095 for “T = ~RF1*RF2”, a symmetric logic gate pair. Similarly, in the human leukemia dataset, we found that from 888 TF-TF-target triplets consistent with AND gates, 71 have one TF whose motif is not present in the target’s promoter. For example (S2 Fig), the triplet of (RF1 is USF2, RF2 is NFYB, T is YPEL1) is consistent with the AND gate, and both TFs have motifs in the YPEL1 promoter region. By contrast, the AND-consistent triplet, (RF1 is USF2, RF2 is NFE2, T is NBPF1) has a USF2 motif but not an NFE2 motif in NBPF1’s promoter region, which is explained by reports that USF2 and NFE2 are connected through protein-protein interactions and that NFE2 regulates NBPF1 through indirect binding [2]. As such, it is possible that those TFs with absent motifs (as above) can potentially regulate their targets by cooperating with directly bound TFs through protein-protein interactions, a phenomenon that has been previously observed [2,24,40–42]. Moreover, we further classified those triplets with indirectly bound TFs using their matched logic gates, and identified the indirectly bound TFs cooperating with bound TFs to regulate their targets in a logical way (S5 and S6 Tables).


Loregic: a method to characterize the cooperative logic of regulatory factors.

Wang D, Yan KK, Sisu C, Cheng C, Rozowsky J, Meyerson W, Gerstein MB - PLoS Comput. Biol. (2015)

Promoter motifs for AND-consistent yeast triplets with directly and indirectly bound TFs.We present two example yeast triplets, (RF1 is the TF YEL009C, RF2 is the TF YER040W, T is the gene YDL066W) at top and (RF1 is the TF YNL216W, RF2 is the TF YNL167C, T is the gene YHR033W) at bottom, both of which are consistent with the AND gate by Loregic. Both TFs in the top triplet have motifs in the target promoter region, but only one TF, YNL216W, in the bottom triplet has a motif in the target promoter region. The other TF, YNL167C, cooperates with YNL216W in an AND logical relation via protein-protein interaction.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401777&req=5

pcbi.1004132.g006: Promoter motifs for AND-consistent yeast triplets with directly and indirectly bound TFs.We present two example yeast triplets, (RF1 is the TF YEL009C, RF2 is the TF YER040W, T is the gene YDL066W) at top and (RF1 is the TF YNL216W, RF2 is the TF YNL167C, T is the gene YHR033W) at bottom, both of which are consistent with the AND gate by Loregic. Both TFs in the top triplet have motifs in the target promoter region, but only one TF, YNL216W, in the bottom triplet has a motif in the target promoter region. The other TF, YNL167C, cooperates with YNL216W in an AND logical relation via protein-protein interaction.
Mentions: Classification of logic-gate-consistent triplets with indirectly bound TFs. TFs can regulate target genes without binding directly to regulatory regions by instead forming protein-protein interactions with already bound TFs [2]. We suggest that evaluating the cooperative logic of TF pairs along with the analysis of promoter motifs can give insights regarding this type of TF-binding activity. We studied TF promoter motifs in target promoter regions (1,000 bps in yeast and 5,000 bps in human upstream of the transcription start site) [35–38]. In a number of cases even when the logic gate assessment predicted cooperation between the two TFs, we could not find a binding motif for one of these TFs (i.e., a Position Weight Matrix) in the target gene’s promoter region. This suggests that the motif-missing TF is only involved with the target gene indirectly—perhaps through a protein-protein interaction (specifically for this assessment, we define a TF binding motif are missing if we couldn’t find any matches in target promoter sequences for TF motifs with at least 80% Position Weight Matrix (PWM) similarity using matchPWM(…, min.score = “80%”) in [39]. Out of 948 yeast TF-TF-target triplets consistent with “T = RF1*RF2” (AND gate) (Fig. 6), 348 have one TF whose motif is not present in the target’s promoter region. The same holds true for 364 out of 1,100 for “T = RF1*~RF2” and 377 out of 1,095 for “T = ~RF1*RF2”, a symmetric logic gate pair. Similarly, in the human leukemia dataset, we found that from 888 TF-TF-target triplets consistent with AND gates, 71 have one TF whose motif is not present in the target’s promoter. For example (S2 Fig), the triplet of (RF1 is USF2, RF2 is NFYB, T is YPEL1) is consistent with the AND gate, and both TFs have motifs in the YPEL1 promoter region. By contrast, the AND-consistent triplet, (RF1 is USF2, RF2 is NFE2, T is NBPF1) has a USF2 motif but not an NFE2 motif in NBPF1’s promoter region, which is explained by reports that USF2 and NFE2 are connected through protein-protein interactions and that NFE2 regulates NBPF1 through indirect binding [2]. As such, it is possible that those TFs with absent motifs (as above) can potentially regulate their targets by cooperating with directly bound TFs through protein-protein interactions, a phenomenon that has been previously observed [2,24,40–42]. Moreover, we further classified those triplets with indirectly bound TFs using their matched logic gates, and identified the indirectly bound TFs cooperating with bound TFs to regulate their targets in a logical way (S5 and S6 Tables).

Bottom Line: We validate it with known yeast transcription-factor knockout experiments.Furthermore, we show that MYC, a well-known oncogenic driving TF, can be modeled as acting independently from other TFs (e.g., using OR gates) but antagonistically with repressing miRNAs.Finally, we inter-relate Loregic's gate logic with other aspects of regulation, such as indirect binding via protein-protein interactions, feed-forward loop motifs and global regulatory hierarchy.

View Article: PubMed Central - PubMed

Affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.

ABSTRACT
The topology of the gene-regulatory network has been extensively analyzed. Now, given the large amount of available functional genomic data, it is possible to go beyond this and systematically study regulatory circuits in terms of logic elements. To this end, we present Loregic, a computational method integrating gene expression and regulatory network data, to characterize the cooperativity of regulatory factors. Loregic uses all 16 possible two-input-one-output logic gates (e.g. AND or XOR) to describe triplets of two factors regulating a common target. We attempt to find the gate that best matches each triplet's observed gene expression pattern across many conditions. We make Loregic available as a general-purpose tool (github.com/gersteinlab/loregic). We validate it with known yeast transcription-factor knockout experiments. Next, using human ENCODE ChIP-Seq and TCGA RNA-Seq data, we are able to demonstrate how Loregic characterizes complex circuits involving both proximally and distally regulating transcription factors (TFs) and also miRNAs. Furthermore, we show that MYC, a well-known oncogenic driving TF, can be modeled as acting independently from other TFs (e.g., using OR gates) but antagonistically with repressing miRNAs. Finally, we inter-relate Loregic's gate logic with other aspects of regulation, such as indirect binding via protein-protein interactions, feed-forward loop motifs and global regulatory hierarchy.

No MeSH data available.


Related in: MedlinePlus