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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

Depiction of two logic circuit regulatory pathways targeting PPIL2.Two logic circuit regulatory pathways targeting the PPIL2 gene, an important cyclophilin member in immunological suppression, are found by Loregic: 1: PPIL2 is co-regulated by HDAC2 and SP1 forming the triplet of (RF1 is HDAC2, RF2 is SP1, T is PPIL2), which is consistent with the “T = ~RF1+RF2” gate (the ORN gate[22]), and SP1 is co-regulated by EGR1 and NFYA forming the triplet of (RF1 is EGR1, RF2 is NFYA, T is SP1), which is consistent with the “T = ~RF1*~RF2 (the NAND gate); 2: PPIL2 is also co-regulated by BRF1 and NFE2 forming the triplet of (RF1 is BRF1, RF2 is NFE2, T is PPIL2), which is consistent with OR gate, and NFE2 is co-regulated by TAL1 and GATA2 forming the triplet of (RF1 is TAL1, RF2 is GATA2, T is NFE2), which is also consistent with OR gate. We replace the triplets on these pathways using matched logic gates, and depict the pathways using logic circuits to summarize the regulatory logics targeting PPIL2 at the pathway level.
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pcbi.1004132.g007: Depiction of two logic circuit regulatory pathways targeting PPIL2.Two logic circuit regulatory pathways targeting the PPIL2 gene, an important cyclophilin member in immunological suppression, are found by Loregic: 1: PPIL2 is co-regulated by HDAC2 and SP1 forming the triplet of (RF1 is HDAC2, RF2 is SP1, T is PPIL2), which is consistent with the “T = ~RF1+RF2” gate (the ORN gate[22]), and SP1 is co-regulated by EGR1 and NFYA forming the triplet of (RF1 is EGR1, RF2 is NFYA, T is SP1), which is consistent with the “T = ~RF1*~RF2 (the NAND gate); 2: PPIL2 is also co-regulated by BRF1 and NFE2 forming the triplet of (RF1 is BRF1, RF2 is NFE2, T is PPIL2), which is consistent with OR gate, and NFE2 is co-regulated by TAL1 and GATA2 forming the triplet of (RF1 is TAL1, RF2 is GATA2, T is NFE2), which is also consistent with OR gate. We replace the triplets on these pathways using matched logic gates, and depict the pathways using logic circuits to summarize the regulatory logics targeting PPIL2 at the pathway level.

Mentions: Logic circuit analysis of regulatory pathways and hierarchies. Target gene expression is a complex process controlled by multiple RFs whose own expressions are in turn dictated by other RFs, forming regulatory pathway cascades. Analyzing these pathways in a systematic fashion, we are able to get a comprehensive picture of a particular gene regulation. Going beyond the prediction of the cooperative logics of individual RFs that directly regulate a target, we are interested in identifying all the logic gates matching triplets involved in the target regulatory pathway, in order to obtain a coherent logic circuit pathway. This logic circuit pathway depicts the logical relationship between all RFs in the regulatory pathway of a target gene. For example in Fig. 7A, Loregic found that there are two regulatory pathways regulating the target gene, PPIL2 in human K562. PPIL2 is an important cyclophilin member in immunological suppression These two pathways contain 4 logic-gate-consistent triplets forming a two-layer hierarchical structure. By replacing these triplets with corresponding matched logic gates, we obtain the logic circuit regulatory pathways for the target gene (Fig. 7B). Studying the circuit logic gates, we are able to deduce the Boolean logic equation that describes the logical relationship between all RFs in the regulatory pathways of the target gene. In addition, a variety of regulatory pathways can be connected to form gene regulatory networks, which have the hierarchical structures [5,26–28]. TFs typically lie at higher layers than non-TFs in hierarchical gene regulatory networks. We found that the consistency scores of the triplets with TF targets are significantly greater than the ones with non-TF targets in both yeast and human (K-S test p value < 4e-6 in yeast and < 0.04 in human), which implies that the regulatory co-operation at higher hierarchical layers more likely follows a clear “logical pattern”. We also constructed the regulatory hierarchical networks with top, middle and bottom layers using yeast TFs [5], and found that the scores for the gate-consistent triplets targeting the bottom TFs are lower than the ones targeting middle and top TFs (S3 Fig), which implies that the regulations of middle and top TFs more likely follow logical operations than the bottom TFs.


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)

Depiction of two logic circuit regulatory pathways targeting PPIL2.Two logic circuit regulatory pathways targeting the PPIL2 gene, an important cyclophilin member in immunological suppression, are found by Loregic: 1: PPIL2 is co-regulated by HDAC2 and SP1 forming the triplet of (RF1 is HDAC2, RF2 is SP1, T is PPIL2), which is consistent with the “T = ~RF1+RF2” gate (the ORN gate[22]), and SP1 is co-regulated by EGR1 and NFYA forming the triplet of (RF1 is EGR1, RF2 is NFYA, T is SP1), which is consistent with the “T = ~RF1*~RF2 (the NAND gate); 2: PPIL2 is also co-regulated by BRF1 and NFE2 forming the triplet of (RF1 is BRF1, RF2 is NFE2, T is PPIL2), which is consistent with OR gate, and NFE2 is co-regulated by TAL1 and GATA2 forming the triplet of (RF1 is TAL1, RF2 is GATA2, T is NFE2), which is also consistent with OR gate. We replace the triplets on these pathways using matched logic gates, and depict the pathways using logic circuits to summarize the regulatory logics targeting PPIL2 at the pathway level.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004132.g007: Depiction of two logic circuit regulatory pathways targeting PPIL2.Two logic circuit regulatory pathways targeting the PPIL2 gene, an important cyclophilin member in immunological suppression, are found by Loregic: 1: PPIL2 is co-regulated by HDAC2 and SP1 forming the triplet of (RF1 is HDAC2, RF2 is SP1, T is PPIL2), which is consistent with the “T = ~RF1+RF2” gate (the ORN gate[22]), and SP1 is co-regulated by EGR1 and NFYA forming the triplet of (RF1 is EGR1, RF2 is NFYA, T is SP1), which is consistent with the “T = ~RF1*~RF2 (the NAND gate); 2: PPIL2 is also co-regulated by BRF1 and NFE2 forming the triplet of (RF1 is BRF1, RF2 is NFE2, T is PPIL2), which is consistent with OR gate, and NFE2 is co-regulated by TAL1 and GATA2 forming the triplet of (RF1 is TAL1, RF2 is GATA2, T is NFE2), which is also consistent with OR gate. We replace the triplets on these pathways using matched logic gates, and depict the pathways using logic circuits to summarize the regulatory logics targeting PPIL2 at the pathway level.
Mentions: Logic circuit analysis of regulatory pathways and hierarchies. Target gene expression is a complex process controlled by multiple RFs whose own expressions are in turn dictated by other RFs, forming regulatory pathway cascades. Analyzing these pathways in a systematic fashion, we are able to get a comprehensive picture of a particular gene regulation. Going beyond the prediction of the cooperative logics of individual RFs that directly regulate a target, we are interested in identifying all the logic gates matching triplets involved in the target regulatory pathway, in order to obtain a coherent logic circuit pathway. This logic circuit pathway depicts the logical relationship between all RFs in the regulatory pathway of a target gene. For example in Fig. 7A, Loregic found that there are two regulatory pathways regulating the target gene, PPIL2 in human K562. PPIL2 is an important cyclophilin member in immunological suppression These two pathways contain 4 logic-gate-consistent triplets forming a two-layer hierarchical structure. By replacing these triplets with corresponding matched logic gates, we obtain the logic circuit regulatory pathways for the target gene (Fig. 7B). Studying the circuit logic gates, we are able to deduce the Boolean logic equation that describes the logical relationship between all RFs in the regulatory pathways of the target gene. In addition, a variety of regulatory pathways can be connected to form gene regulatory networks, which have the hierarchical structures [5,26–28]. TFs typically lie at higher layers than non-TFs in hierarchical gene regulatory networks. We found that the consistency scores of the triplets with TF targets are significantly greater than the ones with non-TF targets in both yeast and human (K-S test p value < 4e-6 in yeast and < 0.04 in human), which implies that the regulatory co-operation at higher hierarchical layers more likely follows a clear “logical pattern”. We also constructed the regulatory hierarchical networks with top, middle and bottom layers using yeast TFs [5], and found that the scores for the gate-consistent triplets targeting the bottom TFs are lower than the ones targeting middle and top TFs (S3 Fig), which implies that the regulations of middle and top TFs more likely follow logical operations than the bottom TFs.

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