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Regulation rewiring analysis reveals mutual regulation between STAT1 and miR-155-5p in tumor immunosurveillance in seven major cancers.

Lin CC, Jiang W, Mitra R, Cheng F, Yu H, Zhao Z - Sci Rep (2015)

Bottom Line: Transcription factors (TFs) and microRNAs (miRNAs) form a gene regulatory network (GRN) at the transcriptional and post-transcriptional level in living cells.We observed that regulation rewiring was prevalent during tumorigenesis and found that the rewired regulatory feedback loops formed by TFs and miRNAs were highly associated with cancer.Our results provide insights on the losing equilibrium of the regulatory feedback loop between STAT1 and miR-155-5p influencing tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA.

ABSTRACT
Transcription factors (TFs) and microRNAs (miRNAs) form a gene regulatory network (GRN) at the transcriptional and post-transcriptional level in living cells. However, this network has not been well characterized, especially in regards to the mutual regulations between TFs and miRNAs in cancers. In this study, we collected those regulations inferred by ChIP-Seq or CLIP-Seq to construct the GRN formed by TFs, miRNAs, and target genes. To increase the reliability of the proposed network and examine the regulation activity of TFs and miRNAs, we further incorporated the mRNA and miRNA expression profiles in seven cancer types using The Cancer Genome Atlas data. We observed that regulation rewiring was prevalent during tumorigenesis and found that the rewired regulatory feedback loops formed by TFs and miRNAs were highly associated with cancer. Interestingly, we identified one regulatory feedback loop between STAT1 and miR-155-5p that is consistently activated in all seven cancer types with its function to regulate tumor-related biological processes. Our results provide insights on the losing equilibrium of the regulatory feedback loop between STAT1 and miR-155-5p influencing tumorigenesis.

No MeSH data available.


Related in: MedlinePlus

Regulation rewiring in cancers.(a) The patterns of joint interactors/interactions between normal and tumor GRNs. For each regulation type, the proportions of the intersection regulators/regulations between normal and tumor GRNs across seven cancer types are shown as a function of the proportion of the top correlated regulations. The P-values are calculated by Wilcoxon rank-sum test to indicate the significance of the difference between the proportions of shared interactors and interactions. (b) The illustration of regulation rewiring. We defined three types of regulation rewiring: I) gain or loss of a regulation but retention of both the regulator and target, II) gain or loss of a regulation with either one regulator or target being kept, and III) gain or loss of a regulation through the gain or loss of both the regulators and targets. (c) The distribution of regulation rewiring. For each regulation forms, the average percentage of regulation rewiring types over seven cancer types is shown as a function of the top 5%, 10%, 15, and 20% highly correlated GRNs. The regulation rewiring types are displayed by color codes (red: Type I, orange: Type II, and green: Type III). (d) The enrichment of cancer-associated regulations within DC BiTM regulations in the seven TCGA cancer types. For each cancer type, the proportion of cancer-associated regulations is shown. The asterisk on the top of each bar represents the significance of cancer-associated regulations with P < 0.05 derived from Fisher′s exact test. Because BiTM regulations possess two types of regulators, i.e., TF and miRNAs, we further specialized these three categories for BiTM as: 1) CN: only TFs are cancer-associated; 2) NC: only miRNAs are cancer-associated; 3) CC: both TFs and miRNAs are cancer-associated (C: cancer-associated, N: non-cancer-associated). In addition, we labeled the significance of the three sub-categorized cancer-associated regulations with P < 0.05 from Fisher’s exact test on the bottom of each bar. The order of asterisks for the sub-categorized cancer-associated regulations is CN, NC, and CC from top to bottom. Red asterisk: overrepresented. Green asterisk: underrepresented.
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f2: Regulation rewiring in cancers.(a) The patterns of joint interactors/interactions between normal and tumor GRNs. For each regulation type, the proportions of the intersection regulators/regulations between normal and tumor GRNs across seven cancer types are shown as a function of the proportion of the top correlated regulations. The P-values are calculated by Wilcoxon rank-sum test to indicate the significance of the difference between the proportions of shared interactors and interactions. (b) The illustration of regulation rewiring. We defined three types of regulation rewiring: I) gain or loss of a regulation but retention of both the regulator and target, II) gain or loss of a regulation with either one regulator or target being kept, and III) gain or loss of a regulation through the gain or loss of both the regulators and targets. (c) The distribution of regulation rewiring. For each regulation forms, the average percentage of regulation rewiring types over seven cancer types is shown as a function of the top 5%, 10%, 15, and 20% highly correlated GRNs. The regulation rewiring types are displayed by color codes (red: Type I, orange: Type II, and green: Type III). (d) The enrichment of cancer-associated regulations within DC BiTM regulations in the seven TCGA cancer types. For each cancer type, the proportion of cancer-associated regulations is shown. The asterisk on the top of each bar represents the significance of cancer-associated regulations with P < 0.05 derived from Fisher′s exact test. Because BiTM regulations possess two types of regulators, i.e., TF and miRNAs, we further specialized these three categories for BiTM as: 1) CN: only TFs are cancer-associated; 2) NC: only miRNAs are cancer-associated; 3) CC: both TFs and miRNAs are cancer-associated (C: cancer-associated, N: non-cancer-associated). In addition, we labeled the significance of the three sub-categorized cancer-associated regulations with P < 0.05 from Fisher’s exact test on the bottom of each bar. The order of asterisks for the sub-categorized cancer-associated regulations is CN, NC, and CC from top to bottom. Red asterisk: overrepresented. Green asterisk: underrepresented.

Mentions: To further explore the characteristics of regulation activity in tumorigenesis, we examined the variability of the regulation correlation between tumor and normal samples in seven studied cancer types. Herein, we considered the top 5%, 10%, 15%, and 20% correlated regulations as four putative data sets showing biologically meaningful regulatory activity within cellular systems. We observed that the proportion of overlapped interactors (regulators and targets) between normal and tumor samples are significantly larger than those of overlapped interactions (regulations), except for the top 5% correlated BiTM (Fig. 2a). This above investigation may uncover that the regulations were rewired during cancer development. Regulation rewiring indicates that changes occurring in regulation between regulators and targets as conditions switched, which has been found to be crucial in gaining or losing biological functions during evolution2021. Moreover, the differential co-expression has been shown to be capable of identifying the dysfunctional regulatory relationships in diseases22. Importantly, this observation showed that regulation rewiring is persistent across seven studied cancer types and therefore suggested that regulation rewiring might be a common mechanism during tumorigenesis (Fig. 2a). Herein, we further categorized regulation rewiring into three types (Fig. 2b). For type I regulation rewiring, the proportion of the shared interactors is large but small for shared interactions. For type III, both the proportions of the shared interactors and interactions are small. Type II has intermediate extent comparing to types I and II in terms of the proportions of shared interactors and interactions.


Regulation rewiring analysis reveals mutual regulation between STAT1 and miR-155-5p in tumor immunosurveillance in seven major cancers.

Lin CC, Jiang W, Mitra R, Cheng F, Yu H, Zhao Z - Sci Rep (2015)

Regulation rewiring in cancers.(a) The patterns of joint interactors/interactions between normal and tumor GRNs. For each regulation type, the proportions of the intersection regulators/regulations between normal and tumor GRNs across seven cancer types are shown as a function of the proportion of the top correlated regulations. The P-values are calculated by Wilcoxon rank-sum test to indicate the significance of the difference between the proportions of shared interactors and interactions. (b) The illustration of regulation rewiring. We defined three types of regulation rewiring: I) gain or loss of a regulation but retention of both the regulator and target, II) gain or loss of a regulation with either one regulator or target being kept, and III) gain or loss of a regulation through the gain or loss of both the regulators and targets. (c) The distribution of regulation rewiring. For each regulation forms, the average percentage of regulation rewiring types over seven cancer types is shown as a function of the top 5%, 10%, 15, and 20% highly correlated GRNs. The regulation rewiring types are displayed by color codes (red: Type I, orange: Type II, and green: Type III). (d) The enrichment of cancer-associated regulations within DC BiTM regulations in the seven TCGA cancer types. For each cancer type, the proportion of cancer-associated regulations is shown. The asterisk on the top of each bar represents the significance of cancer-associated regulations with P < 0.05 derived from Fisher′s exact test. Because BiTM regulations possess two types of regulators, i.e., TF and miRNAs, we further specialized these three categories for BiTM as: 1) CN: only TFs are cancer-associated; 2) NC: only miRNAs are cancer-associated; 3) CC: both TFs and miRNAs are cancer-associated (C: cancer-associated, N: non-cancer-associated). In addition, we labeled the significance of the three sub-categorized cancer-associated regulations with P < 0.05 from Fisher’s exact test on the bottom of each bar. The order of asterisks for the sub-categorized cancer-associated regulations is CN, NC, and CC from top to bottom. Red asterisk: overrepresented. Green asterisk: underrepresented.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4496795&req=5

f2: Regulation rewiring in cancers.(a) The patterns of joint interactors/interactions between normal and tumor GRNs. For each regulation type, the proportions of the intersection regulators/regulations between normal and tumor GRNs across seven cancer types are shown as a function of the proportion of the top correlated regulations. The P-values are calculated by Wilcoxon rank-sum test to indicate the significance of the difference between the proportions of shared interactors and interactions. (b) The illustration of regulation rewiring. We defined three types of regulation rewiring: I) gain or loss of a regulation but retention of both the regulator and target, II) gain or loss of a regulation with either one regulator or target being kept, and III) gain or loss of a regulation through the gain or loss of both the regulators and targets. (c) The distribution of regulation rewiring. For each regulation forms, the average percentage of regulation rewiring types over seven cancer types is shown as a function of the top 5%, 10%, 15, and 20% highly correlated GRNs. The regulation rewiring types are displayed by color codes (red: Type I, orange: Type II, and green: Type III). (d) The enrichment of cancer-associated regulations within DC BiTM regulations in the seven TCGA cancer types. For each cancer type, the proportion of cancer-associated regulations is shown. The asterisk on the top of each bar represents the significance of cancer-associated regulations with P < 0.05 derived from Fisher′s exact test. Because BiTM regulations possess two types of regulators, i.e., TF and miRNAs, we further specialized these three categories for BiTM as: 1) CN: only TFs are cancer-associated; 2) NC: only miRNAs are cancer-associated; 3) CC: both TFs and miRNAs are cancer-associated (C: cancer-associated, N: non-cancer-associated). In addition, we labeled the significance of the three sub-categorized cancer-associated regulations with P < 0.05 from Fisher’s exact test on the bottom of each bar. The order of asterisks for the sub-categorized cancer-associated regulations is CN, NC, and CC from top to bottom. Red asterisk: overrepresented. Green asterisk: underrepresented.
Mentions: To further explore the characteristics of regulation activity in tumorigenesis, we examined the variability of the regulation correlation between tumor and normal samples in seven studied cancer types. Herein, we considered the top 5%, 10%, 15%, and 20% correlated regulations as four putative data sets showing biologically meaningful regulatory activity within cellular systems. We observed that the proportion of overlapped interactors (regulators and targets) between normal and tumor samples are significantly larger than those of overlapped interactions (regulations), except for the top 5% correlated BiTM (Fig. 2a). This above investigation may uncover that the regulations were rewired during cancer development. Regulation rewiring indicates that changes occurring in regulation between regulators and targets as conditions switched, which has been found to be crucial in gaining or losing biological functions during evolution2021. Moreover, the differential co-expression has been shown to be capable of identifying the dysfunctional regulatory relationships in diseases22. Importantly, this observation showed that regulation rewiring is persistent across seven studied cancer types and therefore suggested that regulation rewiring might be a common mechanism during tumorigenesis (Fig. 2a). Herein, we further categorized regulation rewiring into three types (Fig. 2b). For type I regulation rewiring, the proportion of the shared interactors is large but small for shared interactions. For type III, both the proportions of the shared interactors and interactions are small. Type II has intermediate extent comparing to types I and II in terms of the proportions of shared interactors and interactions.

Bottom Line: Transcription factors (TFs) and microRNAs (miRNAs) form a gene regulatory network (GRN) at the transcriptional and post-transcriptional level in living cells.We observed that regulation rewiring was prevalent during tumorigenesis and found that the rewired regulatory feedback loops formed by TFs and miRNAs were highly associated with cancer.Our results provide insights on the losing equilibrium of the regulatory feedback loop between STAT1 and miR-155-5p influencing tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA.

ABSTRACT
Transcription factors (TFs) and microRNAs (miRNAs) form a gene regulatory network (GRN) at the transcriptional and post-transcriptional level in living cells. However, this network has not been well characterized, especially in regards to the mutual regulations between TFs and miRNAs in cancers. In this study, we collected those regulations inferred by ChIP-Seq or CLIP-Seq to construct the GRN formed by TFs, miRNAs, and target genes. To increase the reliability of the proposed network and examine the regulation activity of TFs and miRNAs, we further incorporated the mRNA and miRNA expression profiles in seven cancer types using The Cancer Genome Atlas data. We observed that regulation rewiring was prevalent during tumorigenesis and found that the rewired regulatory feedback loops formed by TFs and miRNAs were highly associated with cancer. Interestingly, we identified one regulatory feedback loop between STAT1 and miR-155-5p that is consistently activated in all seven cancer types with its function to regulate tumor-related biological processes. Our results provide insights on the losing equilibrium of the regulatory feedback loop between STAT1 and miR-155-5p influencing tumorigenesis.

No MeSH data available.


Related in: MedlinePlus