Genome-wide perturbations by miRNAs map onto functional cellular pathways, identifying regulators of chromatin modifiers

Tyler J. Moss, Zijun Luo, Elena G. Seviour, Vasudha Sehgal, Yiling Lu, Steven M. Hill, Rajesha Rupaimoole, Ju Seog Lee, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Anil K. Sood, Robert Azencott, Joe Gray, Sach Mukherjee, Gordon Mills, Prahlad T. Ram

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

BACKGROUND: Regulation of gene expression by microRNAs (miRNAs) is critical for determining cellular fate and function. Dysregulation of miRNA expression contributes to the development and progression of multiple diseases. miRNA can target multiple mRNAs, making deconvolution of the effects of miRNA challenging and the complexity of regulation of cellular pathways by miRNAs at the functional protein level remains to be elucidated. Therefore, we sought to determine the effects of expression of miRNAs in breast and ovarian cancer cells on cellular pathways by measuring systems-wide miRNA perturbations to protein and phosphoproteins. METHODS: We measure protein level changes by reverse-phase protein array (RPPA) in MDA-MB-231, SKOV3.ip1 and HEYA8 cancer cell lines transfected by a library of 879 human miRNA mimics. RESULTS: The effects of multiple miRNAs-protein networks converged in five broad functional clusters of miRNA, suggesting a broad overlap of miRNA action on cellular pathways. Detailed analysis of miRNA clusters revealed novel miRNA/cell cycle protein networks, which we functionally validated. De novo phosphoprotein network estimation using Gaussian graphical modeling, using no priors, revealed known and novel protein interplay, which we also observed in patient ovarian tumor proteomic data. We identified several miRNAs that have pluripotent activities across multiple cellular pathways. In particular we studied miR-365a whose expression is associated with poor survival across several cancer types and demonstrated that anti-miR-365 significantly reduced tumor formation in animal models. CONCLUSIONS: Mapping of miRNA-induced protein and phosphoprotein changes onto pathways revealed new miRNA-cellular pathway connectivity, paving the way for targeting of dysregulated pathways with potential miRNA-based therapeutics.

Original languageEnglish (US)
Article number15001
Journalnpj Systems Biology and Applications
Volume1
DOIs
StatePublished - Sep 28 2015

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MicroRNA
Chromatin
MicroRNAs
Regulator
Pathway
Genome
Genes
Proteins
Perturbation
Protein
Tumors
Cells
Phosphoproteins
Deconvolution
Gene expression
Animals
Tumor
Neoplasms
Cancer
Graphical Modeling

ASJC Scopus subject areas

  • Computer Science Applications
  • Applied Mathematics
  • Modeling and Simulation
  • Biochemistry, Genetics and Molecular Biology(all)
  • Drug Discovery

Cite this

Genome-wide perturbations by miRNAs map onto functional cellular pathways, identifying regulators of chromatin modifiers. / Moss, Tyler J.; Luo, Zijun; Seviour, Elena G.; Sehgal, Vasudha; Lu, Yiling; Hill, Steven M.; Rupaimoole, Rajesha; Lee, Ju Seog; Rodriguez-Aguayo, Cristian; Lopez-Berestein, Gabriel; Sood, Anil K.; Azencott, Robert; Gray, Joe; Mukherjee, Sach; Mills, Gordon; Ram, Prahlad T.

In: npj Systems Biology and Applications, Vol. 1, 15001, 28.09.2015.

Research output: Contribution to journalArticle

Moss, TJ, Luo, Z, Seviour, EG, Sehgal, V, Lu, Y, Hill, SM, Rupaimoole, R, Lee, JS, Rodriguez-Aguayo, C, Lopez-Berestein, G, Sood, AK, Azencott, R, Gray, J, Mukherjee, S, Mills, G & Ram, PT 2015, 'Genome-wide perturbations by miRNAs map onto functional cellular pathways, identifying regulators of chromatin modifiers', npj Systems Biology and Applications, vol. 1, 15001. https://doi.org/10.1038/npjsba.2015.1
Moss, Tyler J. ; Luo, Zijun ; Seviour, Elena G. ; Sehgal, Vasudha ; Lu, Yiling ; Hill, Steven M. ; Rupaimoole, Rajesha ; Lee, Ju Seog ; Rodriguez-Aguayo, Cristian ; Lopez-Berestein, Gabriel ; Sood, Anil K. ; Azencott, Robert ; Gray, Joe ; Mukherjee, Sach ; Mills, Gordon ; Ram, Prahlad T. / Genome-wide perturbations by miRNAs map onto functional cellular pathways, identifying regulators of chromatin modifiers. In: npj Systems Biology and Applications. 2015 ; Vol. 1.
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abstract = "BACKGROUND: Regulation of gene expression by microRNAs (miRNAs) is critical for determining cellular fate and function. Dysregulation of miRNA expression contributes to the development and progression of multiple diseases. miRNA can target multiple mRNAs, making deconvolution of the effects of miRNA challenging and the complexity of regulation of cellular pathways by miRNAs at the functional protein level remains to be elucidated. Therefore, we sought to determine the effects of expression of miRNAs in breast and ovarian cancer cells on cellular pathways by measuring systems-wide miRNA perturbations to protein and phosphoproteins. METHODS: We measure protein level changes by reverse-phase protein array (RPPA) in MDA-MB-231, SKOV3.ip1 and HEYA8 cancer cell lines transfected by a library of 879 human miRNA mimics. RESULTS: The effects of multiple miRNAs-protein networks converged in five broad functional clusters of miRNA, suggesting a broad overlap of miRNA action on cellular pathways. Detailed analysis of miRNA clusters revealed novel miRNA/cell cycle protein networks, which we functionally validated. De novo phosphoprotein network estimation using Gaussian graphical modeling, using no priors, revealed known and novel protein interplay, which we also observed in patient ovarian tumor proteomic data. We identified several miRNAs that have pluripotent activities across multiple cellular pathways. In particular we studied miR-365a whose expression is associated with poor survival across several cancer types and demonstrated that anti-miR-365 significantly reduced tumor formation in animal models. CONCLUSIONS: Mapping of miRNA-induced protein and phosphoprotein changes onto pathways revealed new miRNA-cellular pathway connectivity, paving the way for targeting of dysregulated pathways with potential miRNA-based therapeutics.",
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AU - Moss, Tyler J.

AU - Luo, Zijun

AU - Seviour, Elena G.

AU - Sehgal, Vasudha

AU - Lu, Yiling

AU - Hill, Steven M.

AU - Rupaimoole, Rajesha

AU - Lee, Ju Seog

AU - Rodriguez-Aguayo, Cristian

AU - Lopez-Berestein, Gabriel

AU - Sood, Anil K.

AU - Azencott, Robert

AU - Gray, Joe

AU - Mukherjee, Sach

AU - Mills, Gordon

AU - Ram, Prahlad T.

PY - 2015/9/28

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N2 - BACKGROUND: Regulation of gene expression by microRNAs (miRNAs) is critical for determining cellular fate and function. Dysregulation of miRNA expression contributes to the development and progression of multiple diseases. miRNA can target multiple mRNAs, making deconvolution of the effects of miRNA challenging and the complexity of regulation of cellular pathways by miRNAs at the functional protein level remains to be elucidated. Therefore, we sought to determine the effects of expression of miRNAs in breast and ovarian cancer cells on cellular pathways by measuring systems-wide miRNA perturbations to protein and phosphoproteins. METHODS: We measure protein level changes by reverse-phase protein array (RPPA) in MDA-MB-231, SKOV3.ip1 and HEYA8 cancer cell lines transfected by a library of 879 human miRNA mimics. RESULTS: The effects of multiple miRNAs-protein networks converged in five broad functional clusters of miRNA, suggesting a broad overlap of miRNA action on cellular pathways. Detailed analysis of miRNA clusters revealed novel miRNA/cell cycle protein networks, which we functionally validated. De novo phosphoprotein network estimation using Gaussian graphical modeling, using no priors, revealed known and novel protein interplay, which we also observed in patient ovarian tumor proteomic data. We identified several miRNAs that have pluripotent activities across multiple cellular pathways. In particular we studied miR-365a whose expression is associated with poor survival across several cancer types and demonstrated that anti-miR-365 significantly reduced tumor formation in animal models. CONCLUSIONS: Mapping of miRNA-induced protein and phosphoprotein changes onto pathways revealed new miRNA-cellular pathway connectivity, paving the way for targeting of dysregulated pathways with potential miRNA-based therapeutics.

AB - BACKGROUND: Regulation of gene expression by microRNAs (miRNAs) is critical for determining cellular fate and function. Dysregulation of miRNA expression contributes to the development and progression of multiple diseases. miRNA can target multiple mRNAs, making deconvolution of the effects of miRNA challenging and the complexity of regulation of cellular pathways by miRNAs at the functional protein level remains to be elucidated. Therefore, we sought to determine the effects of expression of miRNAs in breast and ovarian cancer cells on cellular pathways by measuring systems-wide miRNA perturbations to protein and phosphoproteins. METHODS: We measure protein level changes by reverse-phase protein array (RPPA) in MDA-MB-231, SKOV3.ip1 and HEYA8 cancer cell lines transfected by a library of 879 human miRNA mimics. RESULTS: The effects of multiple miRNAs-protein networks converged in five broad functional clusters of miRNA, suggesting a broad overlap of miRNA action on cellular pathways. Detailed analysis of miRNA clusters revealed novel miRNA/cell cycle protein networks, which we functionally validated. De novo phosphoprotein network estimation using Gaussian graphical modeling, using no priors, revealed known and novel protein interplay, which we also observed in patient ovarian tumor proteomic data. We identified several miRNAs that have pluripotent activities across multiple cellular pathways. In particular we studied miR-365a whose expression is associated with poor survival across several cancer types and demonstrated that anti-miR-365 significantly reduced tumor formation in animal models. CONCLUSIONS: Mapping of miRNA-induced protein and phosphoprotein changes onto pathways revealed new miRNA-cellular pathway connectivity, paving the way for targeting of dysregulated pathways with potential miRNA-based therapeutics.

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