Identification of thalidomide-specific transcriptomics and proteomics signatures during differentiation of human embryonic stem cells.
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Identification of thalidomide-specific transcriptomics and proteomics signatures during differentiation of human embryonic stem cells. / Meganathan, Kesavan; Jagtap, Smita; Wagh, Vilas; Winkler, Johannes; Gaspar, John Antonydas; Hildebrand, Diana; Trusch, Maria; Lehmann, Karola; Hescheler, Jürgen; Sachinidis, Agapios; Schlüter, Hartmut.
in: PLOS ONE, Jahrgang 7, Nr. 8, 8, 2012, S. 44228.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Identification of thalidomide-specific transcriptomics and proteomics signatures during differentiation of human embryonic stem cells.
AU - Meganathan, Kesavan
AU - Jagtap, Smita
AU - Wagh, Vilas
AU - Winkler, Johannes
AU - Gaspar, John Antonydas
AU - Hildebrand, Diana
AU - Trusch, Maria
AU - Lehmann, Karola
AU - Hescheler, Jürgen
AU - Sachinidis, Agapios
AU - Schlüter, Hartmut
PY - 2012
Y1 - 2012
N2 - Embryonic development can be partially recapitulated in vitro by differentiating human embryonic stem cells (hESCs). Thalidomide is a developmental toxicant in vivo and acts in a species-dependent manner. Besides its therapeutic value, thalidomide also serves as a prototypical model to study teratogenecity. Although many in vivo and in vitro platforms have demonstrated its toxicity, only a few test systems accurately reflect human physiology. We used global gene expression and proteomics profiling (two dimensional electrophoresis (2DE) coupled with Tandem Mass spectrometry) to demonstrate hESC differentiation and thalidomide embryotoxicity/teratogenecity with clinically relevant dose(s). Proteome analysis showed loss of POU5F1 regulatory proteins PKM2 and RBM14 and an over expression of proteins involved in neuronal development (such as PAK2, PAFAH1B2 and PAFAH1B3) after 14 days of differentiation. The genomic and proteomic expression pattern demonstrated differential expression of limb, heart and embryonic development related transcription factors and biological processes. Moreover, this study uncovered novel possible mechanisms, such as the inhibition of RANBP1, that participate in the nucleocytoplasmic trafficking of proteins and inhibition of glutathione transferases (GSTA1, GSTA2), that protect the cell from secondary oxidative stress. As a proof of principle, we demonstrated that a combination of transcriptomics and proteomics, along with consistent differentiation of hESCs, enabled the detection of canonical and novel teratogenic intracellular mechanisms of thalidomide.
AB - Embryonic development can be partially recapitulated in vitro by differentiating human embryonic stem cells (hESCs). Thalidomide is a developmental toxicant in vivo and acts in a species-dependent manner. Besides its therapeutic value, thalidomide also serves as a prototypical model to study teratogenecity. Although many in vivo and in vitro platforms have demonstrated its toxicity, only a few test systems accurately reflect human physiology. We used global gene expression and proteomics profiling (two dimensional electrophoresis (2DE) coupled with Tandem Mass spectrometry) to demonstrate hESC differentiation and thalidomide embryotoxicity/teratogenecity with clinically relevant dose(s). Proteome analysis showed loss of POU5F1 regulatory proteins PKM2 and RBM14 and an over expression of proteins involved in neuronal development (such as PAK2, PAFAH1B2 and PAFAH1B3) after 14 days of differentiation. The genomic and proteomic expression pattern demonstrated differential expression of limb, heart and embryonic development related transcription factors and biological processes. Moreover, this study uncovered novel possible mechanisms, such as the inhibition of RANBP1, that participate in the nucleocytoplasmic trafficking of proteins and inhibition of glutathione transferases (GSTA1, GSTA2), that protect the cell from secondary oxidative stress. As a proof of principle, we demonstrated that a combination of transcriptomics and proteomics, along with consistent differentiation of hESCs, enabled the detection of canonical and novel teratogenic intracellular mechanisms of thalidomide.
KW - Humans
KW - Time Factors
KW - Kinetics
KW - Dose-Response Relationship, Drug
KW - Gene Expression Regulation, Developmental/drug effects
KW - Gene Expression Profiling
KW - RNA, Messenger/genetics/metabolism
KW - Proteomics
KW - Transcription Factors/genetics/metabolism
KW - Wnt Proteins/genetics/metabolism
KW - Cell Differentiation/drug effects/genetics
KW - Down-Regulation/drug effects/genetics
KW - Embryonic Development/drug effects/genetics
KW - Embryonic Stem Cells/cytology/drug effects/metabolism
KW - Extremities/embryology
KW - Glutathione Transferase/genetics/metabolism
KW - Heart/drug effects/embryology
KW - Protein Transport/drug effects
KW - Thalidomide/pharmacology
KW - Wnt Signaling Pathway/drug effects/genetics
KW - Humans
KW - Time Factors
KW - Kinetics
KW - Dose-Response Relationship, Drug
KW - Gene Expression Regulation, Developmental/drug effects
KW - Gene Expression Profiling
KW - RNA, Messenger/genetics/metabolism
KW - Proteomics
KW - Transcription Factors/genetics/metabolism
KW - Wnt Proteins/genetics/metabolism
KW - Cell Differentiation/drug effects/genetics
KW - Down-Regulation/drug effects/genetics
KW - Embryonic Development/drug effects/genetics
KW - Embryonic Stem Cells/cytology/drug effects/metabolism
KW - Extremities/embryology
KW - Glutathione Transferase/genetics/metabolism
KW - Heart/drug effects/embryology
KW - Protein Transport/drug effects
KW - Thalidomide/pharmacology
KW - Wnt Signaling Pathway/drug effects/genetics
U2 - 10.1371/journal.pone.0044228
DO - 10.1371/journal.pone.0044228
M3 - SCORING: Journal article
VL - 7
SP - 44228
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 8
M1 - 8
ER -
