This SuperSeries is composed of the SubSeries listed below.
Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells.
Specimen part
View SamplesInduced pluripotent stem cells (iPSCs) can be generated by enforced expression of defined transcription factors in somatic cells. It remains controversial whether iPSCs are equivalent to blastocyst-derived embryonic stem cells (ESCs). Using genetically matched cells, we found that the overall mRNA expression patterns of these cell types are indistinguishable with the exception of a few transcripts encoded on chromosome 12qF1.
Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells.
Specimen part
View SamplesPluripotent cells can be derived from somatic cells by either overexpression of defined transcription factors (resulting in induced pluripotent stem cells (iPSCs)) or by nuclear transfer or cloning (resulting in NT-ESCs). To determine whether cloning further reprograms iPSCs, we used iPSCs as donor cells in nuclear transfer experiments.
Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells.
Specimen part
View SamplesOBJECTIVE: Glial progenitor cells are abundant in adult human white matter. This study was designed to identify signaling pathways regulating their self-renewal and fate.
Complementary patterns of gene expression by human oligodendrocyte progenitors and their environment predict determinants of progenitor maintenance and differentiation.
Sex, Age, Disease
View SamplesThe pathognomonic EWS/ETS fusion transcription factors drive Ewing sarcoma (EWS) by orchestrating an oncogenic transcription program. Therapeutic targeting of EWS/ETS has not been successful; therefore identifying mediators of the EWS/ETS function could offer new therapeutic targets. Here we describe the dependency of chromatin reader BET bromodomain proteins in EWS/ETS driven transcription and investigate the potential of BET inhibitors in treating this lethal cancer. Similar to EWS/ETS fusions, knockdown of BET proteins BRD2/3/4 severely impaired the oncogenic phenotype of EWS cells. Notably, EWS/FLI1 and EWS/ERG was found to be in a transcriptional complex consisting of BRD4. RNA-Seq analysis upon BRD4 knockdown or its pharmacologic inhibition by the BET inhibitor JQ1 revealed an attenuated EWS/ETS transcriptional signature. In contrast to other reports, JQ1 reduced proliferation, and induced apoptosis through MYC-independent mechanism without affecting EWS/ETS protein levels, which was further confirmed by depleting BET proteins using PROTAC-BET degrader (BETd). Interestingly, polycomb repressive complex 2 (PRC2) associated factor PHF19 was downregulated by JQ1/BETd or BRD4 knockdown in multiple EWS cells. ChIP-seq analysis revealed occupancy of EWS/FLI1 at a distal regulatory element of PHF19 and its subsequent knockdown resulted in downregulation of PHF19 expression. Furthermore, deletion of PHF19 by CRISPR-Cas9 system lead to a decreased tumorigenic phenotype and increased sensitivity to JQ1. Importantly, PHF19 expression was associated with worse prognosis of Ewing sarcoma patients. In vivo, JQ1 demonstrated anti-tumor efficacy in multiple mouse xenograft models of EWS. Together, these results indicate that EWS/ETS require BET epigenetic reader proteins for its transcriptional program including PHF19 expression, which can be mitigated by BET inhibitors. Moreover, this study provides a clear rationale for the clinical utility of BET inhibitors in treating Ewing sarcoma. Overall design: Gene epxression by RNAseq in the ewing sarcoma cell lines with knockdown of EWS-FLI1, BRD4 or JQ1 treament, knockout of PHF19
EWS/ETS-Driven Ewing Sarcoma Requires BET Bromodomain Proteins.
Specimen part, Cell line, Treatment, Subject
View SamplesInduced pluripotent stem cells (iPSCs) have been derived from various somatic cell populations through ectopic expression of defined factors. It remains unclear whether iPSCs generated from different cell types are molecularly and functionally similar.
Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells.
Specimen part
View SamplesInduced pluripotent stem (iPS) cells have been derived from various somatic cell populations through ectopic expression of defined factors. It remains unclear whether iPS cells generated from different cell types are molecularly and functionally similar. Here, we show that iPS cells obtained from fibroblasts, hematopoietic and myogenic cells exhibit distinct transcriptional and epigenetic patterns. Moreover, we demonstrate that cellular origin influences the in vitro differentiation potentials of iPS cells into embryoid bodies and different hematopoietic cells. Our results suggest that low-passage iPS cells retain a transient epigenetic memory of their somatic cells of origin, which manifests as differential gene expression and altered differentiation capacity. These observations might affect ongoing attempts to use iPS cells for disease modeling and also could be exploited for potential therapeutic applications to enhance differentiation into desired cell lineages.
Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells.
Specimen part
View SamplesGlial progenitor cells (GPCs) of the adult human white matter, which express gangliosides recognized by monoclonal antibody A2B5, are a potential source of glial tumors of the brain. We used A2B5-based sorting to extract progenitor-like cells from a range of human glial tumors, that included low-grade glioma, oligodendroglioma, oligo-astrocytomas, anaplastic astrocytoma, and glioblastoma multiforme. The A2B5+ tumor cells proved tumorigenic upon orthotopic xenograft, and the tumors generated reflected the phenotypes of those from which they derived.
Transcriptional differences between normal and glioma-derived glial progenitor cells identify a core set of dysregulated genes.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression.
Specimen part, Treatment
View SamplesRetinoic acid signaling regulates monocyte differentiation into dendritic cells or macrophages. We used microarrays to uncover gene expression changes associated with retinoic acid exposure in human monocytes.
Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression.
Specimen part, Treatment
View Samples