Transcriptomic and epigenetic profiling of the pancreata from old mice after transient OSKM activation and recovery
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE155740 | GEO | 2022/03/07
REPOSITORIES: GEO
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Project description:The expression of the pluripotency factors OCT4, SOX2, KLF4 and MYC (OSKM) can transform somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Transient OSKM expression perturbs cellular homeostasis in a reversible manner and cycles of such incomplete reprogramming rejuvenate features of aging in cells and progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome and metabolome in naturally aged mice subject to a single period of transient OSKM expression in all tissues. We found that this manipulation is sufficient to rejuvenate a substantial fraction of the DNA methylation changes in gene regulatory elements that occur upon aging in the pancreas, liver and spleen. Similarly, we observed rejuvenation at the transcriptomic level, especially regarding biological processes known to change during aging. Finally, a subset of serum metabolites normally altered with aging were restored to young levels upon reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic and metabolomic changes towards a younger configuration in multiple tissues and in the serum.
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Project description:Transient induction of pluripotent reprogramming factors has been reported to reverse some features of aging in mammalian cells and tissues. However, the impact of transient reprogramming on somatic cell identity programs and the necessity of individual pluripotency factors remain unknown. Here, we mapped trajectories of transient reprogramming in young and aged cells from multiple murine cell types using single cell transcriptomics to address these questions. We found that transient reprogramming restored youthful gene expression in adipogenic cells and mesenchymal stem cells but also temporarily suppressed somatic cell identity programs. We further screened Yamanaka Factor subsets and found that many combinations had an impact on aging gene expression and suppressed somatic identity, but that these effects were not tightly entangled. We also found that a transient reprogramming approach inspired by amphibian regeneration restored youthful gene expression in aged myogenic cells. Our results suggest that transient pluripotent reprogramming poses a neoplastic risk, but that restoration of youthful gene expression can be achieved with alternative strategies.
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Project description:Recent reports have proposed a new paradigm for obtaining mature somatic cell types from fibroblasts without going through a pluripotent state, by briefly expressing canonical iPSC reprogramming factors Oct4, Sox2, Klf4 and c-Myc (abbreviated as OSKM), in cells expanded in lineage differentiation promoting conditions. Here we apply genetic lineage tracing for endogenous Nanog, Oct4 and X chromosome reactivation during OSKM induced trans-differentiation, as these molecular events mark final stages for acquisition of induced pluripotency. Remarkably, the vast majority of reprogrammed cardiomyocytes or neural stem cells derived from mouse fibroblasts via OSKM mediated trans-differentiation were attained after transient acquisition of pluripotency, and followed by rapid differentiation. Our findings underscore a molecular and functional coupling between inducing pluripotency and obtaining “trans-differentiated” somatic cells via OSKM induction, and have implications on defining molecular trajectories assumed during different cell reprogramming methods. poly RNA-Seq was measured before, during and after conversion of mouse embryonic fibroblasts to neural stem cells using OSKM trans-differentiation method.
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Project description:Recent reports have proposed a new paradigm for obtaining mature somatic cell types from fibroblasts without going through a pluripotent state, by briefly expressing canonical iPSC reprogramming factors Oct4, Sox2, Klf4 and c-Myc (abbreviated as OSKM), in cells expanded in lineage differentiation promoting conditions. Here we apply genetic lineage tracing for endogenous Nanog, Oct4 and X chromosome reactivation during OSKM induced trans-differentiation, as these molecular events mark final stages for acquisition of induced pluripotency. Remarkably, the vast majority of reprogrammed cardiomyocytes or neural stem cells derived from mouse fibroblasts via OSKM mediated trans-differentiation were attained after transient acquisition of pluripotency, and followed by rapid differentiation. Our findings underscore a molecular and functional coupling between inducing pluripotency and obtaining “trans-differentiated” somatic cells via OSKM induction, and have implications on defining molecular trajectories assumed during different cell reprogramming methods. WGBS (Whole-Genome-Bisulfite-sequencing) were measured during conversion of mouse embryonic fibroblasts to neural stem cells using OSKM trans-differentiation method, as well as in mouse emrbyonic fibroblasts, and mouse ESCs.
2015-05-07 | E-GEOD-68601 | biostudies-arrayexpress
Project description:Reprogramming cells from one fate to another, using transcription factors, generates cells for research and potential therapy, yet little is known about the initial engagement of reprogramming factors with the genome. We mapped the interactions between Oct4, Sox2, Klf4, and c-Myc (OSKM) and the human genome during the first 48 hours of cellular reprogramming to pluripotency. Unlike that reported in ES/iPS cells, we find extensive overlap in the initial binding of OSKM, demonstrating that the initial regulatory network differs markedly from that in pluripotency. OSK act as pioneer factors for c-Myc, and c-Myc enhances the engagement of OSK, including at many genes that are required for conversion to pluripotency. Distal enhancer sites in closed chromatin dominate the initial OSKM distribution. Hierarchical chromatin binding during reprogramming resembles that employed during development. Four chIP-seq data sets (Oct4, Sox2, Klf4, and c-Myc) are included, one lane per factor, no replicates. Also included is an input lane from the same conditions and two mock lentiviral controls (no exogenous OSKM factors) treated with Oct4 IP and c-Myc IP.
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Project description:Recent reports have proposed a new paradigm for obtaining mature somatic cell types from fibroblasts without going through a pluripotent state, by briefly expressing canonical iPSC reprogramming factors Oct4, Sox2, Klf4 and c-Myc (abbreviated as OSKM), in cells expanded in lineage differentiation promoting conditions. Here we apply genetic lineage tracing for endogenous Nanog, Oct4 and X chromosome reactivation during OSKM induced trans-differentiation, as these molecular events mark final stages for acquisition of induced pluripotency. Remarkably, the vast majority of reprogrammed cardiomyocytes or neural stem cells derived from mouse fibroblasts via OSKM mediated trans-differentiation were attained after transient acquisition of pluripotency, and followed by rapid differentiation. Our findings underscore a molecular and functional coupling between inducing pluripotency and obtaining “trans-differentiated” somatic cells via OSKM induction, and have implications on defining molecular trajectories assumed during different cell reprogramming methods. poly RNA-Seq and Chromatin accesibility (ATAC-seq) were measured during conversion of mouse embryonic fibroblasts to neural stem cells using OSKM trans-differentiation method, as well as in mouse emrbyonic fibroblasts, iPSCs and mouse ESCs.
2015-04-30 | E-GEOD-67298 | biostudies-arrayexpress
Project description:Ectopic expression of the transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM) can reprogram somatic cells into induced pluripotent stem cells (iPSCs). These iPSCs are highly similar to embryonic stem cells and can be used for regenerative medicine, drug screening and disease modelling. Despite recent advances, reprogramming is a slow and inefficient process. This suggests that there are several safeguarding mechanisms to counteract cell fate conversion. Cellular senescence is one of these barriers, which is mediated through activation of the tumour suppressors p53/p21CIP1, p15INK4b and p16INK4a. In this study, we have screened for shRNAs blunting reprogramming-induced senescence. To investigate the effects of OSKM expression on the transcriptome of human primary IMR90 fibroblasts, we performed RNA-sequencing (RNA-Seq). Cells were transduced with OSKM expression or control vector and RNA was extracted after 14 or 20 days. In addition, to study the transcriptome of cells bypassing OSKM-induced senescence due to p21 or mTOR depletion, we performed RNA-seq of cells transduced with OSKM and shRNA expressing vectors targeting p21 or mTOR for 14 or 20 days.
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Project description:Recent reports have proposed a new paradigm for obtaining mature somatic cell types from fibroblasts without going through a pluripotent state, by briefly expressing canonical iPSC reprogramming factors Oct4, Sox2, Klf4 and c-Myc (abbreviated as OSKM), in cells expanded in lineage differentiation promoting conditions. Here we apply genetic lineage tracing for endogenous Nanog, Oct4 and X chromosome reactivation during OSKM induced trans-differentiation, as these molecular events mark final stages for acquisition of induced pluripotency. Remarkably, the vast majority of reprogrammed cardiomyocytes or neural stem cells derived from mouse fibroblasts via OSKM mediated trans-differentiation were attained after transient acquisition of pluripotency, and followed by rapid differentiation. Our findings underscore a molecular and functional coupling between inducing pluripotency and obtaining “trans-differentiated” somatic cells via OSKM induction, and have implications on defining molecular trajectories assumed during different cell reprogramming methods.
2015-05-07 | GSE68601 | GEO
Project description:Recent reports have proposed a new paradigm for obtaining mature somatic cell types from fibroblasts without going through a pluripotent state, by briefly expressing canonical iPSC reprogramming factors Oct4, Sox2, Klf4 and c-Myc (abbreviated as OSKM), in cells expanded in lineage differentiation promoting conditions. Here we apply genetic lineage tracing for endogenous Nanog, Oct4 and X chromosome reactivation during OSKM induced trans-differentiation, as these molecular events mark final stages for acquisition of induced pluripotency. Remarkably, the vast majority of reprogrammed cardiomyocytes or neural stem cells derived from mouse fibroblasts via OSKM mediated trans-differentiation were attained after transient acquisition of pluripotency, and followed by rapid differentiation. Our findings underscore a molecular and functional coupling between inducing pluripotency and obtaining “trans-differentiated” somatic cells via OSKM induction, and have implications on defining molecular trajectories assumed during different cell reprogramming methods.
2015-04-30 | GSE67298 | GEO
Project description:Recent reports have proposed a new paradigm for obtaining mature somatic cell types from fibroblasts without going through a pluripotent state, by briefly expressing canonical iPSC reprogramming factors Oct4, Sox2, Klf4 and c-Myc (abbreviated as OSKM), in cells expanded in lineage differentiation promoting conditions. Here we apply genetic lineage tracing for endogenous Nanog, Oct4 and X chromosome reactivation during OSKM induced trans-differentiation, as these molecular events mark final stages for acquisition of induced pluripotency. Remarkably, the vast majority of reprogrammed cardiomyocytes or neural stem cells derived from mouse fibroblasts via OSKM mediated trans-differentiation were attained after transient acquisition of pluripotency, and followed by rapid differentiation. Our findings underscore a molecular and functional coupling between inducing pluripotency and obtaining “trans-differentiated” somatic cells via OSKM induction, and have implications on defining molecular trajectories assumed during different cell reprogramming methods.
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