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Retrospective identification of cell-intrinsic factors that mark pluripotency potential in rare somatic cells (RNA-seq)

ABSTRACT: Pluripotency can be induced in somatic cells by the expression of the four “Yamanaka” factors OCT4, KLF4, SOX2, and MYC. However, even in homogeneous conditions, usually only a rare subset of cells admit reprogramming, and the molecular characteristics of this subset remain unknown. Here, we apply retrospective clone tracing to identify and characterize the individual human fibroblast cells that are primed for reprogramming. These fibroblasts showed markers of increased cell cycle speed and decreased fibroblast activation. Knockdown of a fibroblast activation factor identified by our analysis led to increased reprogramming efficiency, identifying it as a barrier to reprogramming. Changing the frequency of reprogramming by inhibiting the activity of LSD1 led to an enlarging of the pool of cells that were primed for reprogramming. Our results show that even homogeneous cell populations can exhibit heritable molecular variability that can dictate whether individual rare cells will reprogram or not.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226987 | GEO | 2023/03/11

REPOSITORIES: GEO

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Retrospective identification of cell-intrinsic factors that mark pluripotency potential in rare somatic cells

Project description:Pluripotency can be induced in somatic cells by the expression of the four “Yamanaka” factors OCT4, KLF4, SOX2, and MYC. However, even in homogeneous conditions, usually only a rare subset of cells admit reprogramming, and the molecular characteristics of this subset remain unknown. Here, we apply retrospective clone tracing to identify and characterize the individual human fibroblast cells that are primed for reprogramming. These fibroblasts showed markers of increased cell cycle speed and decreased fibroblast activation. Knockdown of a fibroblast activation factor identified by our analysis led to increased reprogramming efficiency, identifying it as a barrier to reprogramming. Changing the frequency of reprogramming by inhibiting the activity of LSD1 led to an enlarging of the pool of cells that were primed for reprogramming. Our results show that even homogeneous cell populations can exhibit heritable molecular variability that can dictate whether individual rare cells will reprogram or not.

2023-09-25 | GSE243933 | GEO

Retrospective identification of cell-intrinsic factors that mark pluripotency potential in rare somatic cells (scRNA-Seq)

2023-03-11 | GSE227151 | GEO

Defining Essential Regulators of Naïve Human Pluripotent Cell Reprogramming

Project description:Defining how human pluripotent cell identity is controlled and in particular how naïve pluripotency is acquired during cell reprogramming is crucial for the future applications of pluripotent stem cells. However, the regulatory pathways of naïve cell reprogramming remain incompletely understood. Here, we used genome-wide CRISPR-Cas9 screening to identify novel regulators of primed to naïve pluripotent stem cell reprogramming, including genes that are essential for reprogramming and genes that normally impede reprogramming and whose targeted deletion led to enhanced reprogramming. Integrated analysis defined specific chromatin complexes and signalling pathways as critical regulators of naïve reprogramming, and were largely distinct from regulators of somatic cell reprogramming. Mechanistically, PRC1.3 and PRDM14 are jointly required to transcriptionally repress developmental and gene regulatory factors to ensure naïve cell reprogramming. Additionally, small molecule inhibitors of reprogramming impediments increased the efficiency of naïve cell reprogramming, and are of practical benefit that can improve on current reprogramming methods. Taken together, we have identified novel regulators controlling the establishment of naïve pluripotency in human cells, which will open up new ways to exploit the full potential of pluripotent stem cells. These results also provide new insights into mechanisms that destabilise and reconfigure cell identity during cell state transitions.

2022-04-06 | PXD023547 | Pride

The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [Affymetrix gene expression]

Project description:Pluripotency can be induced in somatic cells by ectopic expression of defined transcription factors, however the identity of epigenetic regulators driving the progression of cellular reprogramming requires further investigation. Here we uncover a non-redundant role for the JmjC-domain-containing protein histone H3 methylated Lys 27 (H3K27) demethylase Utx, as a critical regulator for the induction, but not for the maintenance, of primed and naM-CM-/ve pluripotency in mice and in humans. Utx depletion results in aberrant H3K27me3 repressive chromatin demethylation dynamics, which subsequently hampers the reactivation of pluripotency promoting genes during reprogramming. Remarkably, Utx deficient primordial germ cells (PGCs) display a cell autonomous aberrant epigenetic reprogramming in vivo during their embryonic maturation, resulting in the lack of functional contribution to the germ-line lineage. Samples include UTX+/Y (WT) and UTX-/Y (KO) cells from mouse ES cells and mouse embryonic fibroblast (MEF) before and after DOX induction (initiating reprogramming by OSKM factors). One sample is OSKM-induced Nanog-/- fibroblasts.

2012-05-29 | E-GEOD-35775 | biostudies-arrayexpress

The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [ChIP-Seq]

Project description:Pluripotency can be induced in somatic cells by ectopic expression of defined transcription factors, however the identity of epigenetic regulators driving the progression of cellular reprogramming requires further investigation. Here we uncover a non-redundant role for the JmjC-domain-containing protein histone H3 methylated Lys 27 (H3K27) demethylase Utx, as a critical regulator for the induction, but not for the maintenance, of primed and naM-CM-/ve pluripotency in mice and in humans. Utx depletion results in aberrant H3K27me3 repressive chromatin demethylation dynamics, which subsequently hampers the reactivation of pluripotency promoting genes during reprogramming. Remarkably, Utx deficient primordial germ cells (PGCs) display a cell autonomous aberrant epigenetic reprogramming in vivo during their embryonic maturation, resulting in the lack of functional contribution to the germ-line lineage. H3K27me3 and H3K4me3 were measured genome-wide in the following cell types: Utx+/Y (WT) and Utx-/Y (KO) mouse ES cells and mouse embryonic fibroblast (MEF) before and after DOX induction (initiating reprogramming by OSKM factors).

2012-05-30 | E-GEOD-37821 | biostudies-arrayexpress

Gene expression transcriptome of porcine induced pluripotent stem cell

Project description:Pig induced pluripotent stem cells (piPSCs) have significant biomedical and agricultural applications. We analyzed the transcriptional profiles of pig iPSC lines derived from different labs using Affymetrix GeneChip Pig Genome Array and published microarray datasets of mouse and human iPSCs. Our results demonstrated that cell surface proteins of EpCAM (epithelial cells adhesion molecule) were significantly upregulated in complete fully reprogrammed pig iPSCs, but not in partially reprogrammed cells. EpCAM could be markers for evaluating pig cell reprogramming and selecting successful reprogramming. We analyzed gene expression levels of the six key developmental signaling pathways, including JAK-STAT, NOTCH, TGF-M-NM-2b, WNT, MAPK and VEGF in pig, human and mouse iPSCs, respectively. The result demonstrates that the core transcriptional network to maintain pluripotency and self-renewal in pig are different from mouse and human. Pig iPSCs lacked expression of specific naM-CM-/ve state markers (e.g. Klf family genes Klf2/4/5, Tbx3), but expressed unregulated primed state markers (e.g. Otx2 and Fabp7). Dlk1-Dio3 domain was silenced in piPSCs as previously seen in mouse and human iPSCs, which explantsexplains rare success of generation of pig chimeric and cloned offspring. Our analyses decipher pig somatic cells undergoes reprogramming into a primed state and maintains its regulatory network with define feature with human iPSCs and mouse EpiSCs. We compare gene expression profiles of pig iPS cell lines generated by our lab with cell lines derived from other labs with different levels of marker expression and plasticity.

2013-11-21 | E-GEOD-48434 | biostudies-arrayexpress

Changes in replisome composition underlie the rewiring of DNA replication during embryonic stem cell reprogramming

Project description:Pluripotent stem cells can give rise to the three embryonic germ layers and the characterization of their properties is crucial to exploit their therapeutic potential. Mouse embryonic stem cells (mESCs) are isolated and usually maintained in vitro in a primed state that resembles the post-implantation epiblast features. Furthermore, primed mESCs can be de-differentiated to a naive state that resembles the pre-implantation inner cell mass (ICM). Cell differentiation or genotoxic stress, among others, can alter DNA replication, which is a flexible process able to adapt to different cellular contexts. Here, we demonstrate that primed-to-naive mESC reprogramming triggers replication fork slowdown, increased fork asymmetry and a compensatory activation of dormant origins. Using iPOND (“isolation of proteins on nascent DNA”) coupled to mass spectrometry we have characterized the changes in replisome composition between naive and primed mESCs. Several DNA repair factors, including MRE11 nuclease, are enriched in naive mESCs forks, while factors involved in ubiquitin-dependent protein metabolism are enriched in primed mESC forks. We report that primed-to-naive mESC de-differentiation promotes recruitment of MRE11 to the forks in response to transcription-replication conflicts, underlying the DNA replication rewiring required for efficient mESC reprogramming.

2024-04-03 | PXD041946 | Pride

RNA-seq profiling of human somatic, primed and naïve induced Pluripotent Stem cells

Project description:RNA-seq based transcriptome analysis of human fibroblast, primed and naïve induced pluripoent stem cells

2018-12-31 | GSE110364 | GEO

Large intergenic non-coding RNAs as novel modulators of reprogramming

Project description:This SuperSeries is composed of the following subset Series: GSE23968: Large intergenic non-coding RNAs as novel modulators of reprogramming: ESCs, fibroblast, and fibroblast-derived iPSC (gene expression) GSE23970: Large intergenic non-coding RNAs as novel modulators of reprogramming: human embryonic stem cells, CD34+ cells, and CD34+ derived induced pluripotent stem cells (LincRNA expression) GSE23973: Large intergenic non-coding RNAs as novel modulators of reprogramming: siRNA (gene expression) GSE24181: Large intergenic non-coding RNAs as novel modulators of reprogramming: human embryonic stem cells, fibroblasts, and fibroblast-derived induced pluripotent stem cells (LincRNA expression) Refer to individual Series

2010-11-10 | E-GEOD-24182 | biostudies-arrayexpress

Transcriptional dynamics of transposable elements when converting fibroblast cells of Macaca mulatta to neuroepithelial stem cells [mmu-14-samples]

Project description:Transposable elements (TE) account for more than 50% of human genome. It has been reported that some types of TEs are dynamically regulated in the reprogramming of human cell lines. However, it is largely unknown whether some TEs in Macaca mulatta are also regulated during the reprogramming of cell lines of monkey. Here, we systematically examined the transcriptional activities of TEs during the conversion of Macaca mulatta fibroblast cells to neuroepithelial stem cells (NESCs). Hundreds of TEs were dynamically regulated during the reprogramming of Macaca mulatta fibroblast cells. Furthermore, 60 Long Terminal Repeats (LTRs), as well as some integrase elements, of MacERV3 were transiently activated during the early stages of the conversion process. These LTRs were potentially bound by critical transcription factors for reprogramming, such as KLF4 and ETV5. These results suggest that the transcription of TEs are delicately regulated during the reprogramming of Macaca mulatta fibroblast cells. Although the family of ERVs activated during the reprogramming of fibroblast cells in Macaca mulatta are different from those in the reprogramming of human fibroblast cells, our results suggest that the activation of some ERVs is a conserved mechanism in primates for converting fibroblast cells to stem cells.

2020-12-31 | GSE137692 | GEO

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