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Enhancing Mammary Differentiation by Overcoming Lineage Specific Epigenetic Modification and Signature Gene Expression of Fibroblast Derived iPSCs

ABSTRACT: Recent studies showed that Induced pluripotent stem cells (iPSCs) could hold memory of their origin and exhibit skewed differentiation potential. This finding reveals a severe limit for the application of iPSCs in cell-based therapy in case certain cell types are not available for reprograming from patients. Here we show that under a typical condition for mammary differentiation, iPSCs derived from mouse mammary epithelium cells (ME-iPSCs) exhibit mammary signature gene expression and chromatin epigenetic modification, leading to smooth progress for mammary gland formation. In contrast, iPSCs reprogramed from tail fibroblasts (TF-iPSCs) displayed fibroblast specific signature that is not compatible for mammary differentiation both in vitro and in vivo. Strikingly, when co-culturing with ME-iPSCs or under pregnant condition, the fibroblast specific signature of TF-iPSCs was erased and the cells gained enhanced ability for mammary differentiation. These findings provide new insights into the precise control of differentiation conditions for future personalized cell-based therapy. Microarray analysis of three cell types with three biological replications.

ORGANISM(S): Mus musculus

SUBMITTER: WeiPing Chen

PROVIDER: E-GEOD-38471 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Enhancing Mammary Differentiation by Overcoming Lineage Specific Epigenetic Modification and Signature Gene Expression of Fibroblast Derived iPSCs

Project description:Recent studies showed that Induced pluripotent stem cells (iPSCs) could hold memory of their origin and exhibit skewed differentiation potential. This finding reveals a severe limit for the application of iPSCs in cell-based therapy in case certain cell types are not available for reprograming from patients. Here we show that under a typical condition for mammary differentiation, iPSCs derived from mouse mammary epithelium cells (ME-iPSCs) exhibit mammary signature gene expression and chromatin epigenetic modification, leading to smooth progress for mammary gland formation. In contrast, iPSCs reprogramed from tail fibroblasts (TF-iPSCs) displayed fibroblast specific signature that is not compatible for mammary differentiation both in vitro and in vivo. Strikingly, when co-culturing with ME-iPSCs or under pregnant condition, the fibroblast specific signature of TF-iPSCs was erased and the cells gained enhanced ability for mammary differentiation. These findings provide new insights into the precise control of differentiation conditions for future personalized cell-based therapy.

2015-05-28 | GSE38471 | GEO

Mus musculus

Project description:Enhancing Mammary Differentiation by Overcoming Lineage Specific Epigenetic Modification and Signature Gene Expression of Fibroblast Derived iPSCs

| PRJNA168028 | ENA

Deterministic direct reprogramming of somatic cells to pluripotency [Microarray/Expression]

Project description:Somatic cells can be directly reprogrammed to pluripotency by exogenous expression of transcription factors, classically Oct4, Sox2, Klf4 and c-Myc. While distinct types of somatic cells can be reprogramed with varying efficiencies and by different modified reprogramming protocols, induced pluripotent stem cell (iPSC) induction remains inefficient and stochastic where a fraction of the cells converts into iPSCs. The nature of rate limiting barrier(s) preventing majority of cells to convert into iPSCs remains elusive. Here we show that neutralizing Mbd3, a core member of the Mbd3/NURD co-repressor and chromatin-remodeling complex, results in deterministic and synchronized reprogramming of multiple differentiated cell types to pluripotency. 100% of Mbd3 depleted mouse and human somatic cells convert into iPSCs after seven days of reprogramming factor induction. Our findings delineate a critical pathway blocking the reestablishment of pluripotency, and offer a novel platform for future dissection of epigenetic dynamics leading to iPSC formation at high resolution. Samples include Mbd3+/+, Mbd3flox/- and Mbd3-/- cells from mouse ES cells and mouse embryonic fibroblast (MEF) before and after DOX induction (initiating reprogramming by OSKM factors).

2013-09-12 | E-GEOD-45352 | biostudies-arrayexpress

Next Generation Sequencing Facilitates Quantitative Analysis of healthy donor- and LMNA R527C mutant patient-derived MSCs Transcriptomes

Project description:We reprogramed patient derived PBMCs into iPSCs, and differentiated the iPSCs into Mesenchymal stem cells. We performed whole genome wide RNA-seq of patient-derived MSCs and control MSCs. Up-regulated and down-regulated genes of LMNAR527C/R527C patient-derived MSCs were enriched and analyzed.

2021-12-07 | GSE190198 | GEO

Homo sapiens

Project description:Fibroblast Major TF KDs

| PRJNA189487 | ENA

Deterministic direct reprogramming of somatic cells to pluripotency [ChIP-Seq]

2013-09-12 | E-GEOD-49766 | biostudies-arrayexpress

Selective demethylation and altered gene expression are associated with ICF Syndrome in human induced pluripotent stem cells and mesenchymal stem cells

Project description:Immunodeficiency, Centromeric Instability, and Facial Anomalies Type I (ICF1) Syndrome is a rare genetic disease caused by mutations in DNMT3B, a de novo DNA methyltransferase. However, the molecular basis of how DNMT3B-deficiency leads to ICF1 pathogenesis is unclear. Induced pluripotent stem cell (iPSC) technology facilitates the study of early human developmental diseases via facile in vitro paradigms. Here, we generate iPSCs from ICF Type 1 Syndrome patient fibroblasts followed by directed differentiation of ICF1-iPSCs to mesenchymal stem cells (MSCs). By performing genome-scale bisulfite sequencing, we find that DNMT3B-deficient iPSCs exhibit global loss of non-CG methylation and select CG hypomethylation at gene promoters and enhancers. Further unbiased scanning of ICF1 iPSC methylomes also identifies large megabase regions of CG hypomethylation typically localized in centromeric and subtelomeric regions. RNA sequencing of ICF1 and control iPSCs reveals abnormal gene expression in ICF1 iPSCs relevant to ICF Syndrome phenotypes, some directly associated with promoter or enhancer hypomethylation. Upon differentiation of ICF1 iPSCs to mesenchymal stem cells (MSCs), we find virtually all CG hypomethylated regions remained hypomethylated when compared to either wild-type iPSC-derived MSCs or primary bone-marrow MSCs. Collectively, our results show specific methylome and transcriptome defects in both ICF1-iPSCs and differentiated somatic cell lineages, providing a valuable stem cell system for further in vitro study of the molecular pathogenesis of ICF1 Syndrome. MethylC-seq and RNA-Seq in ICF Syndrome patient fibroblast derived induced pluripotent stem cells.

2014-11-17 | E-GEOD-46030 | biostudies-arrayexpress

Tissue memory of DNA methylation in iPSC of diverse somatic cells

Project description:Several studies have discussed the possibility that donor cell type may influence the epigenetics and differentiation potential of iPSCs, but it remains unclear whether iPS cells derived from different tissue sources reserve their epigenetic memory. Here, we clarify that iPSCs obtained from different tissues exhibit specific epigenetic patterns. We determined the DNA methylation profiles of 12 human cell lines, including 3 adult fibroblast cell-derived iPSC lines, 2 peripheral blood-derived mononuclear cell(PBMC)-derived iPSC lines, 2 amniotic cell-derived iPSC lines and the 5 corresponding parent cell lines. We found that the catalog of tissue-specific DNA methylation was preserved in the iPSC line as epigenetic memory during reprogramming.

2016-05-02 | GSE80969 | GEO

Homo sapiens

Project description:KD of Fibroblast specific TF

| PRJNA189486 | ENA

Deterministic direct reprogramming of somatic cells to pluripotency [RRBS]

Project description:Somatic cells can be directly reprogrammed to pluripotency by exogenous expression of transcription factors, classically Oct4, Sox2, Klf4 and c-Myc. While distinct types of somatic cells can be reprogramed with varying efficiencies and by different modified reprogramming protocols, induced pluripotent stem cell (iPSC) induction remains inefficient and stochastic where a fraction of the cells converts into iPSCs. The nature of rate limiting barrier(s) preventing majority of cells to convert into iPSCs remains elusive. Here we show that neutralizing Mbd3, a core member of the Mbd3/NURD co-repressor and chromatin-remodeling complex, results in deterministic and synchronized reprogramming of multiple differentiated cell types to pluripotency. 100% of Mbd3 depleted mouse and human somatic cells convert into iPSCs after seven days of reprogramming factor induction. Our findings delineate a critical pathway blocking the reestablishment of pluripotency, and offer a novel platform for future dissection of epigenetic dynamics leading to iPSC formation at high resolution. Reduced representation bisulfite sequencing (RRBS) was applied to mouse iPS cells and mouse embryonic fibroblast (MEF) before and after DOX induction (initiating reprogramming by OSKM factors) from randomly selected Mbd3+/+ and Mbd3flox/- clonal cell line series. Polyclonal donor cell cultures were harvested at days 0,4 and 8 after DOX reprogramming without selection or sorting for any marker or passaging, and mapped for similarity to subcloned iPSC lines.

2014-12-13 | E-GEOD-64115 | biostudies-arrayexpress

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