CellNet: Network Biology Applied to Stem Cell Engineering

Cahan, Patrick; Li, Hu; Morris, Samantha A.; Rocha, Edroaldo Lummertz da; Daley, George Q.; Collins, James J.

doi:10.1016/j.cell.2014.07.020

Cited by 495 publications

(546 citation statements)

References 56 publications

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“…Based on bulk and single-cell RNA expression studies, we concluded that the hepatocyte-specific transcriptional programme is robustly silenced in iN cells [27]. A more recent survey of various reprogrammed cell populations with the aspiration to measure the authenticity of target cell types came to the conclusion that the degree of transcriptional similarity to target cell types varies between different reprogrammed cells, which is mostly driven by non-proper silencing of the donor cell programmes highlighting the importance of transcriptional repression in reprogramming [28].…”

Section: Induced Neuronal Cells: Direct Lineage Conversion Between DImentioning

confidence: 99%

Direct somatic lineage conversion

Tanabe¹,

Haag²,

Wernig³

2015

Phil. Trans. R. Soc. B

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The predominant view of embryonic development and cell differentiation has been that rigid and even irreversible epigenetic marks are laid down along the path of cell specialization ensuring the proper silencing of unrelated lineage programmes. This model made the prediction that specialized cell types are stable and cannot be redirected into other lineages. Accordingly, early attempts to change the identity of somatic cells had little success and was limited to conversions between closely related cell types. Nuclear transplantation experiments demonstrated, however, that specialized cells even from adult mammals can be reprogrammed into a totipotent state. The discovery that a small combination of transcription factors can reprogramme cells to pluripotency without the need of oocytes further supported the view that these epigenetic barriers can be overcome much easier than assumed, but the extent of this flexibility was still unclear. When we showed that a differentiated mesodermal cell can be directly converted to a differentiated ectodermal cell without a pluripotent intermediate, it was suggested that in principle any cell type could be converted into any other cell type. Indeed, the work of several groups in recent years has provided many more examples of direct somatic lineage conversions. Today, the question is not anymore whether a specific cell type can be generated by direct reprogramming but how it can be induced.

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Section: Induced Neuronal Cells: Direct Lineage Conversion Between DImentioning

confidence: 99%

Direct somatic lineage conversion

Tanabe¹,

Haag²,

Wernig³

2015

Phil. Trans. R. Soc. B

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“…Furthermore, the current training data derive largely from parenchymal tissues and whole organs, which encompass many cell types, while most engineered cells are acclimated to culture in a dish. Despite these limitations, when primary cells are cultured from whole organs or tissues, purified, and then subjected to analysis via CellNet, the de-differentiation effects of cell culture and the heterogeneity of the target tissue does not compromise the utility of CellNet as a robust classifier of a cell's identity [23]. CellNet will be augmented in future versions as transcriptional profiles become available for additional target cells and tissues at multiple stages of development.…”

Section: Cellnet: a Metric For Discerning Cell Identity And Enhancingmentioning

confidence: 99%

“…CellNet is a publicly available network-biology platform (http://cellnet. hms.harvard.edu/) written by Patrick Cahan with input from Hu Li and Edroaldo Lummertz de Rocha that has been tested extensively against both published datasets [23] and used within our own laboratory to enhance the in vitro production of several cell types [24]. At its core, CellNet is founded on the notion that cell-and tissue-specific gene rstb.royalsocietypublishing.org Phil.…”

Section: Cellnet: a Metric For Discerning Cell Identity And Enhancingmentioning

confidence: 99%

Stem cells and the evolving notion of cellular identity

Daley

2015

Phil. Trans. R. Soc. B

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Stem cells are but one class of the myriad types of cells within an organism. With potential to self-renew and capacity to differentiate, stem cells play essential roles at multiple stages of development. In the early embryo, pluripotent stem cells represent progenitors for all tissues while later in development, tissue-restricted stem cells give rise to cells with highly specialized functions. As best understood in the blood, skin and gut, stem cells are the seeds that sustain tissue homeostasis and regeneration, while in other tissues like the muscle, liver, kidney and lung, various stem or progenitor cells play facultative roles in tissue repair and response to injury. Here, I will provide a brief perspective on the evolving notion of cellular identity and how reprogramming and transcription factor-mediated conversions of one cell type into another have fundamentally altered our assumptions about the stability of cell identity, with profound long-term implications for biomedical research and regenerative medicine.

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“…Fiftyfour (54) proteins that were present in two out of four cell lines with unique peptide and at least fivefold higher PSM (peptide spectral match) values than the corresponding control experiment were considered as UHRF2-interacting proteins (supplemental Table S4). Among them, DNMT1, HDAC1, PCNA, EHMT2 (G9a), RB1, and PCNP are annotated as UHRF2 interactors in the STRING PPI database.…”

Section: Uhrf2 Is Recruited To the Cdh1 Promoter For Epigeneticmentioning

confidence: 99%

Multidimensional Proteomics Reveals a Role of UHRF2 in the Regulation of Epithelial-Mesenchymal Transition (EMT)

Lai

Liang

Chen

et al. 2016

Molecular & Cellular Proteomics

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UHRF1 is best known for its positive role in the maintenance of DNMT1-mediated DNA methylation and is implicated in a variety of tumor processes. In this paper, we provided evidence to demonstrate a role of UHRF2 in cell motility and invasion through the regulation of the epithelial-mesenchymal transition (EMT) process by acting as a transcriptional co-regulator of the EMT-transcription factors (TFs). We ectopically expressed UHRF2 in gastric cancer cell lines and performed multidimensional proteomics analyses. Proteome profiling analysis suggested a role of UHRF2 in repression of cell-cell adhesion; analysis of proteome-wide TF DNA binding activities revealed the up-regulation of many EMT-TFs in UHRF2-overexpressing cells. These data suggest that UHRF2 is a regulator of cell motility and the EMT program. Indeed, cell invasion experiments demonstrated that silencing of UHRF2 in aggressive cells impaired their abilities of migration and invasion in vitro. Further ChIP-seq identified UHRF2 genomic binding motifs that coincide with several TF binding motifs including EMT-TFs, and the binding of UHRF2 to CDH1 promoter was validated by ChIP-qPCR. Moreover, the interactome analysis with IP-MS uncovered the interaction of UHRF2 with TFs including TCF7L2 and several protein complexes that regulate chromatin remodeling and histone modifications, suggesting that UHRF2 is a transcription co-regulator for TFs such as TCF7L2 to regulate the EMT process. Taken together, our study identified a role of UHRF2 in EMT and tumor metastasis and demonstrated an effective approach to obtain clues of UHRF2 function without prior knowledge through combining evidence from multidimensional proteomics analyses. Molecular & Cellular

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CellNet: Network Biology Applied to Stem Cell Engineering

Cited by 495 publications

References 56 publications

Direct somatic lineage conversion

Direct somatic lineage conversion

Stem cells and the evolving notion of cellular identity

Multidimensional Proteomics Reveals a Role of UHRF2 in the Regulation of Epithelial-Mesenchymal Transition (EMT)

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