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  1. Article ; Online: Retrospective identification of cell-intrinsic factors that mark pluripotency potential in rare somatic cells.

    Jain, Naveen / Goyal, Yogesh / Dunagin, Margaret C / Cote, Christopher J / Mellis, Ian A / Emert, Benjamin / Jiang, Connie L / Dardani, Ian P / Reffsin, Sam / Arnett, Miles / Yang, Wenli / Raj, Arjun

    Cell systems

    2024  Volume 15, Issue 2, Page(s) 109–133.e10

    Abstract: Pluripotency can be induced in somatic cells by the expression of OCT4, KLF4, SOX2, and MYC. Usually only a rare subset of cells reprogram, and the molecular characteristics of this subset remain unknown. We apply retrospective clone tracing to identify ... ...

    Abstract Pluripotency can be induced in somatic cells by the expression of OCT4, KLF4, SOX2, and MYC. Usually only a rare subset of cells reprogram, and the molecular characteristics of this subset remain unknown. We apply retrospective clone tracing to identify and characterize the rare human fibroblasts 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 increased the reprogramming efficiency. We provide evidence for a unified model in which cells can move into and out of the primed state over time, explaining how reprogramming appears deterministic at short timescales and stochastic at long timescales. Furthermore, inhibiting the activity of LSD1 enlarged the pool of cells that were primed for reprogramming. Thus, even homogeneous cell populations can exhibit heritable molecular variability that can dictate whether individual rare cells will reprogram or not.
    MeSH term(s) Humans ; Cellular Reprogramming ; Induced Pluripotent Stem Cells/metabolism ; Kruppel-Like Factor 4 ; Retrospective Studies ; Fibroblasts
    Chemical Substances Kruppel-Like Factor 4
    Language English
    Publishing date 2024-02-08
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2854138-8
    ISSN 2405-4720 ; 2405-4712
    ISSN (online) 2405-4720
    ISSN 2405-4712
    DOI 10.1016/j.cels.2024.01.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Retrospective identification of intrinsic factors that mark pluripotency potential in rare somatic cells.

    Jain, Naveen / Goyal, Yogesh / Dunagin, Margaret C / Cote, Christopher J / Mellis, Ian A / Emert, Benjamin / Jiang, Connie L / Dardani, Ian P / Reffsin, Sam / Raj, Arjun

    bioRxiv : the preprint server for biology

    2023  

    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 ... ...

    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.
    Language English
    Publishing date 2023-02-10
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.02.10.527870
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Variability within rare cell states enables multiple paths toward drug resistance.

    Emert, Benjamin L / Cote, Christopher J / Torre, Eduardo A / Dardani, Ian P / Jiang, Connie L / Jain, Naveen / Shaffer, Sydney M / Raj, Arjun

    Nature biotechnology

    2021  Volume 39, Issue 7, Page(s) 865–876

    Abstract: Molecular differences between individual cells can lead to dramatic differences in cell fate, such as death versus survival of cancer cells upon drug treatment. These originating differences remain largely hidden due to difficulties in determining ... ...

    Abstract Molecular differences between individual cells can lead to dramatic differences in cell fate, such as death versus survival of cancer cells upon drug treatment. These originating differences remain largely hidden due to difficulties in determining precisely what variable molecular features lead to which cellular fates. Thus, we developed Rewind, a methodology that combines genetic barcoding with RNA fluorescence in situ hybridization to directly capture rare cells that give rise to cellular behaviors of interest. Applying Rewind to BRAF
    MeSH term(s) Antineoplastic Agents/pharmacology ; Cell Line ; Cell Survival/drug effects ; Drug Resistance, Neoplasm ; Extracellular Signal-Regulated MAP Kinases/genetics ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Integrin alpha3/genetics ; Integrin alpha3/metabolism ; Melanoma ; Phosphorylation ; Single-Cell Analysis ; Vemurafenib/pharmacology
    Chemical Substances Antineoplastic Agents ; ITGA3 protein, human ; Integrin alpha3 ; Vemurafenib (207SMY3FQT) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2021-02-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1311932-1
    ISSN 1546-1696 ; 1087-0156
    ISSN (online) 1546-1696
    ISSN 1087-0156
    DOI 10.1038/s41587-021-00837-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2167: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 137: Show issues
    Zs.MG 43: Show issues

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  4. Article: Nuclear speckles regulate HIF-2α programs and correlate with patient survival in kidney cancer.

    Alexander, Katherine A / Yu, Ruofan / Skuli, Nicolas / Coffey, Nathan J / Nguyen, Son / Faunce, Christine / Huang, Hua / Dardani, Ian P / Good, Austin L / Lim, Joan / Li, Catherine / Biddle, Nicholas / Joyce, Eric F / Raj, Arjun / Lee, Daniel / Keith, Brian / Simon, M Celeste / Berger, Shelley L

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Nuclear speckles are membrane-less bodies within the cell nucleus enriched in RNA biogenesis, processing, and export factors. In this study we investigated speckle phenotype variation in human cancer, finding a reproducible speckle signature, based on ... ...

    Abstract Nuclear speckles are membrane-less bodies within the cell nucleus enriched in RNA biogenesis, processing, and export factors. In this study we investigated speckle phenotype variation in human cancer, finding a reproducible speckle signature, based on RNA expression of speckle-resident proteins, across >20 cancer types. Of these, clear cell renal cell carcinoma (ccRCC) exhibited a clear correlation between the presence of this speckle expression signature, imaging-based speckle phenotype, and clinical outcomes. ccRCC is typified by hyperactivation of the HIF-2α transcription factor, and we demonstrate here that HIF-2α drives physical association of a select subset of its target genes with nuclear speckles. Disruption of HIF-2α-driven speckle association via deletion of its speckle targeting motifs (STMs)-defined in this study-led to defective induction of speckle-associating HIF-2α target genes without impacting non-speckle-associating HIF-2α target genes. We further identify the RNA export complex, TREX, as being specifically altered in speckle signature, and knockdown of key TREX component, ALYREF, also compromises speckle-associated gene expression. By integrating tissue culture functional studies with tumor genomic and imaging analysis, we show that HIF-2α gene regulatory programs are impacted by specific manipulation of speckle phenotype and by abrogation of speckle targeting abilities of HIF-2α. These findings suggest that, in ccRCC, a key biological function of nuclear speckles is to modulate expression of a specific subset of HIF-2α-regulated target genes that, in turn, influence patient outcomes. We also identify STMs in other transcription factors, suggesting that DNA-speckle targeting may be a general mechanism of gene regulation.
    Language English
    Publishing date 2023-09-16
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.09.14.557228
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells.

    Goyal, Yogesh / Busch, Gianna T / Pillai, Maalavika / Li, Jingxin / Boe, Ryan H / Grody, Emanuelle I / Chelvanambi, Manoj / Dardani, Ian P / Emert, Benjamin / Bodkin, Nicholas / Braun, Jonas / Fingerman, Dylan / Kaur, Amanpreet / Jain, Naveen / Ravindran, Pavithran T / Mellis, Ian A / Kiani, Karun / Alicea, Gretchen M / Fane, Mitchell E /
    Ahmed, Syeda Subia / Li, Haiyin / Chen, Yeqing / Chai, Cedric / Kaster, Jessica / Witt, Russell G / Lazcano, Rossana / Ingram, Davis R / Johnson, Sarah B / Wani, Khalida / Dunagin, Margaret C / Lazar, Alexander J / Weeraratna, Ashani T / Wargo, Jennifer A / Herlyn, Meenhard / Raj, Arjun

    Nature

    2023  Volume 620, Issue 7974, Page(s) 651–659

    Abstract: Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those ... ...

    Abstract Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells
    MeSH term(s) Humans ; Clone Cells/drug effects ; Clone Cells/metabolism ; Clone Cells/pathology ; DNA Barcoding, Taxonomic ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/pathology ; RNA-Seq ; Single-Cell Gene Expression Analysis ; Tumor Cells, Cultured ; Antineoplastic Agents/pharmacology
    Chemical Substances Antineoplastic Agents
    Language English
    Publishing date 2023-07-19
    Publishing country England
    Document type Journal Article
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-023-06342-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 26: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 9: Show issues
    Zs.MO 244: Show issues

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