Dataset Information

Comparative roadmaps of reprogramming and oncogenic transformation identify Bcl11b and Atoh8 as broad regulators of cellular plasticity.

ABSTRACT: Coordinated changes of cellular plasticity and identity are critical for pluripotent reprogramming and oncogenic transformation. However, the sequences of events that orchestrate these intermingled modifications have never been comparatively dissected. Here, we deconvolute the cellular trajectories of reprogramming (via Oct4/Sox2/Klf4/c-Myc) and transformation (via Ras/c-Myc) at the single-cell resolution and reveal how the two processes intersect before they bifurcate. This approach led us to identify the transcription factor Bcl11b as a broad-range regulator of cell fate changes, as well as a pertinent marker to capture early cellular intermediates that emerge simultaneously during reprogramming and transformation. Multiomics characterization of these intermediates unveiled a c-Myc/Atoh8/Sfrp1 regulatory axis that constrains reprogramming, transformation and transdifferentiation. Mechanistically, we found that Atoh8 restrains cellular plasticity, independent of cellular identity, by binding a specific enhancer network. This study provides insights into the partitioned control of cellular plasticity and identity for both regenerative and cancer biology.

SUBMITTER: Huyghe A

PROVIDER: S-EPMC9481462 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Comparative roadmaps of reprogramming and oncogenic transformation identify Bcl11b and Atoh8 as broad regulators of cellular plasticity.

Huyghe A A Furlan G G Schroeder J J Cascales E E Trajkova A A Ruel M M Stüder F F Larcombe M M Yang Sun Y Bo YB Mugnier F F De Matteo L L Baygin A A Wang J J Yu Y Y Rama N N Gibert B B Kielbassa J J Tonon L L Wajda P P Gadot N N Brevet M M Siouda M M Mulligan P P Dante R R Liu P P Gronemeyer H H Mendoza-Parra M M Polo J M JM Lavial F F

Nature cell biology 20220908 9

Coordinated changes of cellular plasticity and identity are critical for pluripotent reprogramming and oncogenic transformation. However, the sequences of events that orchestrate these intermingled modifications have never been comparatively dissected. Here, we deconvolute the cellular trajectories of reprogramming (via Oct4/Sox2/Klf4/c-Myc) and transformation (via Ras/c-Myc) at the single-cell resolution and reveal how the two processes intersect before they bifurcate. This approach led us to i ...[more]

PMID: 36075976

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Project description:Global proteomic data generated by advanced mass spectrometry (MS) technologies can help bridge the gap between genome/transcriptome and functions and hold great potential in elucidating unbiased functional models of pro-tumorigenic pathways. To this end, we collected the high-throughput, whole-genome MS data and conducted integrative proteomic network analyses of 687 cases across 7 cancer types including breast carcinoma (115 tumor samples; 10,438 genes), clear cell renal carcinoma (100 tumor samples; 9,910 genes), colorectal cancer (91 tumor samples; 7,362 genes), hepatocellular carcinoma (101 tumor samples; 6,478 genes), lung adenocarcinoma (104 tumor samples; 10,967 genes), stomach adenocarcinoma (80 tumor samples; 9,268 genes), and uterine corpus endometrial carcinoma UCEC (96 tumor samples; 10,768 genes). Through the protein co-expression network analysis, we identified co-expressed protein modules enriched for differentially expressed proteins in tumor as disease-associated pathways. Comparison with the respective transcriptome network models revealed proteome-specific cancer subnetworks associated with heme metabolism, DNA repair, spliceosome, oxidative phosphorylation and several oncogenic signaling pathways. Cross-cancer comparison identified highly preserved protein modules showing robust pan-cancer interactions and identified endoplasmic reticulum-associated degradation (ERAD) and N-acetyltransferase activity as the central functional axes. We further utilized these network models to predict pan-cancer protein regulators of disease-associated pathways. The top predicted pan-cancer regulators including RSL1D1, DDX21 and SMC2, were experimentally validated in lung, colon, breast cancer and fetal kidney cells. In summary, this study has developed interpretable network models of cancer proteomes, showcasing their potential in unveiling novel oncogenic regulators, elucidating underlying mechanisms, and identifying new therapeutic targets.

Dataset Information

Comparative roadmaps of reprogramming and oncogenic transformation identify Bcl11b and Atoh8 as broad regulators of cellular plasticity.

Publications

Comparative roadmaps of reprogramming and oncogenic transformation identify Bcl11b and Atoh8 as broad regulators of cellular plasticity.

Similar Datasets

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