Chromatin-state barriers enforce an irreversible mammalian cell fate decision

Blanco, Mario Andres; Sykes, David B.; Gu, Lei; Wu, Mengjun; Petroni, Ricardo; Karnik, Rahul; Wawer, Mathias; Rico, Joshua; Li, Haitao; Jacobus, William D.; Jambhekar, Ashwini; Cheloufi, Sihem; Meissner, Alexander; Hochedlinger, Konrad; Scadden, David T.; Shi, Yang

doi:10.1016/j.celrep.2021.109967

Cited by 34 publications

(27 citation statements)

References 76 publications

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“…The mechanisms by which cells acquire, maintain, and alter their identity are critical to understanding how and why progenitor populations respond to injury and contribute to diseases such as fibrosis, chronic inflammation, and cancer (Blanco et al, 2021; Jiang et al, 2017; Kobayashi et al, 2020; Strunz et al, 2020). Our data provide a novel mechanism for ΔNp63 in maintaining the basal cell identity of intrapulmonary p63 + progenitors, in which ΔNp63 restricts intrapulmonary p63 + progenitor fate by maintaining chromatin in a repressive state at loci required for distal airway and alveolar differentiation.…”

Section: Discussionmentioning

confidence: 99%

ΔNp63 drives dysplastic alveolar remodeling and restricts epithelial plasticity upon severe lung injury

Weiner

Zhao

Zayas

et al. 2022

Preprint

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Unlike many mammalian vital organs, the lung exhibits a robust, multifaceted regenerative response to severe injuries such as influenza infection, which primarily targets epithelial cells in the airways and alveoli. Quiescent lung-resident epithelial progenitors proliferate, migrate, and differentiate following lung injury, participating in two distinct reparative pathways: functionally beneficial regeneration and dysplastic tissue remodeling. Intrapulmonary airway-resident basal-like p63+ progenitors are one such progenitor cell type that migrates from the airways to form ectopic bronchiolar tissue in the alveoli, generating honeycomb-like cysts that fail to resolve after injury. Though this phenomenon is now well described, the cell-autonomous signals that drive dysplastic alveolar remodeling remain uncertain, a question made especially salient by observations that p63+ progenitors also expand dramatically upon diffuse alveolar damage in humans resulting from a variety of insults including SARS-CoV-2-induced ARDS. Here we show that the master basal cell transcription factor ΔNp63 is required for the immense migratory capacity of intrapulmonary p63+ progenitors and consequently for the dysplastic repair pathway manifest by these cells. We further demonstrate that ΔNp63 restricts the fate plasticity of intrapulmonary p63+ progenitors by regulating their epigenetic landscape, and that loss of ΔNp63 alters the deposition of active and repressive histone modifications at key differentiation gene loci, allowing ΔNp63KO progenitors to proceed towards airway or alveolar differentiation depending on their surrounding environment. These insights into the regulatory mechanisms of dysplastic repair and intrapulmonary p63+ progenitor fate choice highlight potential therapeutic targets to promote more effective alveolar regeneration following severe lung injuries.

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Section: Discussionmentioning

confidence: 99%

ΔNp63 drives dysplastic alveolar remodeling and restricts epithelial plasticity upon severe lung injury

Weiner

Zhao

Zayas

et al. 2022

Preprint

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“…Increasing evidence suggests that posttranscriptional mRNA modification plays an essential role in tumor initiation and progression, raising our attention to the epitranscriptome at an unprecedented level ( Bauer et al, 2016 ; Gu H. et al, 2020 ; Gu L. et al, 2020 ; Blanco et al, 2021 ). As an ancient and highly conserved RNA modification in all domains of life, the process, distribution and function of ac4C in mRNAs has been unraveled in the past few years ( Arango et al, 2018 ; Sas-Chen et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Uncovering N4-Acetylcytidine-Related mRNA Modification Pattern and Landscape of Stemness and Immunity in Hepatocellular Carcinoma

Liu

Zhang

Qiu

et al. 2022

Front. Cell Dev. Biol.

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N4-acetylcytidine (ac4C) is an ancient and conserved RNA modification. Previously, ac4C mRNA modification has been reported promoting proliferation and metastasis of tumor cells. However, it remains unclear whether and how ac4C-related mRNA modification patterns influencing the prognosis of hepatocellular carcinoma (HCC) patients. Hereby, we constructed an ac4Cscore model and classified patients into two groups and investigated the potential intrinsic and extrinsic characteristics of tumor. The ac4Cscore model, including COL15A1, G6PD and TP53I3, represented ac4C-related mRNA modification patterns in HCC. According to ac4Cscore, patients were stratified to high and low groups with distinct prognosis. Patients subject to high group was related to advanced tumor stage, higher TP53 mutation rate, higher tumor stemness, more activated pathways in DNA-repair system, lower stromal score, higher immune score and higher infiltrating of T cells regulatory. While patients attributed to low group were correlated with abundance of T cells CD4 memory, less aggressive immune subtype and durable therapy benefit. We also found ac4Cscore as a novel marker to predict patients’ prognosis with anti-PD1 immunotherapy and/or mTOR inhibitor treatment. Our study for the first time showed the association between ac4C-related mRNA modification patterns and tumor intrinsic and extrinsic characteristics, thus influencing the prognosis of patients.

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“…Their studies showed the effect of epigenetics on pyroptosis. Then, chromatin state is not only related to cell differentiation, but also related to cell death ( Benard et al, 2014 ; Blanco et al, 2021 ). Histone modifications in the promoter region of apoptosis gene reflect the transcriptional status of the gene, which can show whether tumor cells are sensitive to various anti-tumor treatments.…”

Section: Introductionmentioning

confidence: 99%

Generation and Analysis of Pyroptosis-Based and Immune-Based Signatures for Kidney Renal Clear Cell Carcinoma Patients, and Cell Experiment

et al. 2022

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Background: Pyroptosis is a programmed cell death caused by inflammasomes, which is closely related to immune responses and tumor progression. The present study aimed to construct dual prognostic indices based on pyroptosis-associated and immune-associated genes and to investigate the impact of the biological signatures of these genes on Kidney Renal Clear Cell Carcinoma (KIRC).Materials and Methods: All the KIRC samples from the Cancer Genome Atlas (TCGA) were randomly and equally divided into the training and testing datasets. Cox and Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis were used to screen crucial pyroptosis-associated genes (PAGs), and a pyroptosis-associated genes prognostic index (PAGsPI) was constructed. Immune-associated genes (IAGs) related to PAGs were identified, and then screened through Cox and LASSO regression analyses, and an immune-associated genes prognostic index (IAGsPI) was developed. These two prognostic indices were verified by using the testing and the Gene Expression Omnibus (GEO) datasets and an independent cohort. The patients’ response to immunotherapy was analyzed. A nomogram was constructed and calibrated. qRT-PCR was used to detect the expression of PAGs and IAGs in the tumor tissues and normal tissues. Functional experiment was carried out.Results: 86 PAGs and 1,774 differentially expressed genes (DEGs) were obtained. After intersecting PAGs with DEGs, 22 differentially expressed PAGs (DEPAGs) were included in Cox and LASSO regression analyses, identifying 5 crucial PAGs. The PAGsPI was generated. Patients in the high-PAGsPI group had a poor prognosis. 82 differentially expressed IAGs (DEIAGs) were highly correlated with DEPAGs. 7 key IAGs were screened out, and an IAGsPI was generated. Patients in the high-IAGsPI group had a poor prognosis. PAGsPI and IAGsPI were verified to be robust and reliable. The results revealed patients in low-PAGsPI group and high-IAGsPI group may be more sensitive to immunotherapy. The calibrated nomogram was proved to be reliable. An independent cohort study also proved that PAGsPI and IAGsPI performed well in prognosis prediction. We found that the expression of AIM2 may affect proliferation of KIRC cells.Conclusion: PAGsPI and IAGsPI could be regarded as potential biomarkers for predicting the prognosis of patients with KIRC.

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Chromatin-state barriers enforce an irreversible mammalian cell fate decision

Cited by 34 publications

References 76 publications

ΔNp63 drives dysplastic alveolar remodeling and restricts epithelial plasticity upon severe lung injury

ΔNp63 drives dysplastic alveolar remodeling and restricts epithelial plasticity upon severe lung injury

Uncovering N4-Acetylcytidine-Related mRNA Modification Pattern and Landscape of Stemness and Immunity in Hepatocellular Carcinoma

Generation and Analysis of Pyroptosis-Based and Immune-Based Signatures for Kidney Renal Clear Cell Carcinoma Patients, and Cell Experiment

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