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BRD4 binding sites in transformed fibroblasts

ABSTRACT: Analysis of BRD4 ChIP-seq data of two types of human transformed fibroblasts (WT and HGPS) to identify specific and common binding sites for BRD4. Transformed cell lines were obtained by retroviral introduction of TERT (T), V12-HRAS (R) and SV40 large and small T antigens (S) of primary skin fibroblasts for HGPS patients (TRS-HGPS) and age-matched control wild-type individuals (TRS-WT) Abstract: Advanced age and DNA damage accumulation are strong risk factors for cancer. The premature-aging disorder Hutchinson Gilford Progeria Syndrome (HGPS) provides a unique opportunity to study the interplay between DNA damage and aging-associated tumor mechanisms, since HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neo-plastic transformation. This resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells leading to inhibition of oncogenic de-differentiation. BRD4 also in-hibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals and BRD4-mediated tumor protection is clinically relevant, since a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific functions for BRD4 in tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE61325 | GEO | 2014/10/02

SECONDARY ACCESSION(S): PRJNA260944

REPOSITORIES: GEO

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BRD4 binding sites in transformed fibroblasts

Project description:Analysis of BRD4 ChIP-seq data of two types of human transformed fibroblasts (WT and HGPS) to identify specific and common binding sites for BRD4. Transformed cell lines were obtained by retroviral introduction of TERT (T), V12-HRAS (R) and SV40 large and small T antigens (S) of primary skin fibroblasts for HGPS patients (TRS-HGPS) and age-matched control wild-type individuals (TRS-WT) Abstract: Advanced age and DNA damage accumulation are strong risk factors for cancer. The premature-aging disorder Hutchinson Gilford Progeria Syndrome (HGPS) provides a unique opportunity to study the interplay between DNA damage and aging-associated tumor mechanisms, since HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neo-plastic transformation. This resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells leading to inhibition of oncogenic de-differentiation. BRD4 also in-hibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals and BRD4-mediated tumor protection is clinically relevant, since a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific functions for BRD4 in tumorigenesis. Examination of BRD4 binding events in TRS-WT and TRS-HGPS fibroblasts (2 independent cell lines in each group)

2014-10-02 | E-GEOD-61325 | biostudies-arrayexpress

Expression data from transformed WT and HGPS cell lines, including HGPS cells after knock-down of BRD4

Project description:Primary skin fibroblasts from a HGPS patient and an age-matched control wild-type individual were challenged in a standard transformation assay by retroviral introduction of TERT (T), V12-HRAS (R) and SV40 large and small T antigens (S). Knock-down of BRD4 in this TRS-HGPS cell line (TRS-HGPS-shBRD4) was achieved by retroviral introduction of independent shRNAs (shBRD4-1 to -3) Abstract: Advanced age and DNA damage accumulation are strong risk factors for cancer. The premature-aging disorder Hutchinson Gilford Progeria Syndrome (HGPS) provides a unique opportunity to study the interplay between DNA damage and aging-associated tumor mechanisms, since HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neo-plastic transformation. This resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells leading to inhibition of oncogenic de-differentiation. BRD4 also in-hibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals and BRD4-mediated tumor protection is clinically relevant, since a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific functions for BRD4 in tumorigenesis. 2 biological replicates are included for TRS-WT and TRS-HGPS cell lines. 3 biological replicates are included for TRS-HGPS-shBRD4 (derived from 3 independent shRNAs against BRD4)

2014-10-02 | E-GEOD-60519 | biostudies-arrayexpress

Expression data from immortalized and transformed WT and HGPS cell lines

Project description:Primary skin fibroblasts from HGPS patients and an age-matched control wild-type individuals were challenged in a standard transformation assay by retroviral introduction of TERT (T), V12-HRAS (R) and SV40 large and small T antigens (S). TERT-Immortalized cell lines from the same sources were also generated. Abstract: Advanced age and DNA damage accumulation are strong risk factors for cancer. The premature-aging disorder Hutchinson Gilford Progeria Syndrome (HGPS) provides a unique opportunity to study the interplay between DNA damage and aging-associated tumor mechanisms, since HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neo-plastic transformation. This resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells leading to inhibition of oncogenic de-differentiation. BRD4 also in-hibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals and BRD4-mediated tumor protection is clinically relevant, since a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific functions for BRD4 in tumorigenesis. 2 independent cell lines are included for each of the 4 groups (TERT-WT, TRS-WT, TERT-HGPS and TRS-HGPS)

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Expression data from transformed WT and HGPS cell lines, including HGPS cells after knock-down of BRD4

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Premature aging effects on COVID-19 pathogenesis: new insights from mouse models

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Expression data from young and old healthy humans, as well as HGPS patients

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Project description:Expression data from transformed WT and HGPS cell lines, including HGPS cells after knock-down of BRD4

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the effect of UMI-77 on HGPS-MSCs gene expression during cellular senescence

Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal disease manifested by premature aging and aging-related phenotypes, making it a disease model for physiological aging. The cellular machinery mediating age-associated hallmarks in HGPS remains largely unknown, resulting in limited therapeutic targets for HGPS treatment. In this study, we showed that deficiencies in mitophagy impaired mitochondrial quality and contributed to cellular phenotypes associated with aging in mesenchymal stem cells derived from HGPS patients (HGPS-MSCs). Mechanistically, we discovered that mitophagy affected the aging-related phenotypes of HGPS-MSCs by inhibiting the cGAS-STING-NF-ĸB pathway and the downstream transcription of senescence-associated secretory phenotype (SASP). Furthermore, by utilizing UMI-77, an effective inducer of mitophagy, we showed that mitophagy induction can alleviate aging-associated phenotypes in both HGPS mice and naturally aged mice. In summary, our results uncover that mitophagy defects mediate mitochondrial dysfunction and aging-associated phenotypes in HGPS models, highlight the function of mitochondrial homeostasis in HGPS progression, and suggest that mitophagy could be exploited as a promising therapeutic target for both HGPS and aging.

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Project description:The premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by constitutive production of progerin, a mutant form of the nuclear architectural protein lamin A1. Progerin is also sporadically expressed in wild type cells and has been linked to physiological aging. HGPS cells exhibit extensive nuclear defects including abnormal chromatin structure and increased DNA damage. At the organismal level, HGPS affects several tissues particularly of mesenchymal origin. How the cellular defects of HGPS cells lead to the organismal defects has been unclear. To begin to unravel how progerin leads to disease phenotypes, we analyzed time-dependent changes in transcriptional profiles in response to progerin expression in a hTERT-immortalized skin fibroblast cell line expressing either GFP-progerin or the GFP-wt lamin A control Keywords: time course, cell line comparison

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