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C/EBP⍺ Aggravated Ferroptosis and Apoptosis in Renal Tubular Epithelial Cell

ABSTRACT: Acute Kidney Injury (AKI) is widely recognized for its rapid deterioration in renal function, often resulting in unfavorable clinical outcomes. An increase in the expression of CCAAT/enhancer binding protein alpha (C/EBP⍺) has been observed in both human and mouse kidneys affected by AKI. We unraveled the downstream pathway of C/EBP⍺ through RNA-sequencing, confirming our findings with qRT-PCR and luciferase reporter assays. Furthermore, we identified a potential target for AKI reversal in a murine AKI model.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242804 | GEO | 2023/09/14

REPOSITORIES: GEO

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C/EBP⍺ Aggravated Ferroptosis and Apoptosis in Renal Tubular Epithelial Cell

Project description:C/EBP⍺ Aggravated Ferroptosis and Apoptosis in Renal Tubular Epithelial Cell

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Impaired DNA demethylation of C/EBP sites causes premature aging

Project description:Changes in DNA methylation are among the best-documented epigenetic alterations accompanying organismal aging. However, whether and how altered DNA methylation is causally involved in aging have remained elusive. GADD45α (growth arrest and DNA damage protein 45A) and ING1 (inhibitor of growth family member 1) are adapter proteins for site-specific demethylation by TET (ten-eleven translocation) methylcytosine dioxygenases. Here we show that Gadd45a/Ing1 double-knockout mice display segmental progeria and phenocopy impaired energy homeostasis and lipodystrophy characteristic of Cebp (CCAAT/enhancer-binding protein) mutants. Correspondingly, GADD45α occupies C/EBPβ/δ-dependent superenhancers and, cooperatively with ING1, promotes local DNA demethylation via long-range chromatin loops to permit C/EBPβ recruitment. The results indicate that enhancer methylation can affect aging and imply that C/EBP proteins play an unexpected role in this process. Our study suggests a causal nexus between DNA demethylation, metabolism, and organismal aging. This SuperSeries is composed of the SubSeries listed below.

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C/EBP? and PPAR?-specific transcriptional programs in mature adipocytes in vivo

Project description:We took a systematic approach to determine the transcriptional programs that are specifically regulated by C/EBP? in mature white adipocytes of mice on chow diet or high fat diet. The hypothesis tested in the present study was that C/EBP?, as a lipogenic transcription factor, has unique direct targets compared to PPAR?. Our inducible adipocyte specific knockout system allows us to test the direct targets of C/EBP? and PPAR? in adipocytes by short-term C/EBP? or PPAR? elimination in mature adipocytes in vivo. Results indicate that although it has been shown that C/EBP? and PPAR? cross-regulate each other, they have distinct direct responsive targets. Moreover, there are very few C/EBP? specific targets in mice on a chow diet, most of the C/EBP? targets in mature adipocytes are genes modulated by HFD feeding. Total RNA obtained from subcutaneous adipose tissue of Adn-C/EBP?-/- mice on doxycycline chow diet for 3 days, doxycycline high fat diet for 3 days or 1 month and Adn-PPAR?-/- mice on doxycycline chow diet for 3 days, compared to control littermates.

2014-11-04 | E-GEOD-62937 | biostudies-arrayexpress

LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer [C/EBP Bulk RNA-seq]

Project description:Background: LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Inactivation of Lkb1 accelerates the growth and progression of oncogenic KRAS-driven lung tumors in mouse models. However, the molecular mechanisms by which LKB1 constrains lung tumorigenesis and whether the aggressive cancer state that stems from Lkb1 deficiency can be reverted remains unknown. Restoration of Lkb1 in established lung tumors promotes the expression of C/EBP target genes as well as features of alveolar type II cell differentiation, which requires the activity of C/EBP transcription factors in the developmental setting. Purpose: To determine the extent to which the disruption of C/EBP transcription factors recapitulates the transcriptional changes induced by the inactivation of Lkb1.Approach: To assess the changes gene expression induced by CRISPR/Cas9-mediated disruption of either C/EBP transcription factors or Lkb1, we induced lung tumors in KrasLSL-G12D/+;R26LSL-tdTomato;H11LSL-Cas9 mice using Lenti-sgNeo1/sgNT/sgNeo2/Cre (sgInert), Lenti-sgLkb1/Cre (sgLkb1), or Lenti-sgCebpa/sgCebpb/sgCebpd/Cre (sgCebpa/b/d). Neoplastic cells were then isolated from lung tumors by FACS for gene expression profiling by RNA-seq. Results: The disruption of C/EBP transcription factors partially recapitulates the gene expression changes induced by Lkb1 inactivation. Among the genes that are jointly dependent upon C/EBP transcription factors and LKB1 is an enrichment of NKX2-1-dependent target genes. Conclusions: C/EBP transcription factors likely operate downstream of LKB1 in an indirect manner, collaborating with another key developmental regulator, NKX2-1, to enforce alveolar type II cell differentiation to constrain tumor growth.

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Mst1-mediated phosphorylation of FoxO1 and C/EBP-β Stimulates Cell-protective Mechanisms in Cardiomyocytes

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Gene expression profiles for genetically engineered murine hepatoma Hepa8F5 cells treated with or without doxycycline, cultured as monolayer or spheroids

Project description:We developed genetically engineered Hepa/8F5 cells (available from RIKEN BioResource Center [RCB4661]), in which genes of eight liver-enriched transcription factors (LETFs)—hepatocyte nuclear factor (HNF)-1α, HNF-1β, HNF-3β [FOXA2], HNF-4α, HNF-6, CCAAT/enhancer binding protein (C/EBP)-α, C/EBP-β and C/EBP-γ—were transduced into murine hepatoma Hepa1-6 cells as drug-inducible expression cassettes [Biochem. Eng. J., 60, 67–73 (2012)]. Hepa/8F5 cells can induce high liver functions by the addition of an inducer drug (doxycycline; Dox) via overexpression of LETF genes.

2017-11-15 | E-MTAB-5770 | biostudies-arrayexpress

A study of the effect of OxLDL on C/EBP beta binding in human macrophages using chromatin immunoprecipitation for C/EBP beta with high throughput sequencing (ChIP-seq)

Project description:We report the C/EBP beta transcription factor binding landscape in human macrophages and oxLDL-induced foam cells ChIP-seq for C/EBP beta binding was performed in human macrophages and oxLDL induced-foam cells with quadruple biological replicates

2015-04-08 | E-GEOD-66192 | biostudies-arrayexpress

Synchronized renal tubular cell death involves ferroptosis.

Project description:Receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is thought to be the pathophysiologically predominant pathway that leads to regulated necrosis of parenchymal cells in ischemia-reperfusion injury (IRI), and loss of either Fas-associated protein with death domain (FADD) or caspase-8 is known to sensitize tissues to undergo spontaneous necroptosis. Here, we demonstrate that renal tubules do not undergo sensitization to necroptosis upon genetic ablation of either FADD or caspase-8 and that the RIPK1 inhibitor necrostatin-1 (Nec-1) does not protect freshly isolated tubules from hypoxic injury. In contrast, iron-dependent ferroptosis directly causes synchronized necrosis of renal tubules, as demonstrated by intravital microscopy in models of IRI and oxalate crystal-induced acute kidney injury. To suppress ferroptosis in vivo, we generated a novel third-generation ferrostatin (termed 16-86), which we demonstrate to be more stable, to metabolism and plasma, and more potent, compared with the first-in-class compound ferrostatin-1 (Fer-1). Even in conditions with extraordinarily severe IRI, 16-86 exerts strong protection to an extent which has not previously allowed survival in any murine setting. In addition, 16-86 further potentiates the strong protective effect on IRI mediated by combination therapy with necrostatins and compounds that inhibit mitochondrial permeability transition. Renal tubules thus represent a tissue that is not sensitized to necroptosis by loss of FADD or caspase-8. Finally, ferroptosis mediates postischemic and toxic renal necrosis, which may be therapeutically targeted by ferrostatins and by combination therapy.

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Project description:Mutation or epigenetic silencing of the transcription factor C/EBP? is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but down-stream targets relevant for leukemogenesis are not known. Here we identify Sox4 as a direct target of C/EBP? whereby its expression is inversely correlated with C/EBP? activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia initiating cells (LICs) from both Sox4 overexpression and murine mutant C/EBP? AML models clustered together, but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBP? inactivation contributes to the development of leukemias with a distinct LIC phenotype. K/L (bi-allelic Cebpa mutations) leukemic mice and Sox4 overexprssing leukemic mice were used for RNA extraction and hybridization on Affymetrix microarrays. We compared these microarray samples with the C57/BL6 wild type mice.

2013-03-23 | E-GEOD-45430 | biostudies-arrayexpress

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