Impaired DNA demethylation of C/EBP sites causes premature aging
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA388882 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5641970.fastq.gz | Fastqsanger.gz | |||
| SRR5641980.fastq.gz | Fastqsanger.gz | |||
| SRR5641990_1.fastq.gz | Fastqsanger.gz | |||
| SRR5641990_2.fastq.gz | Fastqsanger.gz | |||
| SRR5641971.fastq.gz | Fastqsanger.gz |
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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.
2018-06-11 | GSE99607 | GEO
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.
| S-EPMC6049513 | biostudies-literature
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal human premature aging disease1-5, characterized by premature atherosclerosis and degeneration of vascular smooth muscle cells (SMCs)6-8. HGPS is caused by a single-point mutation in the LMNA gene, resulting in the generation of progerin, a truncated mutant of lamin A. Accumulation of progerin leads to various aging-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin9-12. Here, we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature aging. Upon differentiation of HGPS-iPSCs, progerin and its associated aging consequences are restored. In particular, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescent SMC phenotypes associated with vascular aging. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs) as a component of the progerin-containing protein complex. The absence of nuclear DNAPKcs correlates with premature as well as physiological aging. Since progerin also accumulates during physiological aging6,12,13, our results provide an in vitro iPSC-based model with an acceleration progerin accumulation to study the pathogenesis of human premature and physiological vascular aging. Microarray gene expression profiling was done to: (1) Compare differences between WT fibroblasts and fibroblasts from patients suffering of the Hutchinson-Gilford progeria syndrome (2) Check that iPSC originating from WT and patients are in fact similar to ESC
2011-03-14 | E-GEOD-24487 | biostudies-arrayexpress
Project description:Impaired CHD6 function links misregulation of autophagy and DNA damage response to premature ageing
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Project description:Distinct skeletal stem/progenitor cells (SSPCs) have been identified in the bone marrow, growth plate, and periosteum, which are indispensable for the maintenance and remodeling of the adult skeleton. However, the decline of which cell types are responsible for age-related bone loss and what characteristic changes of these cells during aging remain to be determined. Here, we constructed premature skeletal aging models by depleting metalloproteinase Zmpste24 (Z24) in mice and found that Prx1-dependent, but not Osx-dependent, Z24 deletion caused significant bone loss. Single-cell RNA sequencing (scRNA-seq) revealed that Prx1-expressing cells in the periosteum (pSSPCs) and growth plate (gpSSPCs) significantly declined in progeria mice. Consistent with aggrecan (Acan) expression in gpSSPCs but not pSSPCs, Acan-linked Z24 depletion only caused trabecular bone loss. Chromatin and transcriptional profiling demonstrate that premature aged SSPCs gain apoptotic signaling pathway and mechanosensation decline. Moreover, SSPCs increased after physical exersice and Z24 depletion’s effects on cellular apoptosis and extracellular matrix expression were reverted by mechanical stimuli. Overall, this study identifies that Z24 deficiency-induced impairment of mechanosensation in SSPCs causes bone loss, shedding new insight on how physical exercise can be used to improve bone quality and prevent bone aging.
2023-08-01 | GSE207240 | GEO
Project description:Loss of TET reprograms Wnt signaling through impaired demethylation to promote lung cancer development
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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
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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Project description:Cx3cr1-deficient microglia exhibit a premature aging transcriptome
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