EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia-telangiectasia
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE50951 | GEO | 2013/10/25
SECONDARY ACCESSION(S): PRJNA219417
REPOSITORIES: GEO
Similar Datasets
Project description:The symptoms of ataxia-telangiectasia (A-T) include a progressive neurodegeneration caused by ATM protein deficiency. We previously found that nuclear accumulation of histone deacetylase-4, HDAC4, contributes to this degeneration; we now report that increased histone H3K27 trimethylation (H3K27me3) mediated by polycomb repressive complex 2 (PRC2) also plays an important role in the A-T phenotype. Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is identified as a new ATM kinase target, and its S734 phosphorylation reduces protein stability. Thus, PRC2 formation is elevated along with H3K27me3in ATM deficiency. ChIP-sequencing shows a significant increase in H3K27me3 ‘marks’ and a dramatic shift in their location. The change of H3K27me3 chromatin-binding pattern is directly related to cell cycle re-entry and cell death of ATM-deficient neurons. Lentiviral knockdown of EZH2 rescues Purkinje cell degeneration and behavioral abnormalities in Atm / mice, demonstrating that EZH2-mediated H3K27me3 is another key factor in A-T neurodegeneration. Two samples each were run of brain total RNA from Atm+/+ and Atm-/- mice.
2013-10-25 | E-GEOD-50951 | biostudies-arrayexpress
Project description:Cerebellar cortex expression in ataxia-telangiectasia patients and normal controls. The neurodegenerative disease known as ataxia-telangiectasia (A-T) is caused by the absence of the ATM (A-T mutated) protein. A long-standing mystery surrounding A-T is why cerebellar Purkinje cells (PCs) appear uniquely vulnerable to ATM-deficiency. Here, we present that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human A-T and Atm-/- mouse cerebellar PCs. TET1, an enzyme that converts 5mC to 5hmC, responds to DNA damage. Manipulation of TET1 activity directly affects neuronal cell cycle reentry and cell death after the induction of DNA damage. Quantitative, genome-wide analysis of 5hmC of samples from human cerebellum showed that in ATM-deficiency there is a remarkable genome-wide reduction of 5hmC enrichment at both proximal and distal regulatory elements. These results reveal a role of TET1-mediated 5hmC in DNA damage response, and provide insights into the basis of a PC-specific DNA demethylation alteration in ATM-deficiency.
2015-10-30 | GSE61019 | GEO
Project description:Cerebellar cortex expression in ataxia-telangiectasia patients and normal controls. The neurodegenerative disease known as ataxia-telangiectasia (A-T) is caused by the absence of the ATM (A-T mutated) protein. A long-standing mystery surrounding A-T is why cerebellar Purkinje cells (PCs) appear uniquely vulnerable to ATM-deficiency. Here, we present that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human A-T and Atm-/- mouse cerebellar PCs. TET1, an enzyme that converts 5mC to 5hmC, responds to DNA damage. Manipulation of TET1 activity directly affects neuronal cell cycle reentry and cell death after the induction of DNA damage. Quantitative, genome-wide analysis of 5hmC of samples from human cerebellum showed that in ATM-deficiency there is a remarkable genome-wide reduction of 5hmC enrichment at both proximal and distal regulatory elements. These results reveal a role of TET1-mediated 5hmC in DNA damage response, and provide insights into the basis of a PC-specific DNA demethylation alteration in ATM-deficiency. Human frozen tissue was obtained from the NICHD Brain and Tissue Bank of Developmental Disorders at the University of Maryland, Baltimore, MD. RNA was prepared and run on an Illumina Human HT-12 v4 microarray. 3 ataxia-telangiectasia (A-T) cases and 4 normal controls.
2015-10-30 | E-GEOD-61019 | biostudies-arrayexpress
Project description:Ataxia-telangiectasia (A-T) is a disease characterized by genomic instability and severe neurodegeneration. It is caused by mutation in Ataxia-telangiectasia mutated gene (ATM) which encodes ATM, a key player in DNA double-strand break (DSB) repair. While many major symptoms of A-T (including hypersensitivity to ionizing radiation) are readily explained by its deficiency in repair of DSBs, the causes for the devastating cerebellar degeneration are still elusive. Here we report that in A-T, persistent unrepaired DNA damage signals from the nucleus to mitochondria (NM signaling) causing mitochondrial dysfunction leading to neurodegeneration. We find that depletion of NAD+ in A-T across species is likely due to persistent PARylation as inhibition of PARP1 restores NAD+levels.. NAD+ depletion affects the NAD+/SIRT1-PGC1α axis causing accumulation of damaged mitochondria through inhibition of mitophagy. Restoration of NAD+/SIRT1 activity through PARP1 inhibition, NAD+ supplementation or SIRT1 activation rescued the pathological and behavioral defects in A-T, suggesting a conserved role of the NAD+/SIRT1 pathway in inhibiting disease pathology. Notably, increasing the NAD+ levels extends lifespan and rescues A-T-specific behavioral defects in both C. elegans and mouse models of A-T. This is through induction of PINK1-DCT1-regulated mitophagy and DNA-PKcs-associated NHEJ DNA repair. Our results underscore the unified role of SIRT1 (Sir2.1) in mitochondrial health and highlight how Sir2.1 not only regulates mitochondrial biogenesis, but also induces PINK1-DCT1-dependent mitophagy. Our data support a model where by the two major theories on aging, DNA damage accumulation and mitochondrial dysfunction, conspire to promote neurodegeneration in A-T animal models and suggest that therapeutic interventions are possible in A-T and other untreatable DNA repair-deficient disorders.
2018-06-25 | PXD003380 | Pride
Project description:The difficulty associated with generating induced pluripotent stem cells (iPSC) from patients with chromosomal instability syndromes suggests the cellular DNA damage response poses a barrier to reprogramming. Here we demonstrate that fibroblasts from patients with ataxia-telangiectasia (A-T) can be reprogrammed to bona-fide iPSC, albeit at a reduced efficiency. A-T iPSC display defective radiation-induced signaling, radiosensitivity and cell cycle checkpoint defects. Bioinformatic analysis of gene expression in the A-T iPSC identifies abnormalities in DNA damage signaling pathways as well as changes in mitochondrial and pentose phosphate pathways. A-T iPSC can be differentiated into functional neurons and thus represent a suitable model system to investigate A-T associated neurodegeneration. Collectively our data show that iPSC can be generated from a chromosomal instability syndrome and that these cells can be used to discover early developmental consequences of ATM deficiency, such as altered mitochondrial function, that may be relevant to A-T pathogenesis and amenable to therapeutic intervention. Three different cell types: fibroblasts, human embyronic stem cells, and induced pluripotent stem cells with heterozygote, homozygote A-T compared to normal samples.
2012-05-27 | E-GEOD-35347 | biostudies-arrayexpress
Project description:Genomic DNA was prepared, fragmented, and immunoprecipitated with antibodies specific for 5mC or 5hmC prior to standard sequencing. The neurodegenerative disease known as ataxia-telangiectasia (A-T) is caused by the absence of the ATM (A-T mutated) protein. A long-standing mystery surrounding A-T is why cerebellar Purkinje cells (PCs) appear uniquely vulnerable to ATM-deficiency. Here, we present that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human A-T and Atm-/- mouse cerebellar PCs. TET1, an enzyme that converts 5mC to 5hmC, responds to DNA damage. Manipulation of TET1 activity directly affects neuronal cell cycle reentry and cell death after the induction of DNA damage. Quantitative, genome-wide analysis of 5hmC of samples from human cerebellum showed that in ATM-deficiency there is a remarkable genome-wide reduction of 5hmC enrichment at both proximal and distal regulatory elements. These results reveal a role of TET1-mediated 5hmC in DNA damage response, and provide insights into the basis of a PC-specific DNA demethylation alteration in ATM-deficiency. There are two groups, A-T and Control. For each group, cerebellar DNA samples were immunoprecipitated with anti-5mC (n=1) or anti-5hmC (n=3). There were also two replicates of input control for each group.
2015-10-30 | E-GEOD-61133 | biostudies-arrayexpress
Project description:Genomic DNA was prepared, fragmented, and immunoprecipitated with antibodies specific for 5mC or 5hmC prior to standard sequencing. The neurodegenerative disease known as ataxia-telangiectasia (A-T) is caused by the absence of the ATM (A-T mutated) protein. A long-standing mystery surrounding A-T is why cerebellar Purkinje cells (PCs) appear uniquely vulnerable to ATM-deficiency. Here, we present that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human A-T and Atm-/- mouse cerebellar PCs. TET1, an enzyme that converts 5mC to 5hmC, responds to DNA damage. Manipulation of TET1 activity directly affects neuronal cell cycle reentry and cell death after the induction of DNA damage. Quantitative, genome-wide analysis of 5hmC of samples from human cerebellum showed that in ATM-deficiency there is a remarkable genome-wide reduction of 5hmC enrichment at both proximal and distal regulatory elements. These results reveal a role of TET1-mediated 5hmC in DNA damage response, and provide insights into the basis of a PC-specific DNA demethylation alteration in ATM-deficiency.
2015-10-30 | GSE61133 | GEO
Project description:The difficulty associated with generating induced pluripotent stem cells (iPSC) from patients with chromosomal instability syndromes suggests the cellular DNA damage response poses a barrier to reprogramming. Here we demonstrate that fibroblasts from patients with ataxia-telangiectasia (A-T) can be reprogrammed to bona-fide iPSC, albeit at a reduced efficiency. A-T iPSC display defective radiation-induced signaling, radiosensitivity and cell cycle checkpoint defects. Bioinformatic analysis of gene expression in the A-T iPSC identifies abnormalities in DNA damage signaling pathways as well as changes in mitochondrial and pentose phosphate pathways. A-T iPSC can be differentiated into functional neurons and thus represent a suitable model system to investigate A-T associated neurodegeneration. Collectively our data show that iPSC can be generated from a chromosomal instability syndrome and that these cells can be used to discover early developmental consequences of ATM deficiency, such as altered mitochondrial function, that may be relevant to A-T pathogenesis and amenable to therapeutic intervention.
2012-05-28 | GSE35347 | GEO
Project description:Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD+, and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD+ reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD+ also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy. This work links two major theories on aging, DNA damage accumulation, and mitochondrial dysfunction through nuclear DNA damage-induced nuclear-mitochondrial signaling, and demonstrates that they are important pathophysiological determinants in premature aging of A-T, pointing to therapeutic interventions.
2017-12-20 | GSE76380 | GEO
Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.
2018-07-03 | PXD010073 | Pride