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Gene expression - PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation.

ABSTRACT: Gene expression - PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation.

PROVIDER: PRJNA592137 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10545014.fastq.gz	Fastqsanger.gz
	SRR10545015.fastq.gz	Fastqsanger.gz

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Gene expression - PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation.

Project description:Dyskeratosis congenita (DKC) and idiopathic aplastic anemia (AA) are bone marrow failure syndromes that share characteristics of premature aging with severe telomere attrition. In this study, we analyzed blood samples of 62 AA and 13 DKC patients to demonstrate that their epigenetic age predictions are overall increased, albeit not directly correlated with telomere length. Aberrant DNA methylation was observed in the gene PRDM8 in DKC and AA as well as in other diseases with premature aging phenotype, such as Down syndrome, Werner syndrome and Hutchinson-Gilford-Progeria syndrome. To gain further insight into the functional relevance of PRDM8 we generated induced pluripotent stem cells (iPSCs) with heterozygous and homozygous knockout. Loss of PRDM8 impaired hematopoietic and neuronal differentiation of iPSCs, but it did not impact on epigenetic age. Taken together, aberrant DNA methylation in PRDM8 provides a biomarker for bone marrow failure syndromes, which may contribute to the hematopoietic and neuronal phenotypes of premature aging syndromes.

2020-08-31 | GSE141107 | GEO

DNA methylation - PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation.

2020-08-31 | GSE141106 | GEO

PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation.

Project description:PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation.

| PRJNA592127 | ENA

DNA methylation - PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation.

Project description:DNA methylation - PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation.

| PRJNA592138 | ENA

PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation.

Project description:BackgroundDyskeratosis congenita (DKC) and idiopathic aplastic anemia (AA) are bone marrow failure syndromes that share characteristics of premature aging with severe telomere attrition. Aging is also reflected by DNA methylation changes, which can be utilized to predict donor age. There is evidence that such epigenetic age predictions are accelerated in premature aging syndromes, but it is yet unclear how this is related to telomere length. DNA methylation analysis may support diagnosis of DKC and AA, which still remains a challenge for these rare diseases.ResultsIn this study, we analyzed blood samples of 70 AA and 18 DKC patients to demonstrate that their epigenetic age predictions are overall increased, albeit not directly correlated with telomere length. Aberrant DNA methylation was observed in the gene PRDM8 in DKC and AA as well as in other diseases with premature aging phenotype, such as Down syndrome and Hutchinson-Gilford-Progeria syndrome. Aberrant DNA methylation patterns were particularly found within subsets of cell populations in DKC and AA samples as measured with barcoded bisulfite amplicon sequencing (BBA-seq). To gain insight into the functional relevance of PRDM8, we used CRISPR/Cas9 technology to generate induced pluripotent stem cells (iPSCs) with heterozygous and homozygous knockout. Loss of PRDM8 impaired hematopoietic and neuronal differentiation of iPSCs, even in the heterozygous knockout clone, but it did not impact on epigenetic age.ConclusionTaken together, our results demonstrate that epigenetic aging is accelerated in DKC and AA, independent from telomere attrition. Furthermore, aberrant DNA methylation in PRDM8 provides another biomarker for bone marrow failure syndromes and modulation of this gene in cellular subsets may be related to the hematopoietic and neuronal phenotypes observed in premature aging syndromes.

| S-EPMC7439574 | biostudies-literature

PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation.

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-08-31 | GSE141108 | GEO

Targeted Degradation of Aberrant Tau in Frontotemporal Dementia Patient-Derived Neuronal Cell Models

Project description:Tauopathies are a family of neurodegenerative diseases characterized by a shared pathology of aberrant forms of tau protein accumulation leading to neuronal death in focal areas of the brain. Positron emission tomography (PET) tracers that bind to tau aggregates are used to aid diagnosis, but there are no current therapies to eliminate these tau species. We employed targeted protein degradation technology to convert a tau PET probe into a functional degrader of pathogenic tau. The hetero-bifunctional molecule QC-01- 175 was designed to engage both tau and Cereblon (CRBN), a substrate receptor for the Cullin-4 RING E3 ubiquitin ligase family member (CRL4CRBN), to trigger tau ubiquitination and proteasomal degradation. QC-01-175 effected clearance of tau in frontotemporal dementia (FTD) patient-derived neuronal cell models, which recapitulate disease phenotypes of tau accumulation, insolubility and toxicity. Furthermore, QC-01-175 had minimal effect on tau levels in neurons from healthy controls, indicating specificity for degradation of disease-relevant forms of tau. QC-01-175 also rescued vulnerability to stress in FTD neurons, phenocopying CRISPR-mediated MAPT-knockout. This work demonstrates that aberrant tau species formed in ex vivo FTD patient-derived neurons are amenable to targeted protein degradation, representing an important advance towards the development of a tau targeted therapeutic.

2019-03-26 | PXD012515 | Pride

Neuronal impact of patient-specific aberrant NRXN1α splicing [whole]

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Neuronal impact of patient-specific aberrant NRXN1α splicing [targeted]

Project description:Neuronal impact of patient-specific aberrant NRXN1α splicing [targeted]

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Protective effect of neuronal chaperone-mediated autophagy against brain aging and disease-driven neuroproteotoxicity

Project description:Components of the proteostasis network malfunction in the aging brain and this reduced neuronal protein quality control has been proposed to increase risk for neurodegeneration. Here, we have focused on chaperone-mediated autophagy (CMA), a selective type of autophagy that contributes to turnover of neurodegeneration-related proteins. We generated mouse models with CMA blockage in dopaminergic or glutamatergic neurons to investigate the physiological role of CMA in neurons in vivo and the consequences of neuronal CMA loss in aging, We found that loss of neuronal CMA leads to behavioral impairments, altered neuronal function, selective changes in the neuronal proteome and proteotoxicity, all reminiscent of brain aging. Furthermore, imposing CMA loss on an experimental mouse model of Alzheimer’s disease, increased neuronal disease vulnerability and accelerated disease progression. We conclude that functional CMA is essential for neuronal proteostasis and that CMA activation could be an efficient disease-modifying therapy in neurodegenerative disorders.

2021-04-23 | PXD017108 | Pride

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