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.
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.
Project description:Gene expression - 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.
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.
Project description:This SuperSeries is composed of the following subset Series: GSE41130: Expression profiling of Low-Risk Myelodysplastic Syndromes (MDSs) GSE41215: Methylation profiling of Low-Risk Myelodysplastic Syndromes (MDSs) Refer to individual Series