ORCID Profile
0000-0003-1831-9848
Current Organisation
Centre for Addiction and Mental Health
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Publisher: Cold Spring Harbor Laboratory
Date: 12-07-2020
DOI: 10.1101/2020.07.11.198721
Abstract: We establish a genome-wide map of DNA methylation quantitative trait locus (mQTL) effects in CD4 + T cells isolated from multiple sclerosis (MS) patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both MS susceptibility and local ( cis -) DNA methylation. We also identify two distant ( trans -) mQTL effects of MS susceptibility loci: (1) a chromosome 16 MS locus affects PRDM8 methylation (a chromosome 4 region not previously associated with MS susceptibility), and (2) the aggregate effect of MS variants in the major histocompatibility complex (MHC, chromosome 6) influences DNA methylation near PRKCA on chromosome 17. Both effects are replicated in independent s les. Overall, we present a new methylome-wide mQTL resource for a key cell type in inflammatory disease research, uncover functional consequences of MS susceptibility variants, including the convergence of MHC risk alleles onto a new gene target involved in predisposition to MS.
Publisher: Cold Spring Harbor Laboratory
Date: 09-11-2022
DOI: 10.1101/2022.11.08.515615
Abstract: Intracellular inclusions accompanying neurodegeneration are histopathologically and ultrastructurally heterogeneous but the significance of this heterogeneity is unclear. iPSC models, while promising for disease modeling, do not form inclusions in a reasonable timeframe and suffer from limited tractability. Here, we developed an iPSC toolbox utilizing piggyBac-based or targeted transgenes to rapidly induce CNS cells with concomitant expression of aggregation-prone proteins. This system is amenable to screening and longitudinal tracking at single-cell and single-inclusion resolution. For proof-of-principle, cortical neuron α-synuclein “inclusionopathy” models were engineered to form inclusions through exogenous seeding or α-synuclein mutation. These models recapitulated known fibril- and lipid-rich inclusion subtypes, uncovering dynamic interactions between them, and refined the classification of inclusions in postmortem brain. Genetic-modifier and protein-interaction screens pinpointed proteins like RhoA whose sequestration into specific inclusion subtypes is likely to be toxic. This iPSC platform should enhance our understanding of proteinaceous pathologies in neurodegeneration and facilitate therapeutics development.
Publisher: Springer Science and Business Media LLC
Date: 24-07-2018
Publisher: Springer Science and Business Media LLC
Date: 14-01-2021
DOI: 10.1038/S41398-020-01175-9
Abstract: Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer’s disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 540 subjects from two cohort studies of brain aging. Two of these transcriptional programs—modules 113 and 114—relate to the accumulation of β-amyloid, while module 5 relates to tau pathology. We replicate these associations in brain epigenomic data and in two independent datasets. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that three representative module 5 genes ( ACADVL, TRABD , and VASP ) encode proteins that are upregulated in activated microglia in AD.
Publisher: Springer Science and Business Media LLC
Date: 06-12-2021
DOI: 10.1038/S41467-021-27427-W
Abstract: Identifying the effects of genetic variation on the epigenome in disease-relevant cell types can help advance our understanding of the first molecular contributions of genetic susceptibility to disease onset. Here, we establish a genome-wide map of DNA methylation quantitative trait loci in CD4 + T-cells isolated from multiple sclerosis patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both multiple sclerosis susceptibility and local DNA methylation. We also identify two distant methylation effects of multiple sclerosis susceptibility loci: a chromosome 16 locus affects PRDM8 methylation (a chromosome 4 region not previously associated with multiple sclerosis), and the aggregate effect of multiple sclerosis-associated variants in the major histocompatibility complex influences DNA methylation near PRKCA (chromosome 17). Overall, we present a new resource for a key cell type in inflammatory disease research and uncover new gene targets for the study of predisposition to multiple sclerosis.
Publisher: Elsevier BV
Date: 09-2019
Location: United States of America
No related grants have been discovered for Daniel Felsky.