DNA methylation-based classification of MCD in the human brain
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE185090 | GEO | 2021/11/30
REPOSITORIES: GEO
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Project description:DNA methylation-based classification of MCD in the human brain
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Project description:Malformations of cortical development (MCD) are present in up to 40% of children with pharmacoresistant epilepsy. Although epilepsy surgery can be successful in a subset of children, not all forms of MCD are operable. Understanding the genetic and neurobiological mechanisms underlying MCD and MCD-related epilepsy are necessary for the development of novel anti-epilepsy drugs. The tish (telencephalic internal structural heterotopia) rat is a unique model of MCD and spontaneous seizures, but the underlying genetic mutation has been, heretofore, unknown. DNA and RNA-sequencing revealed that a deletion encompassing a previously unannotated exon markedly diminished EML1 transcript and protein abundance in the tish brain. Developmental electrographic characterization of the tish rat demonstrated spontaneous spike-wave discharge (SWD) bursts beginning as early as postnatal day (P) 17. A dihybrid cross demonstrated that the mutantEml1 allele segregates with the observed dysplastic cortex and SWD bursts in monogenic autosomal recessive frequencies. Our data link the development of the bilateral, heterotopic dysplastic cortex of the tish rat to a mutation in Eml1 and provide a novel rat model of MCD.
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Project description:DNA methylation profiling of hippocampus and anterior temporal neocortex from MTLE-HS patients subjected to resective epileptic surgery and cadaveric non-epileptic controls. The Illumina Infinium MethylationEPIC Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpGs in brain homogenates.
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Project description:Introduction: Mosaic gain of chromosome 1q (chr1q) is a recently described driver of malformation of cortical development (MCD) and pharmacoresistant epilepsy. Hyaline protoplasmic astrocytopathy of the neocortex is a rare neuropathological finding seen in cases of pharmacoresistant epilepsy with focal cortical dysplasia or other MCD. The cell-type specificity of mosaic chr1q gain in the brain is unknown, and no data exists on the molecular signatures of hyaline protoplasmic astrocytopathy. Methods: We present a child with pharmacoresistant epilepsy who underwent epileptic focus resections at age 3 and 5 years and was found to have mosaic chr1q gain and hyaline protoplasmic astrocytopathy with partial reduction in seizure burden after the second surgery. We performed single-nucleus RNA-sequencing (snRNA-seq) of brain tissue from the second resection. Results: Remarkably, snRNA-seq showed increased expression of chr1q genes only in select populations of neurons and astrocytes. Differentially expressed genes correlating with inferred chr1q gain included AKT3 and genes associated with cell adhesion or migration. A subcluster of astrocytes demonstrated enrichment for synapse-associated transcripts, possibly linked to the astrocytic inclusions observed in hyaline protoplasmic astrocytopathy. Discussion: snRNA-seq may be used to infer the cell type-specificity of mosaic chromosomal copy number variations and identify associated gene expression alterations, which in the case of chr1q gain may involve aberrations in cell migration. Future studies using spatial profiling could yield further insights on the molecular signatures of hyaline protoplasmic astrocytopathy.
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Project description:Focal Cortical Dysplasia (FCD) is a frequent cause of drug-resistant focal epilepsy in children and young adults. The international FCD classifications of 2011 and 2022 have identified several clinico-pathological subtypes, either occurring isolated, i.e., FCD ILAE Type 1 or 2, or in association with a principal cortical lesion, i.e., FCD Type 3. Here, we addressed the DNA methylation signature of a previously described new subtype of FCD 3D occurring in the occipital lobe of very young children and microscopically defined by neuronal cell loss in cortical layer 4. We studied the DNA methylation profile using 850K BeadChip arrays in a retrospective cohort of 104 patients with FCD 1A, 2A, 2B, 3D, TLE without FCD, and 16 postmortem specimens without neurological disorders as controls, operated in China or in Germany. DNA was extracted from formalin-fixed paraffin-embedded tissue blocks with microscopically confirmed lesions, and DNA methylation profiles were bioinformatically analyzed with a recently developed deep learning algorithm. Our results revealed a distinct position of FCD 3D in the DNA methylation map of common FCD subtypes, also different from non-FCD epilepsy surgery controls or non-epileptic postmortem controls. Within the FCD 3D cohort, the DNA methylation signature separated three histopathology subtypes, i.e., fibrotic scarring around porencephalic cysts, loss of layer 4, and Rasmussen encephalitis. Differential methylation in FCD 3D with loss of layer 4 specifically mapped to biological pathways related to neurodegeneration, biogenesis of ECM components, axon guidance, and regulation of the actin cytoskeleton. Our data suggest that DNA methylation signatures in cortical malformations are not only of diagnostic value but also phenotypically relevant, providing the molecular underpinnings of structural and histopathological features associated with epilepsy. Further studies will be necessary to confirm these results and clarify their functional relevance and epileptogenic potential in these difficult-to-treat children.
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Project description:Explore DNA methylation in traumatic brain injury model of epilepsy and its relationship to gene expression. Examination of methylation changes in stimulated rats compared to sham operated animals in traumatic brain injury model of epilepsy.
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Project description:Polymicrogyria (PMG) is a developmental cortical malformation characterized by an excess of small and frustrane gyration and abnormal cortical lamination. PMG frequently associates with seizures. The molecular pathomechanisms underlying PMG development are not yet understood. About 40 genes have been associated with PMG, and small copy number variations have also been described in selected patients. We recently provided evidence that epilepsy-associated structural brain lesions can be classified based on genomic DNA methylation patterns. Here we analyzed 27 PMG patients employing array-based DNA-methylation profiling on formalin-fixed paraffin-embedded material. A series of 63 well-characterized non-PMG cortical malformations (focal cortical dysplasia type 2a/b and hemimegalencephaly), temporal lobe epilepsy, and non-epilepsy autopsy controls was used as reference cohort. Unsupervised dimensionality reduction and hierarchical cluster analysis of DNA methylation profiles showed that PMG formed a distinct DNA methylation class. Copy number profiling from DNA methylation data identified a uniform duplication spanning the entire long arm of chromosome 1 in 7 out of 27 PMG patients, which was verified by additional fluorescence in situ hybridization analysis. In respective cases about 50% of nuclei in the center of the PMG lesion were 1q triploid. No chromosomal imbalance was seen in adjacent, architecturally normal-appearing tissue indicating mosaicism. Clinically, PMG 1q patients presented with a unilateral frontal or hemispheric PMG without hemimegalencephaly, a severe form of intractable epilepsy with seizure onset in the first months of life, and severe developmental delay. Our results show that PMG can be classified among other structural brain lesions according to their DNA methylation profile. One subset of PMG with distinct clinical features exhibits a duplication of chromosomal arm 1q.
2020-11-18 | GSE156374 | GEO
Project description:Introduction: Minimal change disease (MCD) is a major cause of nephrotic syndrome. With a substantial number of patients requiring long-term immunosuppression leading to significant morbidity, the study aim was to determine MCD glomerular transcriptome to serve as a basis for biomarker discovery and novel drug target identification. Animal work showed podocyte injury induced by IL-7/IL-7R signaling (Zhai S, BBRC, 2018). Methods: Renal biopsies from adult patients representing the following groups were selected from the Norwegian Kidney Biopsy Registry: MCD (n=14), as well as normal tissue (n=8) and primary membranous nephropathy (MN; n=12) as the two reference groups. RNA for 75 base-pair paired-end RNASeq was obtained by dissecting glomeruli via laser capture microdissection (LCM) from FFPE cross-sections. Systematic delineation of condition-specific alteration in transcriptional landscapes was achieved by combining pathway-centered analyses with methodologies derived from network science and integrating multiple bioinformatics resources. Results: Compared to normal glomeruli, glomeuli from MCD displayed an inflammatory signature that appeared to be predominantly governed by the IL1 and IL7 systems. While enrichment of IL1 production and secretion was a shared feature of MCD and MN compared to normal tissue, responses involving IL7 pathway activation were unique to MCD. Indeed, IL7R expressed by glomeruli was the most up-regulated gene of to the interleukin-family in MCD vs normal controls. IL7 pathway activation was paralleled by significant enrichment in adaptive immune system processes and transcriptional regulation and depletion in pathways related to energy metabolism and transcription. Downregulation of these organ function-related themes again occurred predominately in MDC and were significantly less pronounced in MN. Conclusion: Our results demonstrate that archival FFPE-biopsies can be used to generate glomeruli-specific gene expression profiles suitable for systematic delineation of kidney-associated diseases. Here the latter provides a data-driven rationale to experimentally address these MCD-specific features as biomarkers and as novel drug targets. In this context inhibiting activation of the IL7 pathway may be particularly promising.
2023-01-25 | GSE216841 | GEO