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Cortical hypermethylation across an extended region spanning the HOXA gene cluster on chromosome 7 is robustly associated with Alzheimer's disease neuropathology

ABSTRACT: Alzheimer's disease is a progressive neurodegenerative disorder that is hypothesized to involve epigenetic dysfunction. We undertook an epigenome-wide association study across three independent brain tissue cohorts (total n = 999) to identify differential DNA methylation associated with neuropathology in the superior temporal gyrus and prefrontal cortex. We present robust evidence for elevated DNA methylation associated with AD neuropathology across an extended region spanning the HOXA gene cluster on chromosome 7.

ORGANISM(S): Homo sapiens

PROVIDER: GSE80970 | GEO | 2016/08/01

SECONDARY ACCESSION(S): PRJNA320252

REPOSITORIES: GEO

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Cortical hypermethylation across an extended region spanning the HOXA gene cluster on chromosome 7 is robustly associated with Alzheimer's disease neuropathology

Project description:Alzheimer's disease is a progressive neurodegenerative disorder that is hypothesized to involve epigenetic dysfunction. We undertook an epigenome-wide association study across three independent brain tissue cohorts (total n = 999) to identify differential DNA methylation associated with neuropathology in the superior temporal gyrus and prefrontal cortex. We present robust evidence for elevated DNA methylation associated with AD neuropathology across an extended region spanning the HOXA gene cluster on chromosome 7. Prefrontal cortex and superior temporal gyrus tissue from 147 individuals with varying levels of AD pathology. DNA modifications for these samples were quantified using the Illumina Infinium Human 450K Methylation Array.

2016-08-01 | E-GEOD-80970 | biostudies-arrayexpress

Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer's disease neuropathology.

Project description:IntroductionAlzheimer's disease is a neurodegenerative disorder that is hypothesized to involve epigenetic dysregulation of gene expression in the brain.MethodsWe performed an epigenome-wide association study to identify differential DNA methylation associated with neuropathology in prefrontal cortex and superior temporal gyrus samples from 147 individuals, replicating our findings in two independent data sets (N = 117 and 740).ResultsWe identify elevated DNA methylation associated with neuropathology across a 48-kb region spanning 208 CpG sites within the HOXA gene cluster. A meta-analysis of the top-ranked probe within the HOXA3 gene (cg22962123) highlighted significant hypermethylation across all three cohorts (P = 3.11 × 10-18).DiscussionWe present robust evidence for elevated DNA methylation associated with Alzheimer's disease neuropathology spanning the HOXA gene cluster on chromosome 7. These data add to the growing evidence highlighting a role for epigenetic variation in Alzheimer's disease, implicating the HOX gene family as a target for future investigation.

| S-EPMC6438205 | biostudies-literature

Chromatin states in glioblastoma stem cells (HOXA-AS2 depletion)

Project description:Glioblastoma multiform account for about half of all gliomas and are the most deadly and aggressive forms. Its therapeutic resistance and tumor relapse rely on a subpopulation of cells, the so-called Glioma-stem Cells (GSCs). Here, we investigated for the role of the long non-coding RNA HOXA-AS2 in GSC biology by conducting descriptive and functional analyses of glioma samples classified according to their isocitrate dehydrogenase (IDH1) gene mutation status, and of glioma stem cells. We found that HOXA-AS2 is overexpressed only in aggressive (IDHwt) glioma and GSC. Sh-RNA-based depletion of HOXA-AS2 affects GSC both at the cellular and molecular levels with a decrease in proliferation and altered expression of several hundreds of their genes. Integrative analysis revealed that these changes is expression are not associated to changes in DNA methylation or chromatin signature at the promoter of most deregulated genes following HOXA-AS2 silencing in GSC, supporting a post-transcriptional regulation. In addition, transcription factor motif enrichment and correlation analyses sustained that HOXA-AS2 affect, directly or indirectly, expression of key transcription factors of GCS biology, including E2F8, E2F1, STAT1 and ATF3 to, in fine, contributes to their pathological status by promoting proliferation and modulating the inflammation pathway of Glioma Stem Cell.

2022-04-15 | GSE199031 | GEO

Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology

Project description:To assess their utility in routine neuropathology, we prospectively integrated DNA methylation-based CNS tumor classification and targeted gene panel sequencing of tumor and constitutional DNA with blinded neuropathological reference diagnostics for a population-based cohort of > 1,200 newly-diagnosed pediatric patients.

2023-01-30 | GSE215240 | GEO

Deletion of the Hoxa Cluster in MLL-AF9 Is Incompatible with Leukemia Maintenance: RNAseq-based Quantitative Analysis of Wild Type and Hoxa-del Transcriptomes

Project description:High HOXA expression correlates with poor clinical outcome in AML, particularly those harboring MLL rearrangements (MLLr). The necessity of the HOXA cluster for the maintenance of MLLr-leukemia has not been elucidated. Primary leukemias were generated by transduction of MLL-AF9 (MA9) into hematopoietic stem and progenitor cells from compound Cre responsive transgenic mice for conditional deletion of the Hoxa locus. Hoxa deletion resulted in reduced proliferation, colony formation and repopulating ability in transplanted mice in which surviving leukemic cells retained at least one copy of the Hoxa cluster (Hoxa-del). Comparative RNA-seq analysis of leukemic MA9-Hoxa-wild type (WT) and MA9-Hoxa-del cells identified a unique gene signature.

2021-04-16 | GSE113200 | GEO

Transcription profiling of uterine horns from Hoxa-10+/+ and Hoxa-10-/- SvJ/129 mice treated with or without progesterone to study the progesterone-mediated roles of Hoxa-10 in preimplantation uterus.

Project description:This SuperSeries is composed of the following subset Series:; GSE108: OVX/P4/6h/UTX 129 WT vs. Hoxa-10-/-; GSE109: OVX/oil/6h/UTX 129 WT vs. Hoxa-10-/- Experiment Overall Design: Refer to individual Series. Female mice used were SvJ/129, 10-16 weeks of age; Hoxa-10+/+ and Hoxa-10-/- littermates were used in parallel experiments. 14 days after ovariectomy, mice were injected subcutaneously with progesterone dissolved in sesame oil (Sigma; 0.2mg/0.1mL/mouse) or sesame oil (Sigma; 0.1mL/mouse), followed by sacrifice and removal of uterine horns at 6 hours after injection. 8 uterine horns from 4 mice were pooled to form one sample. Total RNA preparation, cRNA labeling and hybridization were performed according to recommendations by Affymetrix.

2007-11-14 | E-GEOD-6439 | biostudies-arrayexpress

Transcriptome of glioblastoma stem cells and H9NSC (HOXA-AS2 depletion or overexpression)

2022-04-15 | GSE199030 | GEO

Transcription profiling of mouse uterine horns from Hoxa-10+/+ and Hoxa-10-/- littermates

Project description:Female mice used were SvJ/129, 10-16 weeks of age; Hoxa-10+/+ and Hoxa-10-/- littermates were used in parallel experiments. 14 days after ovariectomy, mice were injected subcutaneously with progesterone dissolved in sesame oil (Sigma; 0.2mg/0.1mL/mouse), followed by sacrifice and removal of uterine horns at 6 hours after injection. 8 uterine horns from 4 mice were pooled to form one sample. Total RNA preparation, cRNA labeling and hybridization were performed according to recommendations by Affymetrix. The 6 samples were obtained and processed in two batches: (1: GSM3047 and GSM3041), and (2: GSM3048, GSM3049, GSM3042, and GSM3043).

2007-10-06 | E-GEOD-108 | biostudies-arrayexpress

Methylation profiling of normal and cancerous breast cells from human patients and cell lines in a 125 kB region of the HOXA cluster

Project description:To evaluate DNA methylation profile associated with breast cancer in 125 kB region of HOXA cluster we analyzed DNA from normal cancerous breast specimens and cell lines. Analysis was performed on the tiling array covering entire HOXA region with 500bp resolution. Immunoprecipitation with anti-methylcytosine antibody was for target preparation. Cy3 labeling was used for inmmunoprecipitated DNA, Cy5 labeling was used for reference input DNA.

2006-11-03 | E-MEXP-880 | biostudies-arrayexpress

Cortical neuropathology RNA expression time-course after diffuse traumatic brain injury

Project description:Traumatic brain injury (TBI) can lead to significant neuropsychiatric problems and neurodegenerative pathologies, which develop and persist years after injury. Neuroinflammatory processes evolve over this same period. Therefore, we aimed to determine the contribution of microglia to neuropathology at acute (1-day post-injury; dpi), subacute (7 dpi), and chronic (30 dpi) time-points. Microglia were depleted with PLX5622, a CSF1R antagonist, prior to midline fluid percussion injury in male mice and cortical neuropathology/inflammation was assessed using a neuropathology mRNA panel. NanoString Neuropathology gene expression panel was used to quantify expression from RNA microdissected from the mouse cortex.

2020-11-15 | GSE160651 | GEO

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