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CNS infiltration by Tet2-mutant peripheral myeloid cells protects from Alzheimer’s Disease

ABSTRACT: CNS infiltration by Tet2-mutant peripheral myeloid cells protects from Alzheimer’s Disease

PROVIDER: PRJNA1256817 | ENA |

REPOSITORIES: ENA

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CNS infiltration by Tet2-mutant peripheral myeloid cells protects from Alzheimer’s Disease

Project description:CNS infiltration by Tet2-mutant peripheral myeloid cells protects from Alzheimer’s Disease

| PRJNA1270000 | ENA

CNS infiltration by Tet2-mutant peripheral myeloid cells protects from Alzheimer’s Disease

Project description:Bone marrow-derived peripheral immune cells have been found to infiltrate the brain in many neurodegenerative diseases, such as Alzheimer's disease (AD). Using a mouse transplant model of AD (5xFAD mice), we found that loss of the clonal hematopoiesis associated gene Tet2 within peripheral immune cells led to increased myeloid cell brain infiltration when compared to mice with either wildtype or Dnmt3a-mutant peripheral immune cells. scRNA-seq on either CD11a-enriched or CD45-enriched brain cells from 5xFAD mice transplanted with either wildtype, Tet2-/- or Dnmt3a-/- bone marrow, confirmed our finding that loss of Tet2 leads to increased peripheral myeloid cell brain infiltration in AD mice. scRNA-seq identified that the change in infiltrating peripheral immune cells was primarily attributed to increased M1 macrophages and non-classical monocytes in the brains of 5xFAD mice with Tet2-mutant bone marrow. We further identified the upregulation of chemotaxis and migration related pathways in Tet2-mutant infiltrating macrophages and monocytes when compared to wildtype or Dnmt3a-mutant infiltrating cells, providing a mechanism by which loss of Tet2 in peripheral immune cells leads to increased brain infiltration in an AD setting.

2025-06-06 | GSE298597 | GEO

CNS infiltration by Tet2-mutant peripheral myeloid cells protects from Alzheimer’s Disease

Project description:Microglia play a key role in Alzheimer’s disease (AD) pathogenesis by clearing damaged cells and misfolded proteins such as b-amyloid. In a mouse transplant model of AD, we identified a population of bone marrow-derived immune cells that had infiltrated the brain and taken on microglia characteristics. The percentage of these infiltrating microglia-like cells within the brain was increased in AD mice that were transplanted with Tet2-mutant bone marrow when compared to mice transplanted with either wildtype or Dnmt3a-mutant bone marrow following LPS treatment. We explored the effect of mutation of TET2 and DNMT3A in human induced microglial-like cells (iMGLs) and found that TET2-mutant iMGLs were more phagocytic and hyperinflammatory than DNMT3A-mutant or wildtype iMGLs. Bulk RNA sequencing of iMGLs confirmed the upregulation of phagocytic pathways in TET2-mutant iMGLs compared to DNMT3A-mutant or wildtype iMGLs.

2025-07-16 | GSE295935 | GEO

14-3-3 protects AMPK phosphorylated TET2 from dephosphorylation by PP2A

Project description:Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes implicated in cancer and in aging due to its role as a global epigenetic modifier. TET2 has a large N-terminal domain followed by a catalytic C-terminal. Previous reports have demonstrated that the catalytic domain remains active independent of the N-terminal domain. As such, the function of the N-terminus of this large protein remains poorly characterized. Here, we identify that several isoforms of the 14-3-3 family of proteins bind TET2. 14-3-3s bind TET2 when phosphorylated at serine 99 (S99). AMPK-mediated phosphorylation at S99 promotes TET2 stability and increases global DNA 5-hydroxymethylcytosine. 14-3-3s’ interaction with TET2 serves to protect S99 phosphorylation. Disruption of this interaction leads to both reduced TET2 phosphorylation and decreased protein stability. Furthermore, we identify that the protein phosphatase 2A (PP2A) can interact with TET2 and dephosphorylates S99. Collectively, our study provides novel insights into the role of the N-terminal domain in TET2 regulation. Moreover, they demonstrate the dynamic nature of TET2 protein regulation that could have therapeutic implications for disease states resulting from reduced TET2 levels and/or activity.

2020-01-13 | PXD016160 | Pride

TET2 protects the genome from mutagenicity through interacting with MSH6

Project description:Ten eleven translocation 2 (TET2) is a member of dioxygenases that catalyze the multi-step 5-methylcytosine oxidation. Loss-of-function TET2 mutations frequently occur in various types of hematological malignancies; however, the underlying mechanism remains poorly understood. Here, we show that Tet2-/- mice develop spontaneous myeloid, T- and B-cell malignancies. Exome sequencing of Tet2-/- tumors reveals acquisition of numerous mutations. The mutational frequency in Tet2-/- tumors is significantly greater at loci containing Tet2-dependent active demethylation sites. In addition, the analyses of TET2-interacting protein unveil the association between TET2 and MutS Homolog 6 (MSH6). TET2-depleted cells display elevated spontaneous mutational frequencies and increased microsatellite instability, characteristics of mismatch repair deficient cells. Furthermore, myelodysplastic syndrome (MDS) patients with mutant TET2 have significantly higher mutational events than patients with wild-type TET2. Our findings reveal genomic hypermutability driven by the loss of TET2 as a novel contributing mechanism for TET2 loss-mediated pathogenesis of diverse hematological malignancies.

2017-04-25 | GSE74390 | GEO

The dural innate immune barrier protects the CNS from systemic virus invasion

Project description:The dural innate immune barrier protects the CNS from systemic virus invasion

| PRJNA861261 | ENA

Context Dependent Effects of Ascorbic Acid Treatment in TET2 Mutant Myeloid Neoplasia

Project description:Loss-of-function TET2 mutations (TET2MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT MN, clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2MT. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in TET2MT leukemia.

2020-09-09 | PXD020550 | Pride

The dural innate immune barrier protects the CNS from systemic virus invasion [EC_10X]

Project description:The dural innate immune barrier protects the CNS from systemic virus invasion [EC_10X]

| PRJNA861268 | ENA

The dural innate immune barrier protects the CNS from systemic virus invasion [MHCII_10X]

Project description:The dural innate immune barrier protects the CNS from systemic virus invasion [MHCII_10X]

| PRJNA861270 | ENA

The dural innate immune barrier protects the CNS from systemic virus invasion [CD45_10X]

Project description:The dural innate immune barrier protects the CNS from systemic virus invasion [CD45_10X]

| PRJNA861269 | ENA