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Differential Effects of Cancer-Associated Mutations Enriched in Helix H3 of PPAR?.

ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPAR?) has recently been revealed to regulate tumor microenvironments. In particular, genetic alterations of PPAR? found in various cancers have been reported to play important roles in tumorigenesis by affecting PPAR? transactivation. In this study, we found that helix H3 of the PPAR? ligand-binding domain (LBD) has a number of sites that are mutated in cancers. To uncover underlying molecular mechanisms between helix H3 mutations and tumorigenesis, we performed structure?function studies on the PPAR? LBDs containing helix H3 mutations found in cancers. Interestingly, PPAR? Q286E found in bladder cancer induces a constitutively active conformation of PPAR? LBD and thus abnormal activation of PPAR?/RXR? pathway, which suggests tumorigenic roles of PPAR? in bladder cancer. In contrast, other helix H3 mutations found in various cancers impair ligand binding essential for transcriptional activity of PPAR?. These data indicate that cancer-associated mutations clustered in helix H3 of PPAR? LBD exhibit differential effects in PPAR?-mediated tumorigenesis and provide a basis for the development of new biomarkers targeting tumor microenvironments.

SUBMITTER: Jang DM

PROVIDER: S-EPMC7761077 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Differential Effects of Cancer-Associated Mutations Enriched in Helix H3 of PPARγ.

Jang Dong Man DM Jang Jun Young JY Kim Hyun-Jung HJ Han Byung Woo BW

Cancers 20201130 12

Peroxisome proliferator-activated receptor gamma (PPARγ) has recently been revealed to regulate tumor microenvironments. In particular, genetic alterations of PPARγ found in various cancers have been reported to play important roles in tumorigenesis by affecting PPARγ transactivation. In this study, we found that helix H3 of the PPARγ ligand-binding domain (LBD) has a number of sites that are mutated in cancers. To uncover underlying molecular mechanisms between helix H3 mutations and tumorigene ...[more]

PMID: 33266062

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Project description:Alzheimer's disease (AD) is an age-associated neurodegenerative disorder characterized by progressive neuronal loss and pathological accumulation of the misfolded proteins amyloid-β and tau1,2. Neuroinflammation mediated by microglia and brain-resident macrophages plays a crucial role in AD pathogenesis1-5, though the mechanisms by which age, genes, and other risk factors interact remain largely unknown. Somatic mutations accumulate with age and lead to clonal expansion of many cell types, contributing to cancer and many non-cancer diseases6,7. Here we studied somatic mutation in normal aged and AD brains by three orthogonal methods and in three independent AD cohorts. Analysis of bulk RNA sequencing data from 866 samples from different brain regions revealed significantly higher (~two-fold) overall burdens of somatic single-nucleotide variants (sSNVs) in AD brains compared to age-matched controls. Molecular-barcoded deep (>1000X) gene panel sequencing of 311 prefrontal cortex samples showed enrichment of sSNVs and somatic insertions and deletions (sIndels) in cancer driver genes in AD brain compared to control, with recurrent, and often multiple, mutations in genes implicated in clonal hematopoiesis (CH)8,9. Pathogenic sSNVs were enriched in CSF1R+ microglia of AD brains, and the high proportion of microglia (up to 40%) carrying some sSNVs in cancer driver genes suggests mutation-driven microglial clonal expansion (MiCE). Analysis of single-nucleus RNA sequencing (snRNAseq) from temporal neocortex of 62 additional AD cases and controls exhibited nominally increased mosaic chromosomal alterations (mCAs) associated with CH10,11. Microglia carrying mCA showed upregulated pro-inflammatory genes, resembling the transcriptomic features of disease-associated microglia (DAM) in AD. Our results suggest that somatic driver mutations in microglia are common with normal aging but further enriched in AD brain, driving MiCE with inflammatory and DAM signatures. Our findings provide the first insights into microglial clonal dynamics in AD and identify potential new approaches to AD diagnosis and therapy.

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Differential Effects of Cancer-Associated Mutations Enriched in Helix H3 of PPAR?.

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Differential Effects of Cancer-Associated Mutations Enriched in Helix H3 of PPARγ.

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