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METTL3-mediated chromatin contacts promote phase separation during senescence [H3K27Ac-HiChIP-seq]

ABSTRACT: Cellular senescence is a stable state of growth arrest that emerges as a response to stress. The methyltransferase complex (MTC) has been shown to facilitate the expression of the senescence-associated secretion phenotype (SASP) factors via genome-wide redistribution. However, whether and how MTC impacts on the three-dimensional (3D) chromatin organization and its functional implications during senescence remain largely unknown. Here we show that the MTC complex coordinates its enzymatic activity-dependent and -independent functions to enforce cellular senescence. Specifically, METTL3-mediated chromatin loops induce Hexokinase 2 (HK2) expression during senescence. The elevated HK2 expression subsequently promotes liquid-liquid phase separation (LLPS), manifesting as stress granules. These phase-separated stress granules act as reservoirs to sequester cell-cycle related mRNAs harboring polymethylated m6A sites, impeding their efficient translation. Overall, we uncover a mechanism by which senescent cells utilize phase-separated stress granules, facilitated by MTC-mediated HK2 activation, to sequester cell-cycle related mRNAs in governing senescence-associated stable growth arrest.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243043 | GEO | 2024/04/22

REPOSITORIES: GEO

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Project description:Introduction:Repetitive RNA sequences like CAG repeats that trigger aberrant RNA-protein interactions cause several neurodegenerative diseases including Huntington's disease (HD). Importantly, these aberrant RNA-protein complexes also seed the formation of cytoplasmic liquid-like granules, such as the stress granules. Emerging evidence demonstrates that granules formed via liquid-liquid phase separation can mature into gel-like inclusions that persist within the cell and may act as precursor to aggregates that occur in patients’ tissue. Thus, deregulation of RNA granule biology is an important component of neurodegeneration. Interestingly, the formation of intracellular membrane-less organelles like stress granules increases along with the secretion of exosomes. Exosomes are small membrane-bound vesicles that are secreted generally by all cell types. They may participate in the spreading of misfolded proteins and aberrant RNA-protein complexes across the central nervous system in neurodegenerative diseases like HD. Moreover, due to their capability to cross the blood-brain barrier, exosomes hold great potential as sources of biomarkers available from the periphery, e.g., from blood. In this study, we performed a comparative transcriptomic analysis of exosomes and RNA granules in an HD model.Methods: Exosomes and RNA granules were isolated from an HD cell model, stably expressing HTT exon 1 with 83 CAG repeats under an inducible promoter. Both exosomes and RNA granules were isolated from induced (HD) and non-induced (control) cells and analysed by RNA sequencing.Results: Comparative analysis between the transcriptomics data of HD RNA granules and exosomes showed that: (I) intracellular RNA granules and extracellular RNA vesicles share content, (II) several non-coding RNAs translocate to RNA granules, (III) the composition of RNA granules and exosomes is affected by expression of mutant HTT.Discussion: Our data show that intracellular RNA granules and exosomes share content, suggesting that formation of RNA granules and exosome loading may be related. Moreover, our data suggest that both intracellular RNA granules and extracellular RNA vesicles may serve as a source for diagnostic strategies. For example, disease-specific RNA-signatures of exosomes can serve as biomarker of central nervous system diseases. However, the cell-type specific signature of EV-secreted RNAs may make it difficult to detect these biomarkers in blood.