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Super-resolution imaging reveals disrupted higher-order heterochromatin organization at early-stage carcinogenesis on pathological tissue

ABSTRACT: Super-resolution imaging reveals disrupted higher-order heterochromatin organization at early-stage carcinogenesis on pathological tissue

PROVIDER: PRJNA498505 | ENA |

REPOSITORIES: ENA

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Super-resolution imaging reveals disrupted higher-order heterochromatin organization at early-stage carcinogenesis on pathological tissue

Project description:Abnormal chromatin structure is one of the hallmarks in cancer and has long been used for cancer diagnosis, but the observed aberrant chromatin structures characteristic of cancer cells is limited to microscale features, largely due to due to the diffraction-limited resolution of conventional light microscopy. Recent advances in super-resolution microscopy overcome the technical limitations of conventional light microscopy and enable the in-situ visualization of the higher-order chromatin structure down to ~30 nm. Here we present PathSTORM, a variant of stochastic optical reconstruction microscopy (STORM) optimized for super-resolution imaging of densely packed higher-order chromatin organization at different epigenomic states on pathological tissue. We then apply this tool to characterize the structural alteration of higher-order heterochromatin, enriched with H3K9me3 and satellite repeats, at various stages of carcinogenesis in mouse models and human tissue specimens. PathSTORM reveals that a significant disruption of higher-order heterochromatin structure occurs in early carcinogenesis when tissue still appears histologically normal and becomes progressively severe during neoplastic progression. The disrupted higher-order heterochromatin structure also appears to be a common feature that reflects the evolution of carcinogenesis independent of molecular pathways in multiple tumor types. Taken together, PathSTORM can serve as a powerful tool to visualize higher-order chromatin structure in the spatial context of tissue architecture on pathological tissue. Our findings provide new insights on the role of higher-order heterochromatin structure in carcinogenesis, especially at the early stage, and have the potential for improving cancer diagnosis, risk stratification and facilitating the development and evaluation of new preventive strategies.

2020-03-19 | GSE121800 | GEO

Super-resolution imaging reveals the evolution of higher-order chromatin folding in early carcinogenesis.

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Autism-misregulated eIF4G microexons control synaptic translation and higher-order cognitive functions [Ribo-Seq]

Project description:Microexons represent the most highly conserved class of alternative splicing, yet their functions are poorly understood. Here, we focus on closely related neuronal microexons overlapping prion-like domains in the translation initiation factors, eIF4G1 and eIF4G3, the splicing of which is activity-dependent and frequently disrupted in autism. CRISPR-Cas9 deletion of these microexons selectively up-regulates synaptic proteins that control neuronal activity and plasticity and further triggers a gene expression program mirroring that of activated neurons. Mice lacking the Eif4g1 microexon display social behavior, learning and memory deficits, as well as alterations in hippocampal synaptic plasticity. The eIF4G microexons appear to reduce synaptic protein synthesis by causing ribosome stalling, through a mechanism whereby they promote the coalescence of cytoplasmic granule components associated with translation repression, including the Fragile X mental retardation protein, FMRP. The results thus reveal an autism-disrupted mechanism by which alternative splicing specializes translation to control higher-order cognitive functioning.

2020-01-30 | GSE141599 | GEO

Autism-misregulated eIF4G microexons control synaptic translation and higher-order cognitive functions [iCLIP-seq]

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Spectral imaging to visualize higher-order genomic organization.

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Higher-Order Organization Principles of Pre-translational mRNPs [RIPPLiT]

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RNA duplex map in living cells reveals higher order transcriptome structure

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