Visualization of disrupted chromatin folding at nanoscale in early carcinogenesis via super-resolution microscopy

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

10.1101/672105 ◽

2019 ◽

Cited By ~ 1

Author(s):

Jianquan Xu ◽

Hongqiang Ma ◽

Hongbin Ma ◽

Wei Jiang ◽

Meihan Duan ◽

...

Keyword(s):

High Risk ◽

Risk Stratification ◽

Chromatin Structure ◽

Super Resolution ◽

Genomic Stability ◽

Higher Order ◽

Multiple Tumor ◽

Chromatin Folding ◽

Tumor Types ◽

Early Carcinogenesis

SUMMARYAberrant chromatin structure is a hallmark in cancer cells and has long been used for clinical diagnosis of cancer. However, underlying higher-order chromatin folding during malignant transformation remains elusive, due to the lack of molecular scale resolution. Using optimized stochastic optical reconstruction microscopy (STORM) for pathological tissue (PathSTORM), we uncovered a gradual decompaction and fragmented higher-order chromatin folding throughout all stages of carcinogenesis in multiple tumor types, even prior to the tumor formation. Our integrated imaging, genomic, and transcriptomic analyses reveal the functional consequences in enhanced formation of transcription factories, spatial juxtaposition with relaxed nanosized chromatin domains and impaired genomic stability. We also demonstrate the potential of imaging higher-order chromatin decompaction to detect high-risk precursors that cannot be distinguished by conventional pathology. Taken together, our findings reveal the gradual decompaction and fragmentation of higher-order chromatin structure as an enabling characteristic in early carcinogenesis to facilitate malignant transformation, which may improve cancer diagnosis, risk stratification, and prevention.SIGNIFICANCEGenomic DNA is folded into a higher-order structure that regulates transcription and maintains genomic stability. Although much progress has been made on understanding biochemical characteristics of epigenetic modifications in cancer, the higher-order folding of chromatin structure remains largely unknown. Using optimized super-resolution microscopy, we uncover de-compacted and fragmented chromatin folding in tumor initiation and stepwise progression in multiple tumor types, even prior to the presence of tumor cells. This study underlines the significance of unfolding higher-order chromatin structure as an enabling characteristic to promote tumorigenesis, which may facilitate the development and evaluation of new preventive strategies. The potential of imaging higher-order chromatin folding to improve cancer detection and risk stratification is demonstrated by detecting high-risk precursors that cannot be distinguished by conventional pathology.

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

Nature Communications ◽

10.1038/s41467-020-15718-7 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 5

Author(s):

Jianquan Xu ◽

Hongqiang Ma ◽

Hongbin Ma ◽

Wei Jiang ◽

Christopher A. Mela ◽

...

Keyword(s):

Super Resolution ◽

Higher Order ◽

Chromatin Folding ◽

Resolution Imaging ◽

Early Carcinogenesis

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Predicting three-dimensional genome organization with chromatin states

10.1101/282095 ◽

2018 ◽

Cited By ~ 1

Author(s):

Yifeng Qi ◽

Bin Zhang

Keyword(s):

Genome Organization ◽

De Novo ◽

Three Dimensional ◽

Super Resolution ◽

Cell Types ◽

Quantitative Agreement ◽

Chromosome Conformation ◽

Chromatin Loops ◽

Chromatin Folding ◽

Super Resolution Microscopy

ABSTRACTWe introduce a computational model to simulate chromatin structure and dynamics. Starting from one-dimensional genomics and epigenomics data that are available for hundreds of cell types, this model enables de novo prediction of chromatin structures at five-kilo-base resolution. Simulated chromatin structures recapitulate known features of genome organization, including the formation of chromatin loops, topologically associating domains (TADs) and compartments, and are in quantitative agreement with chromosome conformation capture experiments and super-resolution microscopy measurements. Detailed characterization of the predicted structural ensemble reveals the dynamical flexibility of chromatin loops and the presence of cross-talk among neighboring TADs. Analysis of the model’s energy function uncovers distinct mechanisms for chromatin folding at various length scales.

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Super-Resolution Microscopy in Studying the Structure and Function of the Cell Nucleus

Acta Naturae ◽

10.32607/2075851-2017-9-4-42-51 ◽

2017 ◽

Vol 9 (4) ◽

pp. 42-51

Author(s):

S. S. Ryabichko ◽

◽

A. N. Ibragimov ◽

L. A. Lebedeva ◽

E. N. Kozlov ◽

...

Keyword(s):

Cell Nucleus ◽

Super Resolution ◽

Structure And Function ◽

And Function ◽

Super Resolution Microscopy

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Structural Evidence of Photoisomerization Pathways in Fluorescent Proteins

10.26434/chemrxiv.9209450.v1 ◽

2019 ◽

Author(s):

Jeffrey Chang ◽

Matthew Romei ◽

Steven Boxer

Keyword(s):

Rational Design ◽

Fluorescent Protein ◽

Fluorescent Proteins ◽

Super Resolution ◽

Unit Cell Size ◽

Chlorine Substituent ◽

Gfp Chromophore ◽

The One ◽

Green Fluorescent ◽

Super Resolution Microscopy

Double-bond photoisomerization in molecules such as the green fluorescent protein (GFP) chromophore can occur either via a volume-demanding one-bond-flip pathway or via a volume-conserving hula-twist pathway. Understanding the factors that determine the pathway of photoisomerization would inform the rational design of photoswitchable GFPs as improved tools for super-resolution microscopy. In this communication, we reveal the photoisomerization pathway of a photoswitchable GFP, rsEGFP2, by solving crystal structures of cis and trans rsEGFP2 containing a monochlorinated chromophore. The position of the chlorine substituent in the trans state breaks the symmetry of the phenolate ring of the chromophore and allows us to distinguish the two pathways. Surprisingly, we find that the pathway depends on the arrangement of protein monomers within the crystal lattice: in a looser packing, the one-bond-flip occurs, whereas in a tighter packing (7% smaller unit cell size), the hula-twist occurs.

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