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1. Cohesin depleted cells rebuild functional nuclear compartments after endomitosis

   https://doi.org/10.1038/s41467-020-19876-6  

   Cremer, Marion; Brandstetter, Katharina; Maiser, Andreas; Rao, Suhas S.; Schmid, Volker J.; Guirao-Ortiz, Miguel; Mitra, Namita; Mamberti, Stefania; Klein, Kyle N.; Gilbert, David M.; et al (December 2020, Nature Communications)

   null (Ed.)

   Abstract Cohesin plays an essential role in chromatin loop extrusion, but its impact on a compartmentalized nuclear architecture, linked to nuclear functions, is less well understood. Using live-cell and super-resolved 3D microscopy, here we find that cohesin depletion in a human colon cancer derived cell line results in endomitosis and a single multilobulated nucleus with chromosome territories pervaded by interchromatin channels. Chromosome territories contain chromatin domain clusters with a zonal organization of repressed chromatin domains in the interior and transcriptionally competent domains located at the periphery. These clusters form microscopically defined, active and inactive compartments, which likely correspond to A/B compartments, which are detected with ensemble Hi-C. Splicing speckles are observed nearby within the lining channel system. We further observe that the multilobulated nuclei, despite continuous absence of cohesin, pass through S-phase with typical spatio-temporal patterns of replication domains. Evidence for structural changes of these domains compared to controls suggests that cohesin is required for their full integrity. 

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2. Chromatin alternates between A and B compartments at kilobase scale for subgenic organization

   https://doi.org/10.1038/s41467-023-38429-1  

   Harris, Hannah L; Gu, Huiya; Olshansky, Moshe; Wang, Ailun; Farabella, Irene; Eliaz, Yossi; Kalluchi, Achyuth; Krishna, Akshay; Jacobs, Mozes; Cauer, Gesine; et al (December 2023, Nature Communications)

   Abstract Nuclear compartments are prominent features of 3D chromatin organization, but sequencing depth limitations have impeded investigation at ultra fine-scale. CTCF loops are generally studied at a finer scale, but the impact of looping on proximal interactions remains enigmatic. Here, we critically examine nuclear compartments and CTCF loop-proximal interactions using a combination of in situ Hi-C at unparalleled depth, algorithm development, and biophysical modeling. Producing a large Hi-C map with 33 billion contacts in conjunction with an algorithm for performing principal component analysis on sparse, super massive matrices (POSSUMM), we resolve compartments to 500 bp. Our results demonstrate that essentially all active promoters and distal enhancers localize in the A compartment, even when flanking sequences do not. Furthermore, we find that the TSS and TTS of paused genes are often segregated into separate compartments. We then identify diffuse interactions that radiate from CTCF loop anchors, which correlate with strong enhancer-promoter interactions and proximal transcription. We also find that these diffuse interactions depend on CTCF’s RNA binding domains. In this work, we demonstrate features of fine-scale chromatin organization consistent with a revised model in which compartments are more precise than commonly thought while CTCF loops are more protracted. 

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3. Interphase chromosomes of the Aedes aegypti mosquito are liquid crystalline and can sense mechanical cues

   https://doi.org/10.1038/s41467-023-35909-2  

   Contessoto, Vinícius G.; Dudchenko, Olga; Aiden, Erez Lieberman; Wolynes, Peter G.; Onuchic, José N.; Di Pierro, Michele (December 2023, Nature Communications)

   Abstract We use data-driven physical simulations to study the three-dimensional architecture of the Aedes aegypti genome. Hi-C maps exhibit both a broad diagonal and compartmentalization with telomeres and centromeres clustering together. Physical modeling reveals that these observations correspond to an ensemble of 3D chromosomal structures that are folded over and partially condensed. Clustering of the centromeres and telomeres near the nuclear lamina appears to be a necessary condition for the formation of the observed structures. Further analysis of the mechanical properties of the genome reveals that the chromosomes of Aedes aegypti , by virtue of their atypical structural organization, are highly sensitive to the deformation of the nuclei. This last finding provides a possible physical mechanism linking mechanical cues to gene regulation. 

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4. The 3D architecture of the pepper genome and its relationship to function and evolution

   https://doi.org/10.1038/s41467-022-31112-x  

   Liao, Yi; Wang, Juntao; Zhu, Zhangsheng; Liu, Yuanlong; Chen, Jinfeng; Zhou, Yongfeng; Liu, Feng; Lei, Jianjun; Gaut, Brandon S.; Cao, Bihao; et al (December 2022, Nature Communications)

   Abstract The organization of chromatin into self-interacting domains is universal among eukaryotic genomes, though how and why they form varies considerably. Here we report a chromosome-scale reference genome assembly of pepper ( Capsicum annuum ) and explore its 3D organization through integrating high-resolution Hi-C maps with epigenomic, transcriptomic, and genetic variation data. Chromatin folding domains in pepper are as prominent as TADs in mammals but exhibit unique characteristics. They tend to coincide with heterochromatic regions enriched with retrotransposons and are frequently embedded in loops, which may correlate with transcription factories. Their boundaries are hotspots for chromosome rearrangements but are otherwise depleted for genetic variation. While chromatin conformation broadly affects transcription variance, it does not predict differential gene expression between tissues. Our results suggest that pepper genome organization is explained by a model of heterochromatin-driven folding promoted by transcription factories and that such spatial architecture is under structural and functional constraints. 

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5. DiCARN-DNase: Enhancing Cell-to-Cell Hi-C Resolution Using Dilated Cascading ResNet with Self-Attention and DNase-seq Chromatin Accessibility Data

   https://doi.org/10.1101/2024.10.31.621380  

   Olowofila, Samuel; Oluwadare, Oluwatosin (November 2024, bioRxiv)

   The spatial organization of chromatin is fundamental to gene regulation and essential for proper cellular function. The Hi-C technique remains the leading method for unraveling 3D genome structures, but the limited availability of high-resolution Hi-C data poses significant challenges for comprehensive analysis. Deep learning models have been developed to predict high-resolution Hi-C data from low-resolution counterparts. Early CNN-based models improved resolution but struggled with issues like blurring and capturing fine details. In contrast, GAN-based methods encountered difficulties in maintaining diversity and generalization. Additionally, most existing algorithms perform poorly in cross-cell line generalization, where a model trained on one cell type is used to enhance high-resolution data in another cell type. In this work, we propose DiCARN (Dilated Cascading Residual Network) to overcome these challenges and improve Hi-C data resolution. DiCARN leverages dilated convolutions and cascading residuals to capture a broader context while preserving fine-grained genomic interactions. Additionally, we incorporate DNase-seq data into our model, providing a robust framework that demonstrates superior generalizability across cell lines in high-resolution Hi-C data reconstruction. DiCARN is publicly available at https://github.com/OluwadareLab/DiCARN 

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