@article {69548, title = {Cohesin prevents cross-domain gene coactivation.}, journal = {Nat Genet}, year = {2024}, month = {2024 Jul 24}, abstract = {

The contrast between the disruption of genome topology after cohesin loss and the lack of downstream gene expression changes instigates intense debates regarding the structure-function relationship between genome and gene regulation. Here, by analyzing transcriptome and chromatin accessibility at the single-cell level, we discover that, instead of dictating population-wide gene expression levels, cohesin supplies a general function to neutralize stochastic coexpression tendencies of cis-linked genes in single cells. Notably, cohesin loss induces widespread gene coactivation and chromatin co-opening tens of million bases apart in cis. Spatial genome and protein imaging reveals that cohesin prevents gene co-bursting along the chromosome and blocks spatial mixing of transcriptional hubs. Single-molecule imaging shows that cohesin confines the exploration of diverse enhancer and core promoter binding transcriptional regulators. Together, these results support that cohesin arranges nuclear topology to control gene coexpression in single cells.

}, issn = {1546-1718}, doi = {10.1038/s41588-024-01852-1}, url = {https://doi.org/10.1038/s41588-024-01852-1}, author = {Dong, Peng and Zhang, Shu and Gandin, Valentina and Xie, Liangqi and Wang, Lihua and Lemire, Andrew L and Li, Wenhong and Otsuna, Hideo and Kawase, Takashi and Lander, Arthur D and Chang, Howard Y and Liu, Zhe J} } @article {68011, title = {BRD2 compartmentalizes the accessible genome.}, journal = {Nature Genetics}, volume = {54}, year = {2022}, month = {2022 Apr 11}, pages = {481-491}, abstract = {

Mammalian chromosomes are organized into megabase-sized compartments that are further subdivided into topologically associating domains (TADs). While the formation of TADs is dependent on cohesin, the mechanism behind compartmentalization remains enigmatic. Here, we show that the bromodomain and extraterminal (BET) family scaffold protein BRD2 promotes spatial mixing and compartmentalization of active chromatin after cohesin loss. This activity is independent of transcription but requires BRD2 to recognize acetylated targets through its double bromodomain and interact with binding partners with its low-complexity domain. Notably, genome compartmentalization mediated by BRD2 is antagonized on the one hand by cohesin and on the other hand by the BET homolog protein BRD4, both of which inhibit BRD2 binding to chromatin. Polymer simulation of our data supports a BRD2-cohesin interplay model of nuclear topology, in which genome compartmentalization results from a competition between loop extrusion and chromatin-state-specific affinity interactions.

}, keywords = {Animals, Cell Cycle Proteins, Chromatin, Chromosomes, Mammals, Nuclear Proteins, Protein Binding, Protein Domains, Transcription Factors}, issn = {1546-1718}, doi = {10.1038/s41588-022-01044-9}, author = {Xie, Liangqi and Dong, Peng and Qi, Yifeng and Hsieh, Tsung-Han S and English, Brian P and Jung, Seolkyoung and Chen, Xingqi and De Marzio, Margherita and Casellas, Rafael and Chang, Howard Y and Zhang, Bin and Tjian, Robert and Liu, Zhe} } @article {68368, title = {The evolutionary dynamics of extrachromosomal DNA in human cancers.}, journal = {Nature Genetics}, year = {2022}, month = {2022 Sep 19}, abstract = {

Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance-random identity by descent-is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer.

}, issn = {1546-1718}, doi = {10.1038/s41588-022-01177-x}, author = {Lange, Joshua T and Rose, John C and Chen, Celine Y and Pichugin, Yuriy and Xie, Liangqi and Tang, Jun and Hung, King L and Yost, Kathryn E and Shi, Quanming and Erb, Marcella L and Rajkumar, Utkrisht and Wu, Sihan and Taschner-Mandl, Sabine and Bernkopf, Marie and Swanton, Charles and Liu, Zhe and Huang, Weini and Chang, Howard Y and Bafna, Vineet and Henssen, Anton G and Werner, Benjamin and Mischel, Paul S} } @article {67806, title = {ecDNA hubs drive cooperative intermolecular oncogene expression.}, journal = {Nature}, volume = {600}, year = {2021}, month = {2021 Dec 01}, pages = {731-6}, abstract = {

Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation. Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs-clusters of around 10-100 ecDNAs within the nucleus-enable intermolecular enhancer-gene interactions to promote oncogene overexpression. ecDNAs that encode multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumours. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the bromodomain and extraterminal domain (BET) protein BRD4 in a MYC-amplified colorectal cancer cell line. The BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-derived-oncogene transcription. The BRD4-bound PVT1 promoter is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent expression of MYC. Furthermore, the PVT1 promoter on an exogenous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic silencing of ecDNA enhancers by CRISPR interference reveals intermolecular enhancer-gene activation among multiple oncogene loci that are amplified on distinct ecDNAs. Thus, protein-tethered ecDNA hubs enable intermolecular transcriptional regulation and may serve as units of oncogene function and cooperative evolution and as potential targets for cancer therapy.

}, issn = {1476-4687}, doi = {10.1038/s41586-021-04116-8}, author = {Hung, King L and Yost, Kathryn E and Xie, Liangqi and Shi, Quanming and Helmsauer, Konstantin and Luebeck, Jens and Sch{\"o}pflin, Robert and Lange, Joshua T and Chamorro Gonz{\'a}lez, Roc{\'\i}o and Weiser, Natasha E and Chen, Celine and Valieva, Maria E and Wong, Ivy Tsz-Lo and Wu, Sihan and Dehkordi, Siavash R and Duffy, Connor V and Kraft, Katerina and Tang, Jun and Belk, Julia A and Rose, John C and Corces, M Ryan and Granja, Jeffrey M and Li, Rui and Rajkumar, Utkrisht and Friedlein, Jordan and Bagchi, Anindya and Satpathy, Ansuman T and Tjian, Robert and Mundlos, Stefan and Bafna, Vineet and Henssen, Anton G and Mischel, Paul S and Liu, Zhe and Chang, Howard Y} }