Biology subjects

Uebelmesser, N.

Publications and source records attributed to Uebelmesser, N..

3 recordsLinked to original sources

bioRxiv2023

Extreme structural heterogeneity rewires glioblastoma chromosomes to sustain patient-specific transcriptional programs

Glioblastoma multiforme (GBM) encompasses brain malignancies marked by phenotypic and transcriptional heterogeneity thought to render these tumors aggressive, resistant to therapy, and inevitably recurrent. However, little is known about how the spatial organization of GBM genomes underlies this heterogeneity and its effects. Here, we compiled a cohort of 28 patient-derived glioblastoma stem cell-like lines (GSCs) known to reflect the properties of their tumor-of-origin; six of these were primary-relapse tumor pairs from the same patient. We generated and analyzed kbp-resolution chromosome conformation capture (Hi-C) data from all GSCs to systematically map >3,100 standalone and complex structural variants (SVs) and the >6,300 neoloops arising as a result. By combining Hi-C, histone modification, and gene expression data with chromatin folding simulations, we explain how the pervasive, uneven, and idiosyncratic occurrence of neoloops sustains tumor-specific transcriptional programs via the formation of new enhancer-promoter contacts. We also show how even moderately recurrent neoloops can help us infer patient-specific vulnerabilities. Together, our data provide a resource for dissecting GBM biology and heterogeneity, as well as for informing therapeutic approaches.

genomics↗

bioRxiv2022

Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion

Mammalian chromosomes are folded by converging and opposing forces. Here, we tested the role of RNAPII across different scales of interphase chromatin folding in a cellular system allowing for its auxin-mediated degradation. We used Micro-C and computational modeling to characterize subsets of loops differentially gained or lost upon RNAPII depletion. Gained loops, extrusion of which was antagonized by RNAPII, almost invariably formed by engaging new or rewired CTCF anchors. Lost loops selectively concerned contacts between enhancers and promoters anchored by RNAPII. Surprisingly, promoter-promoter contacts were almost insensitive to polymerase depletion and sustained cohesin occupancy in its absence. Selective loss of enhancer-promoter contacts explains the repression of most genes. Together, our findings reconcile the role of RNAPII in transcription with that in setting-up regulatory 3D chromatin architectures genome-wide, while also revealing a direct impact on cohesin loop extrusion.

genomics↗

bioRxiv2020

RNA polymerase II is required for spatial chromatin reorganization following exit from mitosis

Mammalian chromosomes are three-dimensional entities shaped by converging and opposing forces. Mitotic cell division induces drastic chromosome condensation, but following reentry into the G1 cell cycle phase, condensed chromosomes unwind to reestablish interphase organization. Here, we use a cell line allowing auxin-mediated degradation of RNA polymerase II to test its role in this transition. In situ Hi-C showed that RNAPII is required for compartment and loop formation following mitosis. RNAPs often counteract loop extrusion and, in their absence, longer and more prominent loops arise. Evidence from chromatin fractionation, super-resolution imaging and in silico modeling attribute these effects to RNAPII-mediated cohesin loading at active promoters upon reentry into G1. Our findings reconcile the role of RNAPII in gene expression with that in chromatin architecture.

genomics↗