Single Chromosome Aneuploidy Induces Genome-Wide Perturbation of Nuclear Organization and Gene Expression

Abstract

Chromosomal aneuploidy is a defining feature of carcinomas and results in tumor-entity specific genomic imbalances. For instance, most sporadic colorectal carcinomas carry extra copies of chromosome 7, an aneuploidy that emerges already in premalignant adenomas, and is maintained throughout tumor progression and in derived cell lines. A comprehensive understanding on how chromosomal aneuploidy affects nuclear organization and gene expression, i.e., the nucleome, remains elusive. We now analyzed a cell line established from healthy colon mucosa with a normal karyotype (46,XY) and its isogenic derived cell line that acquired an extra copy of chromosome 7 as its sole anomaly (47,XY,+7). We studied structure/function relationships consequent to aneuploidization using genome-wide chromosome conformation capture (Hi-C), RNA sequencing and protein profiling. The gain of chromosome 7 resulted in an increase of transcript levels of resident genes as well as genome-wide gene and protein expression changes. The Hi-C analysis showed that the extra copy of chromosome 7 is reflected in more interchromosomal contacts between the triploid chromosomes. Chromatin organization changes are observed genome-wide, as determined by changes in A/B compartmentalization and topologically associating domain (TAD) boundaries. Most notably, chromosome 4 shows a profound loss of chromatin organization, and chromosome 14 contains a large A/B compartment switch region, concurrent with resident gene expression changes. No changes to the nuclear position of the additional chromosome 7 territory were observed when measuring distances of chromosome painting probes by interphase FISH. Genome and protein data showed enrichment in signaling pathways crucial for malignant transformation, such as the HGF/MET-axis. We conclude that a specific chromosomal aneuploidy has profound impact on nuclear structure and function, both locally and genome-wide. Our study provides a benchmark for the analysis of cancer nucleomes with complex karyotypes.

Hard wiring of normal tissue-specific chromosome-wide gene expression levels is an additional factor driving cancer type-specific aneuploidies

“…The functional implications of many genes that are affected by these alterations remain incompletely understood. We previously showed experimentally that the gain of chromosome 13 in colorectal cancer activates both Notch and Wnt signaling [ 48 ] and that the acquisition of extra copies of chromosome 7 in normal colon cells results in upregulation of cancer-associated pathways [ 49 ], which could imply that tissue type-specific chromosome arm-wide gene expression levels promote cellular fitness. Of note, Sack et al [ 50 ] have demonstrated that the inclusion of tissue-specific growth promoting genes strengthens the correlation between chromosome arm loss/gain ratios and the proliferation-driving capability of each chromosome arm in breast and pancreatic cancers.…”

Chromosomal Density of Cancer Up-Regulated Genes, Aberrant Enhancer Activity and Cancer Fitness Genes Are Associated with Transcriptional Cis-Effects of Broad Copy Number Gains in Colorectal Cancer

“…Evidence that some specific BCNGs may act as driver mutations is mainly based on their rather high recurrence frequency in both chromosomally stable and unstable cancers, on their cancer-type specificity, or on the results of experimental chromosome transfer [5,6,7,8,9,10]. However, very little is known about driver genes or gene networks associated with BCNGs that can provide a selectable advantage to cancer cells.…”

Intelligence Quotient Variability in Klinefelter Syndrome Is Associated With GTPBP6 Expression Under Regulation of X-Chromosome Inactivation Pattern

“…This finding indicates that the SXI pattern somehow stabilizes GTPBP6 expression at levels similar to controls, which may function as a protective factor for cognitive development. Furthermore, it is known that in individuals with sex-chromosome aneuploidies even genes that escape X-inactivation are under the influence of the epigenetic events participating in this molecular mechanism, such as neighboring DNA methylation and changes in topologically associating domain (TAD) boundaries ( Raznahan et al, 2018 ; Braun et al, 2019 ). Thus, these data corroborate the idea of GTPBP6 as a non-inactivated gene reflecting the XCI pattern.…”

“…A P -value of < 0.05 was considered statistically significant. Polysomic patients were not considered in the statistical comparison of gene expression between KS (47,XXY) patients and controls due to their phenotypic and molecular variability ( Braun et al, 2019 ).…”

“…These genes are part of the pseudoautosomal regions (PAR1- short arm and PAR2—long arm) and are not subject to X inactivation. However, as widely known, aneuploid cells present unusual gene expression due to the presence of the extra chromosomes, affecting the nuclear architecture ( Raznahan et al, 2018 ; Braun et al, 2019 ). In the same way, sex chromosome aneuploidies also affect the expression of X-linked genes that escape from XCI ( Zhang et al, 2020 ).…”