Extensive protein dosage compensation in aneuploid human cancers

Schukken, Klaske M.; Sheltzer, Jason M.

doi:10.1101/gr.276378.121

Cited by 56 publications

(58 citation statements)

References 96 publications

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“…Interestingly, despite that PPM1A + cells have a ~20-fold increase in the number of CA compared to WT cells, this only led to a modest ~2-fold increase in the number of DEGs. This indicates that cells have strict control at various levels of processes leading to transcription and protein translation that can be compensated, consistent with a recent report of protein dosage compensation (Schukken and Sheltzer 2022). However, the subset of DAR and DEG that are unique to ΔPPM1A cells compared to WT and PPM1A + cells indicate that PPM1A activity is also involved in gene repression.…”

Section: Discussionsupporting

confidence: 91%

Transcriptome and chromatin accessibility mapping reveals a type I Interferon response triggered by Mycobacterium tuberculosis infection

Madden

Hamra

Berton

et al. 2022

Preprint

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Tuberculosis, a deadly infectious lung disease caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of bacterial disease-related deaths worldwide. The success of Mtb as a human pathogen depends on its ability to manipulate host immune response pathways, many of which are regulated by epigenetic mechanisms that control the accessibility of chromatin to the transcriptional machinery. Recent reports suggest that host phosphatases, such as PPM1A, may play a role in the regulation of chromatin accessibility during bacterial infections. However, changes in genome-wide chromatin accessibility during Mtb infection and whether PPM1A plays a role in this process remains unknown. Using combinatorial chromatin accessibility (ATAC-seq) and transcriptomics (RNA-seq) profiling of wild-type (WT), PPM1A knockout (ΔPPM1A) and PPM1A overexpressing (PPM1A+) macrophages, we demonstrate that Mtb infection induces global chromatin remodeling consistent with changes in gene expression signatures. The strongest concordant chromatin accessibility and gene expression signature triggered by Mtb infection was enriched for genes involved in the type I interferon (IFN) signaling pathways. Modulation of PPM1A expression results in altered chromatin accessibility signatures during Mtb infection that are reflected in the total number, chromosome location and directionality of change. Transcription factor motif analysis revealed an enrichment for transcription factors involved in the type I IFN pathway during Mtb infection, including IRF4, MEF2A, CEBPD and JDP2. In contrast, both deletion and overexpression of PPM1A produced unique transcription factor enrichment signatures linked to the genomic regions with altered chromatin accessibility. Our study demonstrates that altered type I IFN responses in Mtb-infected macrophages occurs as a result of genome-wide changes in chromatin accessibility, and that PPM1A likely plays a role in a subset of these signatures.

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Section: Discussionsupporting

confidence: 91%

Transcriptome and chromatin accessibility mapping reveals a type I Interferon response triggered by Mycobacterium tuberculosis infection

Madden

Hamra

Berton

et al. 2022

Preprint

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“…In line with this, a recent study by Schukken et al, investigated the extent of dosage compensation in human cancer cell lines both on RNA level as well as protein level. Their data showed that dosage compensation occurs both upon chromosome gains and losses to a similar extent [69]. Furthermore, they indeed provide evidence that chromosome gains and losses have distinct mechanisms of dosage compensation.…”

Section: Trisomies Cause Cin Levels That Correlate With the Number Of...mentioning

confidence: 82%

The impact of monosomies, trisomies and segmental aneuploidies on chromosomal stability

et al. 2022

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Aneuploidy and chromosomal instability are both commonly found in cancer. Chromosomal instability leads to karyotype heterogeneity in tumors and is associated with therapy resistance, metastasis and poor prognosis. It has been hypothesized that aneuploidy per se is sufficient to drive CIN, however due to limited models and heterogenous results, it has remained controversial which aspects of aneuploidy can drive CIN. In this study we systematically tested the impact of different types of aneuploidies on the induction of CIN. We generated a plethora of isogenic aneuploid clones harboring whole chromosome or segmental aneuploidies in human p53-deficient RPE-1 cells. We observed increased segregation errors in cells harboring trisomies that strongly correlated to the number of gained genes. Strikingly, we found that clones harboring only monosomies do not induce a CIN phenotype. Finally, we found that an initial chromosome breakage event and subsequent fusion can instigate breakage-fusion-bridge cycles. By investigating the impact of monosomies, trisomies and segmental aneuploidies on chromosomal instability we further deciphered the complex relationship between aneuploidy and CIN.

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“…In addition to participation in protein complexes, we investigated other parameters, including biophysical properties and evolutionary conservation, for their association with gene regulation (DNA–RNA or RNA–protein correlation) ( Schukken and Sheltzer, 2022 ). Some of these properties, including protein polyampholyte score, protein polarity, and protein aggregation score, had no significant association with the type of gene regulation ( Supplementary file 2J ).…”

Section: Resultsmentioning

confidence: 99%

Proteogenomic analysis of cancer aneuploidy and normal tissues reveals divergent modes of gene regulation across cellular pathways

Pan

Zhao

Katsnelson

et al. 2022

eLife

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How cells control gene expression is a fundamental question. The relative contribution of protein-level and RNA-level regulation to this process remains unclear. Here, we perform a proteogenomic analysis of tumors and untransformed cells containing somatic copy number alterations (SCNAs). By revealing how cells regulate RNA and protein abundances of genes with SCNAs, we provide insights into the rules of gene regulation. Protein complex genes have a strong protein-level regulation while non-complex genes have a strong RNA-level regulation. Notable exceptions are plasma membrane protein complex genes, which show a weak protein-level regulation and a stronger RNA-level regulation. Strikingly, we find a strong negative association between the degree of RNA-level and protein-level regulation across genes and cellular pathways. Moreover, genes participating in the same pathway show a similar degree of RNA- and protein-level regulation. Pathways including translation, splicing, RNA processing, and mitochondrial function show a stronger protein-level regulation while cell adhesion and migration pathways show a stronger RNA-level regulation. These results suggest that the evolution of gene regulation is shaped by functional constraints and that many cellular pathways tend to evolve one predominant mechanism of gene regulation at the protein level or at the RNA level.

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Extensive protein dosage compensation in aneuploid human cancers

Cited by 56 publications

References 96 publications

Transcriptome and chromatin accessibility mapping reveals a type I Interferon response triggered by Mycobacterium tuberculosis infection

Transcriptome and chromatin accessibility mapping reveals a type I Interferon response triggered by Mycobacterium tuberculosis infection

The impact of monosomies, trisomies and segmental aneuploidies on chromosomal stability

Proteogenomic analysis of cancer aneuploidy and normal tissues reveals divergent modes of gene regulation across cellular pathways

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