A high-resolution transcriptome map of cell cycle reveals novel connections between periodic genes and cancer

Domínguez, Daniel; Tsai, Yi-Hsuan; Gomez, Nicholas C.; Jha, Deepak Kumar; Davis, Ian J.; Wang, Zefeng

doi:10.1038/cr.2016.84

Cited by 99 publications

(104 citation statements)

References 60 publications

(80 reference statements)

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“…Notably, gene set enrichment analysis (GSEA) revealed a higher tendency of PALB2 to bind to periodically expressed genes (Fig. S2B), which are associated with a high level of H3K36me3 (30). Conversely, we found little correlation between the level of gene expression and PALB2 association (Fig.…”

Section: Resultscontrasting

confidence: 44%

MRG15-mediated tethering of PALB2 to unperturbed chromatin protects active genes from genotoxic stress

Bleuyard

Fournier

Nakato

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The partner and localiser of BRCA2 (PALB2) plays important roles in the maintenance of genome integrity and protection against cancer. Although PALB2 is commonly described as a repair factor recruited to sites of DNA breaks, recent studies provide evidence that PALB2 also associates with unperturbed chromatin. Here, we investigated the previously poorly described role of chromatin-associated PALB2 in undamaged cells. We found that PALB2 associates with active genes through its major binding partner, MRG15, which recognizes histone H3 trimethylated at lysine 36 (H3K36me3) by the SETD2 methyltransferase. Missense mutations that ablate PALB2 binding to MRG15 confer elevated sensitivity to the topoisomerase inhibitor camptothecin (CPT) and increased levels of aberrant metaphase chromosomes and DNA stress in gene bodies, which were suppressed by preventing DNA replication. Remarkably, the level of PALB2 at genic regions was frequently decreased, rather than increased, upon CPT treatment. We propose that the steady-state presence of PALB2 at active genes, mediated through the SETD2/H3K36me3/MRG15 axis, ensures an immediate response to DNA stress and therefore effective protection of these regions during DNA replication. This study provides a conceptual advance in demonstrating that the constitutive chromatin association of repair factors plays a key role in the maintenance of genome stability and furthers our understanding of why PALB2 defects lead to human genome instability syndromes.nherited mutations in the partner and localiser of BRCA2 (PALB2) gene predispose to breast and pancreatic cancer (1-3) and also congenital malformations, growth retardation, and early childhood cancer in a rare subgroup of Fanconi anemia (FA-N) patients (4, 5). The best characterized function of PALB2 is to physically link the two main breast cancer susceptibility gene products, BRCA1 and BRCA2, at sites of DNA damage (6-8), thus playing a pivotal role in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR). BRCA1 facilitates DNA-end resection to produce single-stranded (ss) DNA (9) and concomitantly attracts PALB2, together with BRCA2 and RAD51, to DSB sites (6-8). In turn, BRCA2 promotes the loading of the RAD51 recombinase onto ssDNA (10-12), which is critical for the strand invasion and exchange phase of HR (13). This mechanism of repair factor recruitment is important for the timely activation of HR at sites of DNA damage, and its perturbation in individuals with impaired PALB2 function is presumed to cause human pathologies. Although PALB2 is commonly described as a repair factor recruited to sites of DNA breaks, we and others have provided evidence that PALB2 also associates with chromatin in the absence of DNA damage (14-17). A recent genome-wide analysis of PALB2 chromatin occupancy revealed enrichment at highly active genes, with PALB2 occupying the entire body of these genes (18). PALB2 was shown to support the transcription of a subset of NF-κB-and retinoic acid-responsive genes. However, PALB2 does...

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Section: Resultscontrasting

confidence: 44%

MRG15-mediated tethering of PALB2 to unperturbed chromatin protects active genes from genotoxic stress

Bleuyard

Fournier

Nakato

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The dataset was filtered to remove cells with <500 genes, >5% mitochondrial reads per cell or that expressed lymphocyte markers (CD3, CD79A or CD79B, n=33 cells) leaving a total of n=2420 unstimulated, n=3149 LPS stimulated and n=2273 LPS + anti-IL-10R stimulated monocytes. Per-cell UMI counts were then normalised, scaled and the effects of total UMI counts, percentage of mitochondrial counts and cell cycle ("all" effects; using known G2 and S phase associated genes 56 ) regressed out with the Seurat R package (version 2.3.4).…”

Section: Cross-condition Analysis Of Single-cell Rna-sequencing Data mentioning

confidence: 99%

Systems-level analysis of monocyte responses in inflammatory bowel disease identifies IL-10 and IL-1 cytokine networks that regulate IL-23

Aschenbrenner

Quaranta

Banerjee

et al. 2019

Preprint

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BACKGROUND & AIMSDysregulated immune responses are the cause of inflammatory bowel diseases. Studies in both mice and humans suggest a central role of IL-23 producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for select IL-23 targeting therapies as part of personalized medicine.METHODSWe performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA-sequencing to derive a transcriptomic signature of hyper-inflammatory monocytes. Using gene network correlation analysis, we deconvolve this signature into components associated with homeostasis and inflammation in patient biopsy samples.RESULTSWe characterized monocyte subsets of healthy individuals and patients with inflammatory bowel disease that express IL-23. We identified auto- and paracrine sensing of IL-1α/IL-1β and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion, uptake of whole bacteria induced IL-23 production via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to anti-TNF therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease.CONCLUSIONOur work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyper-inflammation-associated IL-23 production in patients with severe ulcerating active Crohn’s disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with inflammatory bowel disease that might benefit from IL-23p19 and/or IL-1α/IL-1β-targeting therapies upstream of IL-23.

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“…Periodic gene selection 63 Microarray and RNA-seq time series data sets were obtained from Eser et al (S. 64 cerevisiae) [44] and Dominguez et al (HeLa, human cervical cancer) [45]. For 65 consistency and due to its higher resolution, the S. cerevisiae data set was chosen to 66 produce all images and movies in this article, but both data sets were analyzed.…”

Section: Models 62mentioning

confidence: 99%

Cell cycle time series gene expression data encoded as cyclic attractors in Hopfield systems

Szedlak

Sims

Smith

et al. 2017

Preprint

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Modern time series gene expression and other omics data sets have enabled unprecedented resolution of the dynamics of cellular processes such as cell cycle and response to pharmaceutical compounds. In anticipation of the proliferation of time series data sets in the near future, we use the Hopfield model, a recurrent neural network based on spin glasses, to model the dynamics of cell cycle in HeLa (human cervical cancer) and S. cerevisiae cells. We study some of the rich dynamical properties of these cyclic Hopfield systems, including the ability of populations of simulated cells to recreate experimental expression data and the effects of noise on the dynamics. Next, we use a genetic algorithm to identify sets of genes which, when selectively inhibited by local external fields representing gene silencing compounds such as kinase inhibitors, disrupt the encoded cell cycle. We find, for example, that inhibiting the set of four kinases BRD4, MAPK1, NEK7, and YES1 in HeLa cells causes simulated cells to accumulate in the M phase. Finally, we suggest possible improvements and extensions to our model. Author SummaryCell cycle -the process in which a parent cell replicates its DNA and divides into two daughter cells -is an upregulated process in many forms of cancer. Identifying gene inhibition targets to regulate cell cycle is important to the development of effective therapies. Although modern high throughput techniques offer unprecedented resolution of the molecular details of biological processes like cell cycle, analyzing the vast quantities of the resulting experimental data and extracting actionable information remains a formidable task. Here, we create a dynamical model of the process of cell cycle using the Hopfield model (a type of recurrent neural network) and gene expression data from human cervical cancer cells and yeast cells. We find that the model recreates the oscillations observed in experimental data. Tuning the level of noise (representing the inherent randomness in gene expression and regulation) to the "edge of chaos" is crucial for the proper behavior of the system. We then use this model to identify potential gene targets for disrupting the process of cell cycle. This method could be applied to other time series data sets and used to predict the effects of untested targeted perturbations.

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A high-resolution transcriptome map of cell cycle reveals novel connections between periodic genes and cancer

Cited by 99 publications

References 60 publications

MRG15-mediated tethering of PALB2 to unperturbed chromatin protects active genes from genotoxic stress

MRG15-mediated tethering of PALB2 to unperturbed chromatin protects active genes from genotoxic stress

Systems-level analysis of monocyte responses in inflammatory bowel disease identifies IL-10 and IL-1 cytokine networks that regulate IL-23

Cell cycle time series gene expression data encoded as cyclic attractors in Hopfield systems

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