Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma

Kfoury, Najla; Qi, Zongtai; Prager, Briana C.; Wilkinson, Michael; Broestl, Lauren; Berrett, Kristopher; Moudgil, Arnav; Sankararaman, Sumithra; Chen, Xuhua; Gertz, Jason; Rich, Jeremy; Mitra, Robi D.; Rubin, Joshua B.

doi:10.1101/199059

Cited by 11 publications

(15 citation statements)

References 89 publications

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“…The same authors reported that sex differences in tumor phenotype are dependent on differential Brd4-bound enhancer regulation of stem cell–like phenotypes in male and female, both in mice and human GBM cells; and that inhibition of Brd4 resulted in decreased in vitro clonogenicity and in vivo growth of male tumors and opposite effects on female cells and tumors [ 113 ]. Sex-specific transcriptome expression in GBM patients has been studied recently.…”

Section: Disease Phenotypementioning

confidence: 99%

Sex-Specific Differences in Glioblastoma

Carrano

Juarez

Incontri‐Abraham

et al. 2021

Cells

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Sex differences have been well identified in many brain tumors. Even though glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has the worst outcome, well-established differences between men and women are limited to incidence and outcome. Little is known about sex differences in GBM at the disease phenotype and genetical/molecular level. This review focuses on a deep understanding of the pathophysiology of GBM, including hormones, metabolic pathways, the immune system, and molecular changes, along with differences between men and women and how these dimorphisms affect disease outcome. The information analyzed in this review shows a greater incidence and worse outcome in male patients with GBM compared with female patients. We highlight the protective role of estrogen and the upregulation of androgen receptors and testosterone having detrimental effects on GBM. Moreover, hormones and the immune system work in synergy to directly affect the GBM microenvironment. Genetic and molecular differences have also recently been identified. Specific genes and molecular pathways, either upregulated or downregulated depending on sex, could potentially directly dictate GBM outcome differences. It appears that sexual dimorphism in GBM affects patient outcome and requires an individualized approach to management considering the sex of the patient, especially in relation to differences at the molecular level.

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Section: Disease Phenotypementioning

confidence: 99%

Sex-Specific Differences in Glioblastoma

Carrano

Juarez

Incontri‐Abraham

et al. 2021

Cells

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“…Unfused piggyBac has an insertion preference at super-enhancers which are a class of enhancers regulating genes linked to cell identity 45,46 . Leveraging this property, calling cards have been used to read out these important regulatory elements 3,16,47 . To record these sites in vivo , we co-transduced mouse cortexes with unfused piggyBac and barcoded or non-barcoded SRTs.…”

Section: Resultsmentioning

confidence: 99%

“…Further, insertion profiles can depend on chromatin state 50 so SRTs can potentially be used to read out chromatin status and histone modifications. For example, unfused piggyBac has an insertion preference at super-enhancers which are a class of enhancers regulating genes linked to cell identity 50,51 , and it has been used to read out these important regulatory elements 3,16,52 . Joint measurements of piggyBac insertions and gene expression with this method may help link super-enhancers to gene regulatory networks.…”

Section: Discussionmentioning

confidence: 99%

“…Further, insertion profiles can depend on chromatin state 45 so SRTs can potentially be used to read out chromatin status and histone modifications. For example, we have shown that calling card experiments using unfused piggyBac can identify super-enhancers 3,16,47 . Joint measurements of piggyBac insertions and gene expression with this method may help link super-enhancers to gene regulatory networks.…”

Section: Discussionmentioning

confidence: 99%

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Measuring Transcription Factor Binding and Gene Expression using Barcoded Self-Reporting Transposon Calling Cards and Transcriptomes

Lalli

Dong

Chen

et al. 2021

Preprint

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Calling cards technology using self-reporting transposons enables the identification of DNA-protein interactions through RNA sequencing. By introducing a DNA barcode into the calling card itself, we have drastically reduced the cost and labor requirements of calling card experiments in bulk populations of cells. An additional barcode incorporation during reverse transcription enables simultaneous transcriptome measurement in a facile and affordable protocol. We demonstrate that barcoded self-reporting transposons recover in vitro binding sites for four basic helix-loop-helix transcription factors with important roles in cell fate specification: ASCL1, MYOD1, NEUROD2, and NGN1. Further, simultaneous calling cards and transcriptional profiling during transcription factor overexpression identified both binding sites and gene expression changes for two of these factors. RNA-based identification of transcription factor binding sites and gene expression through barcoded self-reporting transposon calling cards and transcriptomes is a novel and powerful method to infer gene regulatory networks in a population of cells.

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“…This study is not the first study providing evidence that novel anti-cancer therapeutics currently in clinical trials might have sex-specific effects. It was recently reported that clinically utilized bromodomain inhibitors could produce sex-specific responses (Kfoury et al, 2021). Together, these studies emphasize the importance of including sex as a variable in basic research and clinical settings.…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in Brain Tumor Glutamine Metabolism Reveal Sex-Specific Vulnerabilities to Treatment

Sponagel

Frankfater

et al. 2021

Preprint

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Sex differences in normal metabolism are well described, but whether they persist in cancerous tissue is unknown. We assessed metabolite abundance in glioblastoma surgical specimens and found that male glioblastomas are enriched for amino acids, including glutamine. Using PET imaging, we found that gliomas in male patients exhibit significantly higher glutamine uptake. These sex differences were well-modeled in murine transformed astrocytes, in which male cells imported and metabolized more glutamine and were more sensitive to glutaminase 1 (GLS1) inhibition. The sensitivity to GLS1 inhibition in males was driven by their dependence on glutamine-derived glutamate for α-ketoglutarate synthesis and TCA cycle replenishment. Females were resistant to GLS inhibition through greater pyruvate carboxylase-mediated TCA cycle replenishment. Thus, clinically important sex differences exist in targetable elements of metabolism. Recognition of sex-biased metabolism is an opportunity to improve treatments for all patients through further laboratory and clinical research.

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Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma

Cited by 11 publications

References 89 publications

Sex-Specific Differences in Glioblastoma

Sex-Specific Differences in Glioblastoma

Measuring Transcription Factor Binding and Gene Expression using Barcoded Self-Reporting Transposon Calling Cards and Transcriptomes

Sex Differences in Brain Tumor Glutamine Metabolism Reveal Sex-Specific Vulnerabilities to Treatment

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