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:10.1073/pnas.2017148118

Cited by 31 publications

(29 citation statements)

References 83 publications

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“…Importantly, region-specific differences in response to (+)-JQ1 have been identified in the rodent brain, particularly in the context of dendritic spine density, suggesting brain cell type may be a major determining factor in the expression of these phenotypes (Wang et al, 2021b). Moreover, a recent study found sex divergent effects of Brd4 on cellular and transcriptional phenotypes in both human and mouse (Kfoury et al, 2021), further supporting the hypothesis that the impacts of BET inhibition are highly context dependent.…”

Section: Resultsmentioning

confidence: 53%

An automated high-content synaptic phenotyping platform in human neurons and astrocytes reveals a role for BET proteins in synapse assembly

Berryer

Rizki

Susco

et al. 2022

Preprint

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Resolving fundamental molecular and functional processes underlying human synaptic development is crucial for understanding normal brain function as well as dysfunction in disease. Based upon increasing evidence of species divergent features of brain cell types, coupled with emerging studies of complex human disease genetics, we developed the first automated and quantitative high-content synaptic phenotyping platform using human neurons and astrocytes. To establish the robustness of our platform, we screened the effects of 376 small molecules on presynaptic density, neurite outgrowth and cell viability, validating six small molecules which specifically enhanced human presynaptic density in vitro. Astrocytes were essential for mediating the effects of all six small molecules, underscoring the relevance of non-cell autonomous factors in synapse assembly and their importance in synaptic screening applications. Bromodomain and extraterminal (BET) inhibitors emerged as the most prominent hit class and global transcriptional analyses using multiple BET inhibitors confirmed upregulation of synaptic gene expression programs. Through these analyses, we demonstrate the robustness of our automated screening platform for identifying potent synaptic modulators, which can be further leveraged for scaled analyses of human synaptic mechanisms and drug discovery efforts.

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Section: Resultsmentioning

confidence: 53%

An automated high-content synaptic phenotyping platform in human neurons and astrocytes reveals a role for BET proteins in synapse assembly

Berryer

Rizki

Susco

et al. 2022

Preprint

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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: 86%

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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“…Sex differences in transcriptional processes related to membrane ion transport, excitability and interaction with drugs (7), as well as in chromatin regulation and epigenetic influences (21,65) have been previously reported for various organs. In the heart, the consequences of such sex differences may be of prime importance when developing and testing new drug compounds, including HDAC inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent transcription of cardiac electrophysiology and links to acetylation modifiers based on the GTEx database

Pressler

Horvath

Entcheva

2022

Front. Cardiovasc. Med.

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Development of safer drugs based on epigenetic modifiers, e.g., histone deacetylase inhibitors (HDACi), requires better understanding of their effects on cardiac electrophysiology. Using RNAseq data from the genotype-tissue-expression database (GTEx), we created models that link the abundance of acetylation enzymes (HDAC/SIRT/HATs), and the gene expression of ion channels (IC) via select cardiac transcription factors (TFs) in male and female adult human hearts (left ventricle, LV). Gene expression data (transcripts per million, TPM) from GTEx donors (21–70 y.o.) were filtered, normalized and transformed to Euclidian space to allow quantitative comparisons in 84 female and 158 male LVs. Sex-specific partial least-square (PLS) regression models, linking gene expression data for HDAC/SIRT/HATs to TFs and to ICs gene expression, revealed tight co-regulation of cardiac ion channels by HDAC/SIRT/HATs, with stronger clustering in the male LV. Co-regulation of genes encoding excitatory and inhibitory processes in cardiac tissue by the acetylation modifiers may help explain their predominantly net-neutral effects on cardiac electrophysiology. ATP1A1, encoding for the Na/K pump, represented an outlier—with orthogonal regulation by the acetylation modifiers to most of the ICs. The HDAC/SIRT/HAT effects were mediated by strong (+) TF regulators of ICs, e.g., MEF2A and TBX5, in both sexes. Furthermore, for male hearts, PLS models revealed a stronger (+/-) mediatory role on ICs for NKX25 and TGF1B/KLF4, respectively, while RUNX1 exhibited larger (-) TF effects on ICs in females. Male-trained PLS models of HDAC/SIRT/HAT effects on ICs underestimated the effects on some ICs in females. Insights from the GTEx dataset about the co-expression and transcriptional co-regulation of acetylation-modifying enzymes, transcription factors and key cardiac ion channels in a sex-specific manner can help inform safer drug design.

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Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma

Cited by 31 publications

References 83 publications

An automated high-content synaptic phenotyping platform in human neurons and astrocytes reveals a role for BET proteins in synapse assembly

An automated high-content synaptic phenotyping platform in human neurons and astrocytes reveals a role for BET proteins in synapse assembly

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

Sex-dependent transcription of cardiac electrophysiology and links to acetylation modifiers based on the GTEx database

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