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SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111463 | GEO | 2018/04/05

REPOSITORIES: GEO

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SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis.

Project description:Defining direct targets of transcription factors and regulatory pathways is key to understanding their roles in physiology and disease. We combined SLAM-seq [thiol(SH)-linked alkylation for the metabolic sequencing of RNA], a method for direct quantification of newly synthesized messenger RNAs (mRNAs), with pharmacological and chemical-genetic perturbation in order to define regulatory functions of two transcriptional hubs in cancer, BRD4 and MYC, and to interrogate direct responses to BET bromodomain inhibitors (BETis). We found that BRD4 acts as general coactivator of RNA polymerase II-dependent transcription, which is broadly repressed upon high-dose BETi treatment. At doses triggering selective effects in leukemia, BETis deregulate a small set of hypersensitive targets including MYC. In contrast to BRD4, MYC primarily acts as a selective transcriptional activator controlling metabolic processes such as ribosome biogenesis and de novo purine synthesis. Our study establishes a simple and scalable strategy to identify direct transcriptional targets of any gene or pathway.

| S-EPMC6409205 | biostudies-literature

SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [SLAM-seq]

Project description:Defining direct targets of transcription factors and regulatory pathways is key to understanding their role in physiology and disease. Here we combine SLAM-seq, a novel method for direct quantification of newly synthesized mRNAs, with pharmacological and rapid chemical-genetic perturbation to interrogate primary transcriptional targets of BRD4 and MYC and define the response to BET bromodomain inhibitors (BETi). While BRD4 acts as a global co-activator of Pol2-dependent transcription in a BET bromodomain-dependent manner, therapeutic BETi doses deregulate a small set of hypersensitive target genes. In contrast to BRD4, MYC primarily acts as a selective transcriptional activator that controls basic metabolic processes such as ribosome biogenesis and de-novo purine synthesis across diverse cancer contexts. Beyond defining primary regulatory functions of BRD4 and MYC in cancer, our study establishes a simple, robust and scalable approach to dissect direct transcriptional targets of any gene or pathway.

2018-04-05 | GSE100708 | GEO

SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [ChIP-Seq]

2018-04-05 | GSE111460 | GEO

SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [Quant-Seq]

2018-04-05 | GSE111457 | GEO

SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis

Project description:SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis

| PRJNA437109 | ENA

SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [Quant-Seq]

Project description:SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [Quant-Seq]

| PRJNA437106 | ENA

SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [ChIP-Seq]

Project description:SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis [ChIP-Seq]

| PRJNA437112 | ENA

Bromodomain member BRD4 is required for hematopoietic stem cell functions

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-08-20 | GSE189836 | GEO

Toggling of BRD4 functions is triggered through its phosphorylation by JNK.

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-09-16 | GSE252982 | GEO

SLAM family receptors and the SLAM-associated protein (SAP) modulate T cell functions.

Project description:One or more of the signaling lymphocytic activation molecule (SLAM) family (SLAMF) of cell surface receptors, which consists of nine transmembrane proteins, i.e., SLAMF1-9, are expressed on most hematopoietic cells. While most SLAMF receptors serve as self-ligands, SLAMF2 and SLAMF4 use each other as counter structures. Six of the receptors carry one or more copies of a unique intracellular tyrosine-based switch motif, which has high affinity for the single SH2-domain signaling molecules SLAM-associated protein and EAT-2. Whereas SLAMF receptors are costimulatory molecules on the surface of CD4+, CD8+, and natural killer (NK) T cells, they also involved in early phases of lineage commitment during hematopoiesis. SLAMF receptors regulate T lymphocyte development and function and modulate lytic activity, cytokine production, and major histocompatibility complex-independent cell inhibition of NK cells. Furthermore, they modulate B cell activation and memory generation, neutrophil, dendritic cell, macrophage and eosinophil function, and platelet aggregation. In this review, we will discuss the role of SLAM receptors and their adapters in T cell function, and we will examine the role of these receptors and their adapters in X-linked lymphoproliferative disease and their contribution to disease susceptibility in systemic lupus erythematosus.

| S-EPMC2868096 | biostudies-literature

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