Glucocorticoid receptor collaborates with pioneer factors and AP-1 to execute genome-wide regulation

Wissink, Erin M.; Dm, Martinez; Ehmsen, Kirk T.; Kr, Yamamoto; Lis, John T.

doi:10.1101/2021.06.01.444518

Cited by 4 publications

(5 citation statements)

References 98 publications

(157 reference statements)

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“…We found that GR-bound cis-regulatory loci newly synthesize unstable and lowly expressed non-coding RNAs, termed enhancer RNAs (eRNAs), in murine macrophages and livers [ 92 , 93 ]. Our profiles of eRNA expression from GR binding sites agree with reports from BEAS-2B epithelial cells stimulated with TNFα and Dexamethasone, and from A549 and U2OS cancer cell lines [ 94 , 95 ]. We found that GR-driven eRNA transcription occurred under physiological (liver in response to diurnal changes in glucocorticoid release) and inflammatory (activated macrophages) conditions.…”

Section: Discussionsupporting

confidence: 88%

Enhancer RNA Expression in Response to Glucocorticoid Treatment in Murine Macrophages

Greulich

Bielefeld

Scheundel

et al. 2021

Cells

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Glucocorticoids are potent anti-inflammatory drugs; however, their molecular mode of action remains complex and elusive. They bind to the glucocorticoid receptor (GR), a nuclear receptor that controls gene expression in almost all tissues in a cell type-specific manner. While GR’s transcriptional targets mediate beneficial reactions in immune cells, they also harbor the potential of adverse metabolic effects in other cell types such as hepatocytes. Here, we have profiled nascent transcription upon glucocorticoid stimulation in LPS-activated primary murine macrophages using 4sU-seq. We compared our results to publicly available nascent transcriptomics data from murine liver and bioinformatically identified non-coding RNAs transcribed from intergenic GR binding sites in a tissue-specific fashion. These tissue-specific enhancer RNAs (eRNAs) correlate with target gene expression, reflecting cell type-specific glucocorticoid responses. We further associate GR-mediated eRNA expression with changes in H3K27 acetylation and BRD4 recruitment in inflammatory macrophages upon glucocorticoid treatment. In summary, we propose a common mechanism by which GR-bound enhancers regulate target gene expression by changes in histone acetylation, BRD4 recruitment and eRNA expression. We argue that local eRNAs are potential therapeutic targets downstream of GR signaling which may modulate glucocorticoid response in a cell type-specific way.

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Section: Discussionsupporting

confidence: 88%

Enhancer RNA Expression in Response to Glucocorticoid Treatment in Murine Macrophages

Greulich

Bielefeld

Scheundel

et al. 2021

Cells

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“…Outliers were removed to limit the y-axis range. b , c) The ratio between PRO-Seq reads per base pair in downstream introns UHP, DHP, or type 0 exons and the sum of these values for the corresponding gene, for every UHP, DHP, or type 0 exon, from the Wissink et al dataset (b) (45) and the Gupta et al dataset (c) (46). Outliers were removed to limit the y-axis range.…”

Section: Resultsmentioning

confidence: 99%

“…In order to estimate the difference in transcription speed of UHP and DHP exons compared to type 0 exons, we used two PRO-Seq datasets (45, 46) (Methods). These datasets sequenced nascent mRNA in addition to mature mRNA, and therefore allowed reads to be counted in the intronic parts of the nascent mRNA of each gene.…”

Section: Resultsmentioning

confidence: 99%

“…We obtained the aligned reads for the dataset of (45) in .bam file format from the ENCODE website using the PRO-Seq filter, which retrieves 8 files corresponding to two biological samples. For the dataset of (46) we obtained the fastq files from SRA and processed them using the pipeline described in (47), using the ‘output-genome-bam’ option of RSEM.…”

Section: Methodsmentioning

confidence: 99%

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Alternative splicing is coupled to gene expression in a subset of variably expressed genes

Karlebach

Steinhaus

Daniš

et al. 2023

Preprint

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Numerous factors regulate alternative splicing of human genes at a co-transcriptional level. However, how alternative splicing depends on the regulation of gene expression is poorly understood. We leveraged data from the Genotype-Tissue Expression (GTEx) project to show a significant association of gene expression and splicing for 6874 (4.9%) of 141,043 exons in 1106 (13.3%) of 8314 genes with substantially variable expression in ten GTEx tissues. About half of these exons demonstrate higher inclusion with higher gene expression, and half demonstrate higher exclusion, with the observed direction of coupling being highly consistent across different tissues and in external datasets. The exons differ with respect to sequence characteristics, enriched sequence motifs, and RNA polymerase II binding. Pro-Seq data suggests that introns downstream of exons displaying coupled expression and splicing are transcribed at a slower rate than downstream introns of other exons. Our findings provide an extensive characterization of a class of exons associated with a coupling of expression and alternative splicing that can be observed in a substantial subset of genes.

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“…We find GR and AP1 are conditionally dependent upon one another in their potential to activate local genes. A recent study suggests that both AP1 and CEBP act as pioneer factors that prime the genome for GR-induced transcription activation (Wissink et al 2021). We find all three of these factor families activate the initial wave of transcription changes, both in combination and in isolation.…”

Section: Discussionmentioning

confidence: 99%

Kinetic networks identify Twist2 as a key regulatory node in adipogenesis

Dutta

Nguyen

Anderson

et al. 2021

Preprint

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Sequence-specific transcription factors (TFs) bind DNA, modulate chromatin structure, regulate gene expression, and or- chestrate transcription cascades. Activation and repression of TFs drive tightly controlled regulatory programs that lead to cellular processes such as differentiation. We measured chromatin accessibility and nascent transcription at seven time points over the first four hours of induced adipogenesis of 3T3-L1 mouse preadipocytes to construct dynamic gene regulatory networks. Regulatory networks describe successive waves of TF binding and dissociation followed by direct regulation of proximal genes. We identified 14 families of TFs that coordinate with and antagonize each other to regulate early adipogenesis. We developed a compartment model to quantify individual TF contributions to RNA polymerase initiation and pause release rates. Network analysis showed that the glucocorticoid receptor and AP1 drive immediate gene activation, including induction of Twist2. Twist2 is a highly interconnected node within the network and its expression leads to repression of target genes. Although Twist2’s role in adipogenesis has not been previously appreciated, both Twist2 knockout mice and Setleis syndrome (Twist2-/-) patients lack subcutaneous and brown adipose tissue. We found that kinetic networks integrating chromatin structure and nascent transcription dynamics identify key genes, TF functions, and coordinate interactions within regulatory cascades.

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Glucocorticoid receptor collaborates with pioneer factors and AP-1 to execute genome-wide regulation

Cited by 4 publications

References 98 publications

Enhancer RNA Expression in Response to Glucocorticoid Treatment in Murine Macrophages

Enhancer RNA Expression in Response to Glucocorticoid Treatment in Murine Macrophages

Alternative splicing is coupled to gene expression in a subset of variably expressed genes

Kinetic networks identify Twist2 as a key regulatory node in adipogenesis

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