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BRD4 maintains chromaffin-cell identity and promotes pheochromocytoma progression through a SMAD2-dependent transcriptional program

ABSTRACT: To determine whether BRD4 directly regulates chromaffin-cell identity genes at the chromatin level, we performed CUT&Tag (Cleavage Under Targets and Tagmentation) using a BRD4-specific antibody in PC12 cells, in parallel with chromatin immunoprecipitation (ChIP). This approach allowed genome-wide mapping of BRD4 occupancy. Our CUT&Tag and ChIP analyses revealed that BRD4 directly occupies the regulatory regions of key chromaffin-cell genes, including TH, CHGB, and PHOX2A. These findings demonstrate that BRD4 acts as a direct transcriptional regulator of genes essential for chromaffin-cell identity and catecholamine biosynthesis, providing a mechanistic basis for its role in maintaining chromaffin-cell function and pheochromocytoma progression.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE346274 | GEO | 2026/09/10

REPOSITORIES: GEO

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BRD4 maintains chromaffin-cell identity and promotes pheochromocytoma progression through a SMAD2-dependent transcriptional program

Project description:Chromaffin cells synthesize and release catecholamines, epinephrine and norepinephrine, into the systemic circulation to coordinate the stress response and regulate a variety of behavioral, endocrine, metabolic, immune, and cardiovascular functions. The mechanisms responsible for the development and maintenance of chromaffin cell differentiation and how these pathways are disrupted in pheochromocytomas (PCs) remain poorly understood.Here, we identify BRD4 as a critical regulator of chromaffin-cell biology through a PROTAC-based screen in human chromaffin organoids. Integrated analyses of human embryonic adrenal tissues, patient-derived pheochromocytomas, chromaffin organoids, and chromaffin cell-specific BRD4 conditional knockout mice demonstrated that BRD4 is required for maintaining chromaffin-cell identity and epinephrine-producing capacity. BRD4 deficiency disrupted chromaffin-cell differentiation programs, reduced expression of key lineage and functional genes, depleted mature PNMT-positive chromaffin cells, and impaired epinephrine production in vivo. Conversely, BRD4 overexpression enhanced chromaffin-cell gene expression and epinephrine secretion. Mechanistically, we identified SMAD2 as a BRD4-interacting transcriptional cofactor. CUT&Tag and chromatin immunoprecipitation analyses revealed direct BRD4 occupancy at key chromaffin-cell genes, including TH, CHGB, and PHOX2A. Pharmacological inhibition of BRD4 suppressed catecholamine-associated metabolic pathways, disrupted chromaffin-cell transcriptional programs, and inhibited pheochromocytoma growth. Together, our findings establish the BRD4-SMAD2 axis as a central regulator of chromaffin-cell identity and reveal a lineage-dependent mechanism linking catecholamine production to pheochromocytoma progression, highlighting BRD4 as a potential therapeutic target for pheochromocytoma.

2026-09-08 | GSE346218 | GEO

BRD4 maintains chromaffin-cell identity and promotes pheochromocytoma progression through a SMAD2-dependent transcriptional program

Project description:BRD4 maintains chromaffin-cell identity and promotes pheochromocytoma progression through a SMAD2-dependent transcriptional program

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BRD4 maintains chromaffin-cell identity and promotes pheochromocytoma progression through a SMAD2-dependent transcriptional program

Project description:BRD4 maintains chromaffin-cell identity and promotes pheochromocytoma progression through a SMAD2-dependent transcriptional program

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One deficiency, different outcomes: Succinate dehydrogenase loss in chromaffin cell vs. fibroblast models of paraganglioma

Project description:Heterozygosity for loss‐of‐function alleles of the genes encoding the four subunits of succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD), as well as the SDHAF2 assembly factor predispose affected individuals to pheochromocytoma and paraganglioma (PPGL), two rare neuroendocrine tumors that arise from neural crest-derived paraganglia. Tumorigenesis results from loss of the remaining functional Sdhx gene copy, leading to a cell with no functional SDH and a defective tricarboxylic acid (TCA) cycle. It is believed that the subsequent accumulation of succinate competitively inhibits multiple dioxygenase enzymes that normally suppress hypoxic signaling and demethylate histones and DNA, ultimately leading to increased expression of genes involved in angiogenesis and cell proliferation. Why SDH loss is selectively tumorigenic in neuroendocrine cells remains poorly understood. Here we characterize two available murine SDH-loss cell lines, one representing PPGL-susceptible chromaffin cells and the other PPGL-resistant fibroblasts. Consistent with previous analyses, we find strikingly different effects of SDH loss in these two cellular contexts, including evidence of residual Complex I activity only in SDH-loss immortalized mouse chromaffin cells. This work supports the hypothesis that chromaffin cells may uniquely tolerate SDH loss and sets the stage for analyses of unique vulnerabilities in SDH-loss chromaffin cells.

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Effect of PACAP treatment on Bovine chromaffin cells

Project description:The effect of PACAP treatment on the bovine chromaffin cells in vitro were investigated using mouse Mm36kd3 arrays. Although chromaffin cells have indigenous PACAP, the experiment was designed to find out the effect of additional PACAP on additional activation or suppression of transcription. Keywords: compound treatment design cy5 labelled RNA from PACAP treated bovine chromaffin cells were paired with cy3 labelled RNA from control chromaffin cells for hybridization. Four biological repeats were carried out.

2010-05-26 | E-GEOD-7406 | biostudies-arrayexpress

Effect of PACAP treatment on Bovine chromaffin cells

2008-03-01 | GSE7406 | GEO

Super enhancers orchestrate osteogenesis program through navigation and initiation effects of Brd4 on Zbtb16 [CUT&TAG]

Project description:We performed multiomic high-throughput sequencing to recapitulated the primary mechanism of mesenchymal stem cells osteogenesis. We analysed the H3K27ac ChIP-seq, BRD4 CUT&Tag and RNA-seq data before and after osteogenesis, and identified super enhancers (SEs) regulated osteogenic identity genes in MSCs.

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2026-09-10 | GSE346273 | GEO

Developmental heterogeneity of embryonic neuroendocrine chromaffin cells and their maturation dynamics

Project description:During embryonic development, nerve-associated Schwann cell precursors (SCPs) give rise to chromaffin cells of the adrenal gland via the “bridge” transient stage, according to recent functional experiments and single cell data from humans and mice. However, currently existing data do not resolve the finest heterogeneity of developing chromaffin populations. Here we took advantage of deep SmartSeq2 transcriptomic sequencing to expand our collection of individual cells from developing murine sympatho-adrenal anlage and uncover the microheterogeneity of embryonic chromaffin cells and corresponding developmental paths. After improving our atlas of sympatho-adrenal development and performing experimental validations, we discovered that SCPs in the local nerve show high degree of microheterogeneity corresponding to early biases towards either Schwann or chromaffin terminal fates. Furthermore, we found that a post-“bridge” population of developing chromaffin cells gives rise to persisting immature chromaffin cells and the two terminal populations (adrenergic and noradrenergic) via diverging differentiation paths. Taken together, we provide a thorough identification of novel markers of adrenergic and noradrenergic populations in developing adrenal glands and report novel differentiation micro-paths leading to them.

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Comprehensive proteomic characterization identifies potential molecular targets for therapy and imaging in the Cluster 1 human pheochromocytoma and paraganglioma

Project description:In order to identify new proteins with a potential to become targets for therapy or tumor imaging in pheochromocytoma and paraganglioma, we performed detailed proteomic analysis of 22 well-characterized human PPGL samples and normal chromaffin tissue from adrenal medulla. A standard quantitative proteomic analysis of tumor tissue was accompanied by specific membrane proteome-aimed methods, namely glycopeptide capture using lectin-affinity (Zielinska 2010) or hydrazide chemistry (Tian 2007) and enrichment of membrane-embedded hydrophobic transmembrane segment (Vit et al 2016 ). The parallel application of these complementary methods recently presented as “Pitchfork strategy”, enables deep quantitative profiling of human membrane proteomes without sacrificing the information on soluble non-membrane proteins (Vit et al 2019).

2023-09-25 | PXD039788 | Pride

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