An Intra-BET Epigenetic Mechanism Driven by BRD4 Controls Pancreatic α-cell Expansion [scRNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE346272 | GEO | 2026/09/10
REPOSITORIES: GEO
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Project description:Bromodomain and extraterminal motif (BET) inhibitors, such as JQ1, are promising cancer therapeutics that target epigenetic regulators, particularly BRD4. However, resistance to BET inhibitors (BETi) limits their clinical utility, necessitating a better understanding of adaptive mechanisms. We identified BRD2 upregulation as a conserved response to BET inhibition across multiple cancer types and hypothesized that BRD2 compensates for BRD4 loss, sustaining essential transcriptional programs during treatment. Consistent with this, BRD2 knockdown sensitized cancer cells to BETi in vitro, and combining BRD2 depletion and JQ1 treatment significantly impaired tumor growth in vivo. At the chromatin level, BRD2 and BRD4 ChIP-seq analysis of pancreatic cancer cells showed consistent BRD4 loss from chromatin after JQ1 treatment, while BRD2 displacement differed by sensitivity. Resistant cells maintained higher BRD2 occupancy than sensitive cells, suggesting a link between BRD2 retention and drug response. To dissect the underlying mechanism of BRD2 upregulation upon BET inhibition, we analyzed co-expression networks and observed that NFYA is co-expressed with BRD2 across diverse tissues and cancer types. Consistently, NFYA binds the BRD2 promoter. NFYA depletion abrogated BRD2 upregulation upon BETi treatment, indicating that NFYA is required for BRD2 induction following BET inhibition. Collectively, our findings establish BRD2 as a critical mediator of adaptive resistance to BETi in pan-cancer and identify NFYA as a novel transcriptional regulator of this process. Co-targeting BRD2 or its regulatory network offers a rational strategy to enhance the durability and efficacy of BET-based therapies.
2026-04-29 | GSE307285 | GEO
Project description:Bromodomain and extraterminal motif (BET) inhibitors, such as JQ1, are promising cancer therapeutics that target epigenetic regulators, particularly BRD4. However, resistance to BET inhibitors (BETi) limits their clinical utility, necessitating a better understanding of adaptive mechanisms. We identified BRD2 upregulation as a conserved response to BET inhibition across multiple cancer types and hypothesized that BRD2 compensates for BRD4 loss, sustaining essential transcriptional programs during treatment. Consistent with this, BRD2 knockdown sensitized cancer cells to BETi in vitro, and combining BRD2 depletion and JQ1 treatment significantly impaired tumor growth in vivo. At the chromatin level, BRD2 and BRD4 ChIP-seq analysis of pancreatic cancer cells showed consistent BRD4 loss from chromatin after JQ1 treatment, while BRD2 displacement differed by sensitivity. Resistant cells maintained higher BRD2 occupancy than sensitive cells, suggesting a link between BRD2 retention and drug response. To dissect the underlying mechanism of BRD2 upregulation upon BET inhibition, we analyzed co-expression networks and observed that NFYA is co-expressed with BRD2 across diverse tissues and cancer types. Consistently, NFYA binds the BRD2 promoter. NFYA depletion abrogated BRD2 upregulation upon BETi treatment, indicating that NFYA is required for BRD2 induction following BET inhibition. Collectively, our findings establish BRD2 as a critical mediator of adaptive resistance to BETi in pan-cancer and identify NFYA as a novel transcriptional regulator of this process. Co-targeting BRD2 or its regulatory network offers a rational strategy to enhance the durability and efficacy of BET-based therapies.
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Project description:To study the impact of an heterozygous missense variant in GLI2 in pancreatic cell differentiation and function, we established a patient-like pluripotent stem cell model. Interestingly, engineered iPSC lines carrying the identified missense variant in the gene GLI2 showed impaired differentiation into endocrine progenitors. To further characterize putative downstream mechanisms underlying the impaired endocrine differentiation of iPSCs, we performed bulk RNA-seq at three stages of differentiation (iPSC, gut tube and endocrine progenitor stages). At early stages (iPSC and gut tube stage), the transcriptome of GLI2-CTRL and GLI2-MUT-derived cells was highly comparable, with only 48 genes significantly dysregulated at gut tube stage. By contrast, differences at the transcriptome level became evident at endocrine progenitor stage [928 genes upregulated and 1070 downregulated in mutant versus control cells].
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Project description:We utilized the 10x Genomics Chromium Single Cell 3’ RNAseq platform to examine the genomic makeup of human induced pluripotent stem cell-derived islets following their differentiation under full suspension conditions using PBS vertical wheel bioreactors. Our investigation aimed to assess the efficacy of the SC-islet differentiation process in suspension, transitioning from a 0.1L to a scaled-up 0.5L volume. Our primary objective was to showcase the effectiveness of a modified protocol for pancreatic endocrine differentiation, with a specific focus on the final stage of maturation during scale-up. To gain a comprehensive understanding of these developmental changes, we integrated our transcriptomic analyses post the final maturation process with transcript data from human donor islets and existing SC-islet datasets.
2025-05-30 | GSE266878 | GEO
Project description:Understanding the precise functions and relationship of BRD2 with other bromodomain and extraterminal motif (BET) proteins is central for the application of BET-specific and pan inhibitors. Here, we used acute protein degradation and quantitative genomic and proteomic approaches to investigate the primary functions of BRD2 in transcription. We report that BRD2 is required for TAF3-mediated Pol II initiation at low levels of H3K4me3-modified promoters and Pol II elongation by suppressing R-loops. Single and double depletion revealed that BRD2 and BRD3, but not BRD4, redundantly and independently function in Pol II transcription at different promoters and cooperatively occupy enhancers. Interestingly, we found that depletion of BRD2 affects the expression of different genes during differentiation processes, priming with promoter regulation in ES cells. Therefore, our results suggest complex interconnections between BRD2 and BRD3 at promoters to fine-tune Pol II initiation and elongation for control of cell state.
2024-05-22 | PXD030774 | Pride
Project description:Using 10x Genomics Chromium Single Cell 3’ RNAseq platform, we sequenced human stem cell derived pancreatic islet cells during different stages of development and maturation process. We optimized a protocol for pancreatic endocrine differentiation, particularly focusing on the final, extended maturation stage during which significant reorganization of the cytoarchitecture of islet-like aggregates took place correlating with a remarkable maturation of glucose-induced insulin secretion. The transcriptomic changes during the time-course were combined with detailed physiological studies including dynamic insulin secretion assays, respirometry measurements, electrophysiological profiling as well as imaging of calcium and cAMP signaling and exocytosis.
2021-12-22 | GSE167880 | GEO
Project description:Little is known about the molecular mechanisms that underlie the allocation of human pluripotent stem cell-derived pancreatic progenitors (hPSC-PPs) into specific endocrine lineages. By systematically interrogating the components of pancreatic differentiation media, we identify methods to reliably generate hPSC-PPs with high-grade NKX6-1 expression, but find that this alone has a minimal effect on modulating the endocrine composition of hPSC-derived islets. We then test the effect of altering the signaling cues provided after progenitor specification and find that the BMP and FGF/MEK pathways can be manipulated to shift hPSC-PPs between islet and non-islet endocrine lineages. We further find that the method of hPSC-PP specification integrates with these later cues in a way that can be leveraged to selectively increase the frequencies of specific islet lineages or enterochromaffin (EC)-like cells. Using a model of disrupted murine islet development that gives rise to pancreatic EC-like cells, we identify prolonged NEUROG3 expression as a conserved feature associated with both human and murine pancreatic EC-like cell differentiation. In addition to expanding our understanding of pancreatic endocrine lineage allocation, these findings provide some of the first tools to fine-tune composition of hPSC-derived islets for research and therapeutic applications.
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Project description:Knockdown of the oncogene, BRD4-NUT, in a rare cancer, termed NUTmidline carcinoma (NMC), results in morphologic features consistent with squamous differentiation. Treatment with the HDAC-inhibitor, TSA, appears to cause the same phenotype. Here, we use gene expression profiling to compare the changes in gene expression following BRD4-NUT knockdown and TSA treatment. RNA was extracted from two BRD4-NUT-expressing NMC cell lines, PER-403 and TC-797, 24h following siRNA knockdown versus control in duplicate. RNA was extracted from two BRD4-NUT-expressing NMC cell lines, PER-403 and TC-797, 24h following treatment with TSA versus etoh control in triplicate
2011-07-01 | E-GEOD-18668 | biostudies-arrayexpress
Project description:deBack2012 - Lineage Specification in Pancreas Development
This model of two neighbouring pancreas precursor cells, describes the exocrine versus endocrine lineage specification process. To account for the tissue scale patterns, this couplet model has been extended to hundreds of coupled cells.
This model is described in the article:
On the role of lateral stabilization during early patterning in the pancreas
de Back W., Zhou JX, Brusch L
J. R. Soc. Interface 6 February 2013 vol. 10 no. 79 20120766
Abstract:
The cell fate decision of multi-potent pancreatic progenitor cells between the exocrine and endocrine lineages is regulated by Notch signalling, mediated by cell–cell interactions. However, canonical models of Notch-mediated lateral inhibition cannot explain the scattered spatial distribution of endocrine cells and the cell-type ratio in the developing pancreas. Based on evidence from acinar-to-islet cell transdifferentiation in vitro, we propose that lateral stabilization, i.e. positive feedback between adjacent progenitor cells, acts in parallel with lateral inhibition to regulate pattern formation in the pancreas. A simple mathematical model of transcriptional regulation and cell–cell interaction reveals the existence of multi-stability of spatial patterns whose simultaneous occurrence causes scattering of endocrine cells in the presence of noise. The scattering pattern allows for control of the endocrine-to-exocrine cell-type ratio by modulation of lateral stabilization strength. These theoretical results suggest a previously unrecognized role for lateral stabilization in lineage specification, spatial patterning and cell-type ratio control in organ development.
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2024-09-02 | BIOMD0000000435 | BioModels
Project description:To understand the pathophysiology of diabetes and to develop more effective treatments, we need to unravel how pancreatic endocrine lineages are generated. ISL1 transcription factor has important role in differentiation, maturation and maintenace of endocrine cells. Eliminating ISL1 in mouse pancreatic endocrine progenitors leads to the diabetic phenotype with altered islet architecture. To evaluate effects of lacking transcription factor on molecular level we performed single cell transcriptomics.
2026-02-07 | GSE268657 | GEO