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Aberrant enhancer reprogramming drives hepatic carcinogenesis through global transcriptional reprogramming [RNA-seq]

ABSTRACT: Hepatocellular carcinomas (HCC) exhibit distinct promoter hypermethylation patterns, but the epigenetic regulation and function of transcriptional enhancers remain unclear. Here, our affinity- and bisulfite-based whole-genome sequencing analyses reveal global enhancer hypomethylation in human HCCs. Integrative epigenomic characterization further pinpoints a recurrent hypomethylated enhancer of CCAAT/enhancer-binding protein-beta (C/EBPβ) which correlates with C/EBPβ over-expression and poorer prognosis of patients. Demethylation of C/EBPβ enhancer reactivates a self-reinforcing enhancer-target loop via direct transcriptional up-regulation of enhancer RNA. Conversely, deletion of this enhancer via CRISPR/Cas9 reduces C/EBPβ expression and its genome-wide co-occupancy with BRD4 at H3K27ac-marked enhancers and super-enhancers, leading to drastic suppression of driver oncogenes and abrogation of HCC tumorigenicity. Hepatitis B X protein transgenic mouse model of HCC recapitulates this paradigm, as C/ebpβ enhancer hypomethylation associates with oncogenic activation in early tumorigenesis. These results support a causal link between aberrant enhancer hypomethylation and C/EBPβ over-expression, thereby driving hepatocarcinogenesis through global transcriptional reprogramming.

ORGANISM(S): Homo sapiens

PROVIDER: GSE123098 | GEO | 2019/01/06

REPOSITORIES: GEO

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Aberrant enhancer reprogramming drives hepatic carcinogenesis through global transcriptional reprogramming [ChIP-seq]

Project description:Hepatocellular carcinomas (HCC) exhibit distinct promoter hypermethylation patterns, but the epigenetic regulation and function of transcriptional enhancers remain unclear. Here, our affinity- and bisulfite-based whole-genome sequencing analyses reveal global enhancer hypomethylation in human HCCs. Integrative epigenomic characterization further pinpoints a recurrent hypomethylated enhancer of CCAAT/enhancer-binding protein-beta (C/EBPβ) which correlates with C/EBPβ over-expression and poorer prognosis of patients. Demethylation of C/EBPβ enhancer reactivates a self-reinforcing enhancer-target loop via direct transcriptional up-regulation of enhancer RNA. Conversely, deletion of this enhancer via CRISPR/Cas9 reduces C/EBPβ expression and its genome-wide co-occupancy with BRD4 at H3K27ac-marked enhancers and super-enhancers, leading to drastic suppression of driver oncogenes and abrogation of HCC tumorigenicity. Hepatitis B X protein transgenic mouse model of HCC recapitulates this paradigm, as C/ebpβ enhancer hypomethylation associates with oncogenic activation in early tumorigenesis. These results support a causal link between aberrant enhancer hypomethylation and C/EBPβ over-expression, thereby driving hepatocarcinogenesis through global transcriptional reprogramming.

2019-01-06 | GSE123097 | GEO

Identification of C/EBPβ Target Genes in ALK+ Anaplastic Large Cell Lymphoma (ALCL) by Gene Expression Profiling and Chromatin Immunoprecipitation

Project description:C/EBPβ (CCAAT enhancer binding protein) is a transcription factor that plays a crucial role in survival and transformation of ALK+ anaplastic large cell lymphoma (ALCL). The aim of this study was to identify the downstream targets of C/EBPβ responsible for ALK-mediated oncogenesis. C/EBPβ was knocked down in ALK+ ALCL cell lines with a C/EBPβ-shRNA, followed by gene expression profiling (GEP). GEP analysis revealed a reproducible signature of genes that were significantly regulated by C/EBPβ. Classification into biological categories revealed overrepresentation of genes involved in the immune response, apoptosis and cell proliferation. Transcriptional regulation by C/EBPβ was found in 6 of 11 (BCL2A1, G0S2, TRIB1, S100A9, DDX21 and DDIT4) genes investigated by chromatin immunoprecipitation. We demonstrated that BCL2A1, G0S2 and DDX21 play a crucial role in survival and proliferation of ALK+ ALCL cells. DDX21, a gene involved in rRNA biogenesis, was found differentially overexpressed in primary ALK+ ALCL cases. All three candidate genes were validated in primary ALCL cases by either immunohistochemistry or RT-qPCR. In conclusion, we identified and validated several key C/EBPβ-regulated genes with major impact on survival and cell growth in ALK+ ALCL, supporting the central role of C/EBPβ in ALK-mediated oncogenesis. Kijk and SUDHL1 cell lines transfected with shRNA for C/EBPbeta were compared to control cells (3 biological replicates per group) and untreated cells (1 biological replicate)

2013-07-10 | E-GEOD-23368 | biostudies-arrayexpress

Identification of C/EBPβ Target Genes in ALK+ Anaplastic Large Cell Lymphoma (ALCL) by Gene Expression Profiling and Chromatin Immunoprecipitation

2013-07-10 | GSE23368 | GEO

Deregulation of the endogenous C/EBPβ LIP isoform predisposes to tumorigenesis

Project description:Two long and one truncated isoforms (termed LAP*, LAP, and LIP, respectively) of the transcription factor CCAAT enhancer binding protein beta (C/EBPβ) are expressed from a single intronless Cebpb gene by alternative translation initiation. Isoform expression is sensitive to mammalian target of rapamycin (mTOR)-mediated activation of the translation initiation machinery and relayed through an upstream open reading frame (uORF) on the C/EBPβ mRNA. The truncated C/EBPβ LIP, initiated by high mTOR activity, has been implied in neoplasia, but it was never shown whether endogenous C/EBPβ LIP may function as an oncogene. In this study, we examined spontaneous tumor formation in C/EBPβ knockin mice that constitutively express only the C/EBPβ LIP isoform from its own locus. Our data show that deregulated C/EBPβ LIP predisposes to oncogenesis in many tissues. Gene expression profiling suggests that C/EBPβ LIP supports a protumorigenic microenvironment, resistance to apoptosis, and alteration of cytokine/chemokine expression. The results imply that enhanced translation reinitiation of C/ EBPβ LIP promotes tumorigenesis. Accordingly, pharmacological restriction of mTOR function might be a therapeutic option in tumorigenesis that involves enhanced expression of the truncated C/EBPβ LIP isoform.

2014-12-16 | GSE53770 | GEO

C/EBPβ deficiency reshapes microglial gene expression

Project description:CCAAT/enhancer binding protein β (C/EBPβ) is a transcription factor that regulates the expression of important pro-inflammatory genes in microglia. Mice deficient for C/EBPβ show protection against excitotoxic and ischemic CNS damage but the involvement of the various C/EBPβ expressing cell types in this neuroprotective effect is not solved. Since C/EBPβ-deficient microglia show attenuated neurotoxicity in culture we hypothesized that specific C/EBPβ deficiency in microglia could be neuroprotective in vivo. In this study we have tested this hypothesis by generating mice with myeloid C/EBPβ deficiency. Mice with myeloid C/EBPβ deficiency were generated by crossing LysMCre and C/EBPβfl/fl mice . Primary microglial cultures from C/EBPβfl/fl (named here as WT) and LysMCre-C/EBPβfl/fl (named here as KO) mice were treated with lipopolysaccharide ± interferon γ (IFNγ) for 6 h and gene expression was analyzed by RNA sequencing. LysMCre-C/EBPβfl/fl mice showed an efficiency of C/EBPβ deletion of 100% in cultured microglia. Transcriptomic analysis of C/EBPβ-deficient primary microglia revealed C/EBPβ-dependent expression of 1068 genes, significantly enriched in inflammatory and innate immune responses GO terms. This study provides new data that support a central role for C/EBPβ in the biology of activated microglia.

2017-06-13 | GSE90046 | GEO

BCR-ABL-mediated recruitment of STAT5 revealed by ChIPseq

Project description:Even in the era of ABL tyrosine kinase inhibitors, eradication of chronic myeloid leukemia (CML) stem cells still remains to be a prerequisite for the complete cure of the disease. Interferon-α (IFNα), which has been used long for the treatment for CML-chronic phase, are now being re-evaluated. However, the molecular mechanism involved in the action of IFNα on CML stem cells have not been elucidated yet. In this study we have found that IFNα upregulates CCAAT/Enhancer Binding Protein β (C/EBPβ), a transcription factor required for demand-driven granulopoiesis, through activation of STAT1 and STAT5 in BCR-ABL-expressing cells. Activated STAT1 and STAT5 were recruited to the newly identified 3’ distal enhancer region of Cebpb, which contains tandemly aligned interferon-g activated sequences (GAS). Genome editing-mediated repression or deletion of the GAS elements significantly abrogated the IFNα-dependent upregulation of C/EBPβ. IFNα induces differentiation and exhaustion of CML stem cells both in vitro and in vivo in a C/EBPβ-dependent manner. In addition, IFNα upregulates C/EBPβ and induces exhaustion of CD34+ CML stem cells obtained from CML patients. Collectively, these data clearly show that C/EBPβ is a critical factor in IFNα signaling that induces differentiation and exhaustion of CML stem cells.

2019-02-12 | GSE102809 | GEO

Global hyperactivation of enhancers stabilizes human and mouse naïve pluripotency

Project description:The transition of pluripotent stem cells (PSCs) from primed to naïve states constitutes a prototypical example of cellular plasticity. The naïve state can be stabilized by defined chemical cocktails that block extracellular signals, notably including the MEK pathway. However, little is known regarding the underlying transcriptional mechanisms. Here, we report that the transcriptional landscape of the naïve state can be mimicked in mouse and human PSCs by stimulating transcriptional enhancers. This is attained by inhibiting the CDK8 and CDK19 kinases, which are negative regulators of Mediator, a critical component of enhancer function. Mechanistically, CDK8/19i triggers a global increase in the recruitment of RNA Pol II at promoters and enhancers, hyperactivating enhancers and their target genes. Lastly, the emergence of naïve pluripotency in the pre-implantation epiblast coincides with a marked reduction in CDK8/19 activity, and CDK8/19i blocks its subsequent developmental progression. These findings suggest that naïve pluripotency during development includes hyperactivation of enhancers and can be captured in vitro, either by blunting extracellular signaling, or by stimulating enhancer-driven transcription. These principles may apply to other cellular transitions.

2020-09-29 | PXD009200 | Pride

SWI-SNF-like fetal gene reprogramming dynamically regulates epicardial progenitor activity

Project description:Epicardium-derived cells (EPDCs) contribute cardiac cell types during development and in adulthood respond to Thymosin β4 (Tβ4) and myocardial infarction (MI) by reactivating a fetal gene program to promote neovascularization and cardiomyogenesis. The mechanism for epicardial gene activation remains elusive. Here we reveal that SWI/SNF chromatin-remodeling complexes restored embryonic potential upon MI. BRG1, the essential ATPase subunit of SWI/SNF, physically interacted with Tβ4 and was recruited by CCAAT/enhancer-binding protein β (C/EBPβ) to discrete regulatory elements in the Wilm’s tumor 1 (Wt1) locus. BRG1-Tβ4 co-operative binding promoted transcription of Wt1 as the master regulator of embryonic EPDCs and Wt1as, an antisense lncRNA produced from within intron 1, which increased Wt1 mRNA stability through heteroduplex formation. ChIP-seq revealed global BRG1 binding which was enhanced by Tβ4 at key embryonic epicardial loci downstream of Wt1. These findings reveal novel essential functions for chromatin-remodeling and antisense RNA in the embryonic programming of EPDCs during cardiac development and repair.

2017-08-31 | GSE76239 | GEO

Genome-wide analysis of epicardial gene expression in E11.5 mouse hearts

Project description:Identification of epicardium-enriched genes in the embryonic heart. The epicardium encapsulates the heart and functions as a source of multipotent progenitor cells and paracrine factors essential for cardiac development and repair. Injury of the adult heart results in re-activation of a developmental gene program in the epicardium, but the transcriptional basis of epicardial gene expression has not been delineated. We established a mouse embryonic heart organ culture and gene expression system that facilitated the identification of epicardial enhancers activated during heart development and injury. Epicardial activation of these enhancers depends on a combinatorial transcriptional code centered on CCAAT/enhancer binding protein (C/EBP) transcription factors. Disruption of C/EBP signaling in the adult epicardium reduced injury-induced neutrophil infiltration and improved cardiac function. These findings reveal a transcriptional basis for epicardial activation and heart injury, providing a platform for enhancing cardiac regeneration. Total RNA obtained from lacZ-positive epicardial cells isolated from the E11.5 Tcf21lacZ hearts compared to total dissociated heart cells

2012-11-01 | E-GEOD-41959 | biostudies-arrayexpress

Impaired DNA demethylation of C/EBP sites causes premature aging

Project description:Changes in DNA methylation are among the best-documented epigenetic alterations accompanying organismal aging. However, whether and how altered DNA methylation is causally involved in aging have remained elusive. GADD45α (growth arrest and DNA damage protein 45A) and ING1 (inhibitor of growth family member 1) are adapter proteins for site-specific demethylation by TET (ten-eleven translocation) methylcytosine dioxygenases. Here we show that Gadd45a/Ing1 double-knockout mice display segmental progeria and phenocopy impaired energy homeostasis and lipodystrophy characteristic of Cebp (CCAAT/enhancer-binding protein) mutants. Correspondingly, GADD45α occupies C/EBPβ/δ-dependent superenhancers and, cooperatively with ING1, promotes local DNA demethylation via long-range chromatin loops to permit C/EBPβ recruitment. The results indicate that enhancer methylation can affect aging and imply that C/EBP proteins play an unexpected role in this process. Our study suggests a causal nexus between DNA demethylation, metabolism, and organismal aging. This SuperSeries is composed of the SubSeries listed below.

2018-06-11 | GSE99607 | GEO

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