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Separate transcription and splicing gene networks are linked and coordinated by the pRb-E2F pathway

ABSTRACT: E2F is a family of master transcription regulators involved in mediating diverse cell fates, and loss of control of the pathway is regarded as a hallmark of cancer. Recent studies have highlighted the pRb-E2F axis as a regulator of a large cellular network, which in addition to its classical target genes includes RNA splicing and non-coding genes. Here, we have addressed the generality of these effects by studying the role of the other key components of the pathway, including pRb, DP and PRMT5. Like E2F1, both pRb and DP1 influence transcription and alternative RNA splicing (AS) which is additionally impacted by PRMT5 activity. A detailed proteomics analysis of the E2F1 interactome revealed SRSF2 and HNRNPC as partner proteins that assist E2F1 in mediating the effects on RNA splicing. The ability of E2F1 to influence AS activity was apparent as cells progress through the cell cycle and during the DNA damage response. Our results highlight the role of the pRb-E2F pathway in mediating cell cycle regulation of gene expression mediated by transcription and RNA splicing, and provide a mechanistic understanding for how this is likely to occur.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278461 | GEO | 2026/02/04

REPOSITORIES: GEO

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Widespread cancer relevant splicing events driven by the pRb-E2F pathway

Project description:E2F is a family of master transcription regulators involved in mediating diverse cell fates, and loss of control of the pathway is regarded as a hallmark of cancer. Recent studies have highlighted the pRb-E2F axis as a regulator of a large cellular network, which in addition to its classical target genes includes RNA splicing and non-coding genes. Here, we have addressed the generality of these effects by studying the role of the other key components of the pathway, including pRb, DP and PRMT5. Like E2F1, both pRb and DP1 influence transcription and alternative RNA splicing (AS) which is additionally impacted by PRMT5 activity. A detailed proteomics analysis of the E2F1 interactome revealed SRSF2 and HNRNPC as partner proteins that assist E2F1 in mediating the effects on RNA splicing. The ability of E2F1 to influence AS activity was apparent as cells progress through the cell cycle and during the DNA damage response. Our results highlight the role of the pRb-E2F pathway in mediating cell cycle regulation of gene expression mediated by transcription and RNA splicing, and provide a mechanistic understanding for how this is likely to occur.

2026-02-09 | PXD056505 | Pride

E2F4 cooperates with pRB in the development of extra-embryonic, not embryonic, tissues

Project description:Homozygous mutation of the murine retinoblastoma tumor suppressor gene, Rb, results in embryonic lethality between E13.5 and E15.5 with defects in cellular proliferation, differentiation and apoptosis. Many of these defects are suppressed by mutation of an activating E2F, E2f1 or E2f3, indicating that they are key downstream targets of the retinoblastoma protein, pRB. In this study, we assess how E2F4 contributes to the developmental consequences of pRb-loss. In stark contrast to the activating E2Fs, the homozygous mutation of E2f4 shortened the lifespan of Rb-/- embryos. This resulted from an exacerbation of the placental defect of the Rb-/- mice indicating that E2F4 and pRB cooperate in the development of this tissue. Further analyses indicated that this defect reflects an increase in trophectoderm-like cells. Under conditions where the placenta was wild-type but the embryo mutant for E2f4 and pRb embryos survived to birth and exhibited all of the defects that were observed in the E2f4 and Rb single mutant embryos. Thus, while pRB and E2F4 cooperate in placental development, they play largely non-overlapping roles the development of many embryonic tissues. Keywords: genetically modified tissue comparison

2009-06-08 | GSE13753 | GEO

A commonly inactivated tumor suppressor silences endogenous retroelements in somatic cells [ChIP-Seq]

Project description:Upon G1-S transition, cyclin-dependent kinases (CDKs) phosphorylate the retinoblastoma tumor suppressor protein (pRB) to release E2F transcription factors, which activate transcriptional programs, required for S-phase entry. Beyond the G1-S transition, pRB activity remains poorly understood. Our lab has discovered that hyperphosphorylated pRB (ppRB), found beyond G1, retains exclusive binding to E2F1 through an alternate E2F1-‘specific’ binding site at the pRB c-terminus. We have developed a gene-targeted mouse model that is defective for the E2F1-‘specific’ interaction. We are exploring the function of this complex through genome-wide expression profiling. Overall, this work suggests an alternate pRB-E2F1 complex persists beyond the G1-S transition to establish regions of constitutive heterochromatin

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A commonly inactivated tumor suppressor silences endogenous retroelements in somatic cells [Affymetrix expression]

Project description:Upon G1-S transition, cyclin-dependent kinases (CDKs) phosphorylate the retinoblastoma tumor suppressor protein (pRB) to release E2F transcription factors, which activate transcriptional programs, required for S-phase entry. Beyond the G1-S transition, pRB activity remains poorly understood. Our lab has discovered that pRB retains exclusive binding to E2F1 through an alternate E2F1-‘specific’ binding site at the pRB c-terminus independent of CDK phosphorylation. We have developed a gene-targeted mouse model that is defective for the E2F1-‘specific’ interaction. We are exploring the function of this complex through genome-wide binding and expression profiling. Overall, this work suggests an alternate pRB-E2F1 complex persists independent of CDK phosphorylation to establish regions of constitutive heterochromatin

2016-10-31 | GSE85638 | GEO

A commonly inactivated tumor suppressor silences endogenous retroelements in somatic cells [ChIP-Seq]

Project description:Upon G1-S transition, cyclin-dependent kinases (CDKs) phosphorylate the retinoblastoma tumor suppressor protein (pRB) to release E2F transcription factors, which activate transcriptional programs, required for S-phase entry. Beyond the G1-S transition, pRB activity remains poorly understood. Our lab has discovered that pRB retains exclusive binding to E2F1 through an alternate E2F1-‘specific’ binding site at the pRB c-terminus independent of CDK phosphorylation. We have developed a gene-targeted mouse model that is defective for the E2F1-‘specific’ interaction. We are exploring the function of this complex through genome-wide binding and expression profiling. Overall, this work suggests an alternate pRB-E2F1 complex persists independent of CDK phosphorylation to establish regions of constitutive heterochromatin.

2016-10-31 | GSE85639 | GEO

Rb1+/+ versus Rb1ΔS/ΔS RNA Seq

2016-10-31 | GSE62040 | GEO

Separate transcription and splicing gene networks are linked and coordinated by the pRb-E2F pathway

Project description:Separate transcription and splicing gene networks are linked and coordinated by the pRb-E2F pathway

| PRJNA1167313 | ENA

E2F1 loss induces spontaneous tumour development in Rb-deficient epidermis

Project description:The specific ablation of Rb1 gene in epidermis (RbF/F;K14cre) promotes proliferation and altered differentiation but does not produce spontaneous tumour development. These phenotypic changes are associated with increased expression of E2F members and E2F-dependent transcriptional activity. Here, we have focused on the possible dependence on E2F1 gene function. We have generated mice that lack Rb1 in epidermis in an inducible manner (RbF/F;K14creERTM). These mice are indistinguishable from those lacking pRb in this tissue in a constitutive manner (RbF/F;K14cre). In an E2F1-null background (RbF/F;K14creERTM; E2F1-/- mice), the phenotype due to acute Rb1 loss is not ameliorated by E2F1 loss, but rather exacerbated, indicating that pRb functions in epidermis do not rely solely on E2F1. On the other hand, RbF/F;K14creERTM;E2F1-/- mice develope spontaneous epidermal tumours of hair follicle origin with high incidence. These tumours, which retain a functional p19arf/p53 axis, also show aberrant activation of βcatenin/Wnt pathway. Gene expression studies revealed that these tumours display relevant similarities with specific human tumours. These data demonstrate that the Rb/E2F1 axis exerts essential functions not only in maintaining epidermal homeostasis, but also in suppressing tumour development in epidermis, and that the disruption of this pathway may induce tumour progression through specific alteration of developmental programs. Gene expression was compared between normal mouse skin, skin from transgenic RbF/F;K14creERTM; E2F1-/- , E2F1-/-, and RbF/F;K14creERTM; E2F1-/- mouse, and carcinomas arising in the skin of RbF/F;K14creERTM; E2F1-/- mouse. All mice were treated with tamoxifen.

2012-08-20 | E-GEOD-38048 | biostudies-arrayexpress

E2F1 loss induces spontaneous tumour development in Rb-deficient epidermis

2012-08-20 | GSE38048 | GEO

Palbociclib interferes with origin firing in a pRb independent manner

Project description:Over the last decade, CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have emerged as promising anticancer drugs. Numerous studies have demonstrated that CDK4/6 inhibitors efficiently block the pRb-E2F pathway and induce cell cycle arrest in pRb-proficient cells. Based on these studies, the inhibitors have been approved by the FDA for treatment of advanced hormonal receptor (HR) positive breast cancers in combination with hormonal therapy. However, some evidence has recently shown unexpected effects of the inhibitors, promoting needs to understand more about the mechanism of inhibitors beyond pRb. Our study demonstrates here for the first time how palbociclib impairs the origin firing in the DNA replication process in pRb-deficient cell lines. Strikingly, despite the absence of pRb, cells treated with palbociclib synthesize less DNA without any induced cell cycle arrest. Furthermore, palbociclib treatment disturbs the temporal program of DNA replication and reduces the density of replication forks. Cells treated with palbociclib show a defect in the loading of proteins of the Pre-initiation complex (Pre-IC) on chromatin, indicating a reduced initiation of DNA replication. Our findings highlight hidden effects of palbociclib on the dynamics of DNA replication and on its cytotoxic consequences on cell viability in the absence of pRb. This study provides a potential therapeutic application of palbociclib to target genomic instability towards pRb deficient patient

2023-07-01 | GSE180530 | GEO

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