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Project description:TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and PRC2 dependence
| PRJNA1002371 | ENA
Project description:Patients with lymphoma harboring TP63 rearrangements have aggressive clinical course and dismal prognosis with no target therapy available. Thus, there is an urgent need to elucidate the molecular mechanisms and to develop novel therapeutic options for these patients. We then generated a TBL1XR1::TP63 fusion knockin trangenic mouse model and crossed with CD2/iCre mouse. This project is to study the role and function of TP63 fusion in mouse lymphomagenesis.
2023-10-01 | GSE240201 | GEO
Project description:The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative transdifferentiation event in PDA pathogenesis remains unclear. Here, we show that expression of the transcription factor TP63 (?Np63) is sufficient to install and sustain the enhancer landscape and transcriptional signature of the squamous lineage in human PDA cells. We also demonstrate that TP63-driven enhancer reprogramming promotes aggressive tumor phenotypes, including enhanced cell motility and invasion, and an accelerated growth of primary PDA tumors and metastases in vivo. This process ultimately leads to a powerful addiction of squamous PDA cells to continuous TP63 expression. Our study demonstrates the functional significance of squamous transdifferentiation in PDA and reveals TP63-based reprogramming as an experimental tool for investigating mechanisms and vulnerabilities linked to this aberrant cell fate transition.
| S-EPMC6296757 | biostudies-literature
Project description:Distinctive patterns of chromatin modification control gene expression and define cellular identity during development and cell differentiation. Polycomb repressive complex 2 (PRC2), the sole mammalian enzymatic complex capable of establishing gene-repressive high-degree methylation of histone H3 at lysine 27 (H3K27), plays crucial roles in regulation of normal and malignant hematopoiesis. Recently, increasing evidence has indicated that recurrent gain-of-function mutation and overexpression of EZH2, the catalytic subunit of PRC2, drive and promote malignant transformation such as B-cell lymphomagenesis, providing a rationale for PRC2 inhibition as a novel anticancer strategy. Here, we summarize the recently developed strategies for inhibition of PRC2, which include a series of highly specific, highly potent, small-molecule inhibitors of EZH2 and EZH1, an EZH2-related methyltransferase. PRC2 establishes functional crosstalk with numerous epigenetic machineries during dynamic regulation of gene transcription. Perturbation of such functional crosstalk caused by genetic events observed in various hematologic cancers, such as inactivation of SNF5 and somatic mutation of UTX, confers PRC2 dependence, thus rendering an increased sensitivity to PRC2 inhibition. We discuss our current understanding of EZH2 somatic mutations frequently found in B-cell lymphomas and recurrent mutations in various other epigenetic regulators as novel molecular predictors and determinants of PRC2 sensitivity. As recent advances have indicated a critical developmental or tumor-suppressive role for PRC2 and EZH2 in various tissue types, we discuss concerns over potentially toxic or even adverse effects associated with EZH2/1 inhibition in certain biological contexts or on cancer genetic background. Collectively, inhibition of PRC2 catalytic activity has emerged as a promising therapeutic intervention for the precise treatment of a range of genetically defined hematologic malignancies and can be potentially applied to a broader spectrum of human cancers that bear similar genetic and epigenetic characteristics.
| S-EPMC4706459 | biostudies-literature
Project description:Transcriptional enhancers can be in physical proximity with their target genes via chromatin looping. The enhancer at the beta-globin locus (LCR) contacts the fetal (HBG) and adult (HBB) type beta-globin genes during corresponding developmental stages. We previously demonstrated that forcing proximity between the LCR and HBG genes in cultured adult-stage erythroid cells can activate HBG transcription. Activation of HBG expression in erythroid cells is of benefit to patients with sickle cell disease. Here, using the beta-globin locus as a model we provide proof-of-concept at the organismal level that forced enhancer re-wiring might present a strategy to alter gene expression for therapeutic purposes. Hematopoietic stem and progenitor cells (HSPC) from mice bearing human beta-globin genes were transduced with lentiviral vectors expressing a synthetic transcription factor (ZF-Ldb1) that fosters LCR-HBG contacts. When engrafted into host animals, HSPCs gave rise to adult-type erythroid cells with elevated HBG expression. Vectors containing ZF-Ldb1 were optimized for activity in cultured human and rhesus erythroid cells. Upon transplantation into rhesus macaques, erythroid cells from HSPCs expressing ZF-Ldb1 displayed elevated HBG production. These findings in two animal models suggest that forced redirection of gene regulatory elements may be used to alter gene expression to treat disease.
2023-02-08 | GSE221182 | GEO
Project description:BACKGROUND:Enhancers are genomic cis-regulatory sequences that integrate spatiotemporal signals to control gene expression. Enhancer activity depends on the combination of bound transcription factors as well as-in some cases-the arrangement and spacing of binding sites for these factors. Here, we examine evolutionary changes to the sequence and structure of sparkling, a Notch/EGFR/Runx-regulated enhancer that activates the dPax2 gene in cone cells of the developing Drosophila eye. RESULTS:Despite functional and structural constraints on its sequence, sparkling has undergone major reorganization in its recent evolutionary history. Our data suggest that the relative strengths of the various regulatory inputs into sparkling change rapidly over evolutionary time, such that reduced input from some factors is compensated by increased input from different regulators. These gains and losses are at least partly responsible for the changes in enhancer structure that we observe. Furthermore, stereotypical spatial relationships between certain binding sites ("grammar elements") can be identified in all sparkling orthologs-although the sites themselves are often recently derived. We also find that low binding affinity for the Notch-regulated transcription factor Su(H), a conserved property of sparkling, is required to prevent ectopic responses to Notch in noncone cells. CONCLUSIONS:Rapid DNA sequence turnover does not imply either the absence of critical cis-regulatory information or the absence of structural rules. Our findings demonstrate that even a severely constrained cis-regulatory sequence can be significantly rewired over a short evolutionary timescale.
| S-EPMC3143281 | biostudies-literature
Project description:Mutations in VAV1, a multifunctional signaling protein essential for T lymphocytes, have been recently found in peripheral T cell lymphoma (PTCL) and other tumors. However, their pathobiological significance remains unsettled. Here, we show that these mutations belong to several subclasses according to the spectra of VAV1 signaling branches deregulated by them. These mutations target both known and new regulatory hotspots as well as transitional activation states of the protein. The most frequent VAV1 mutant subclass drives PTCL formation in mice by exacerbating normal VAV1- dependent signaling responses in follicular helper T cells.
2021-09-01 | GSE165006 | GEO
Project description:Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder with a unique, platelet-dependent, gain-of-function defect in fibrinolysis, without systemic fibrinolysis. The hallmark feature of QPD is a >100-fold overexpression of PLAU, specifically in megakaryocytes. This overexpression leads to a >100-fold increase in platelet stores of urokinase plasminogen activator (PLAU/uPA); subsequent plasmin-mediated degradation of diverse α-granule proteins; and platelet-dependent, accelerated fibrinolysis. The causative mutation is a 78-kb tandem duplication of PLAU. How this duplication causes megakaryocyte-specific PLAU overexpression is unknown. To investigate the mechanism that causes QPD, we used epigenomic profiling, comparative genomics, and chromatin conformation capture approaches to study PLAU regulation in cultured megakaryocytes from participants with QPD and unaffected controls. QPD duplication led to ectopic interactions between PLAU and a conserved megakaryocyte enhancer found within the same topologically associating domain (TAD). Our results support a unique disease mechanism whereby the reorganization of sub-TAD genome architecture results in a dramatic, cell-type-specific blood disorder phenotype.
| S-EPMC7735161 | biostudies-literature
Project description:SUMOylation is a post-translational modification of proteins that regulates these proteins’ localization, turnover or function. Aberrant SUMOylation is frequently found in cancers but its origin remains elusive. Using a genome-wide transposon mutagenesis screen in a MYC-driven B-cell lymphoma model, we identified the SUMO isopeptidase (or deconjugase) SENP6 as a tumor suppressor that links unrestricted SUMOylation to tumor development and progression. Notably, SENP6 is recurrently deleted in human lymphomas and SENP6 deficiency results in unrestricted SUMOylation. Mechanistically, SENP6 loss triggers release of DNA repair- and genome maintenance-associated protein complexes from chromatin thereby impairing DNA repair in response to DNA damages and ultimately promoting genomic instability. In line with this hypothesis, SENP6 deficiency drives synthetic lethality to PARP inhibition. Together, our results link SENP6 loss to defective genome maintenance and reveal the potential therapeutic application of PARP inhibitors in B-cell lymphoma.
2021-07-16 | GSE180052 | GEO
Project description:Squamous cell carcinomas (SCCs) are aggressive malignancies. Previous report demonstrated that master transcription factors (TFs) TP63 and SOX2 exhibited overlapping genomic occupancy in SCCs. However, functional consequence of their frequent co-localization at super-enhancers remains incompletely understood. Here, epigenomic profilings of different types of SCCs reveal that TP63 and SOX2 cooperatively and lineage-specifically regulate long non-coding RNA (lncRNA) CCAT1 expression, through activation of its super-enhancers and promoter. Silencing of CCAT1 substantially reduces cellular growth both in vitro and in vivo, phenotyping the effect of inhibiting either TP63 or SOX2. ChIRP analysis shows that CCAT1 forms a complex with TP63 and SOX2, which regulates EGFR expression by binding to the super-enhancers of EGFR, thereby activating both MEK/ERK1/2 and PI3K/AKT signaling pathways. These results together identify a SCC-specific DNA/RNA/protein complex which activates TP63/SOX2-CCAT1-EGFR cascade and promotes SCC tumorigenesis, advancing our understanding of transcription dysregulation in cancer biology mediated by master TFs and super-enhancers.
| S-EPMC6127298 | biostudies-literature