Genome-wide analysis of enhancer-related DNA methylation in myelofibrosis reveals ZFP36L1 as a potential tumor suppressor gene
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PROVIDER: PRJNA484946 | ENA |
REPOSITORIES: ENA
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Project description:In this study we have interrogated the DNA methylome of myelofibrosis (MF) patients using high-density DNA methylation arrays. Interestingly, primary and secondary MF showed no differences in DNA methylation profiles, whereas a total of 35,238 differentially methylated CpGs (DMC) corresponding to 10,904 genes were detected between MF patients and healthy controls. Remarkably, the majority of DMCs were located outside gene promoter regions and significantly associated with enhancer regions. This enhancer aberrant hypermethylation showed a negative correlation with the expression of 27 genes in the MF patient cohort. Of these, we focused on ZFP36L1 gene and validated its decreased expression and enhancer DNA hypermethylation in an independent cohort of MF patients and myeloid cell-lines. In vitro reporter assay and 5’ azacitidine treatment confirmed the functional relevance of the intronic-enhancer hypermethylation of ZFP36L1. Finally, in vitro rescue of ZFP36L1 expression had an impact in cell proliferation and induced apoptosis in SET-2 cell line indicating a possible role of ZFP36L1 as a tumor suppressor gene in MF. Overall, we describe for the first time the MF DNA methylation profile, showing enhancer DNA hypermethylation as a potential functional mechanism playing an important role in silencing of a tumor suppressor gene in this disease.
2019-08-27 | GSE118241 | GEO
Project description:In this study we interrogated the DNA methylome of myelofibrosis patients using high-density DNA methylation arrays. We detected 35,215 differentially methylated CpG, corresponding to 10,253 genes, between myelofibrosis patients and healthy controls. These changes were present both in primary and secondary myelofibrosis, which showed no differences between them. Remarkably, most differentially methylated CpG were located outside gene promoter regions and showed significant association with enhancer regions. This aberrant enhancer hypermethylation was negatively correlated with the expression of 27 genes in the myelofibrosis cohort. Of these, we focused on the ZFP36L1 gene and validated its decreased expression and enhancer DNA hypermethylation in an independent cohort of patients and myeloid cell-lines. In vitro reporter assay and 5'-azacitidine treatment confirmed the functional relevance of hyper-methylation of ZFP36L1 enhancer. Furthermore, in vitro rescue of ZFP36L1 expression had an impact on cell proliferation and induced apoptosis in SET-2 cell line indicating a possible role of ZFP36L1 as a tumor suppressor gene in myelofibrosis. Collectively, we describe the DNA methylation profile of myelofibrosis, identifying extensive changes in enhancer elements and revealing ZFP36L1 as a novel candidate tumor suppressor gene.
| S-EPMC6669145 | biostudies-literature
Project description:ZFP36L1 is a tandem zinc-finger RNA-binding protein that recognizes conserved Adenylate-Uridylate-rich Elements (AREs) located in 3' untranslated regions (UTRs) to mediate RNA decay. We hypothesized that ZFP36L1 is a negative regulator of a post-transcriptional hub involved in the RNA half-life regulation of cancer-related transcripts. Forced expression of ZFP36L1 in cancer cells markedly reduced cell proliferation in vitro and in vivo; whereas silencing of ZFP36L1 enhanced tumor cell growth. To identify direct downstream targets of ZFP36L1, systematic screening using RNA pull-down of wildtype and mutant ZFP36L1 as well as whole transcriptome sequencing of bladder cancer cells ± tet-on ZFP36L1, was performed. A network of 1,410 genes was identified as potential direct targets of ZFP36L1, including HIF1A, CCND1, and E2F1. ZFP36L1 specifically bound to the 3' UTRs of these targets for RNA degradation, thus suppressing their expression. Collectively, our findings reveal an indispensable role of ZFP36L1 as a post-transcriptional safeguard against aberrant hypoxic signaling and abnormal cell cycle progression.
2020-10-02 | GSE136180 | GEO
Project description:High-throughput sequencing analysis of transcriptome from LPS-activated B cells from Lymph node of Zfp36l1(fl/fl) and Zfp36l1(fl/fl) x Cd79a(Cre/+) mice
2020-11-20 | GSE146073 | GEO
Project description:Roles of Zfp36l1 and Zfp36l1 in retinal development
| PRJNA666343 | ENA
Project description:We report our study of the function of two members of the TTP (tristetraprolin) mRNA binding protein family, Zfp36l1 and Zfp36l2, in retinal development. We found that Zfp36l1 and Zfp36l2 were expressed in retinal progenitor cells during development and Müller glial cells and photoreceptors in the mature retina. Our analysis of the mutant retinas showed that, whereas the single knockout retinas appeared largely normal, the double knockout (DKO) retina manifested decreased RPC proliferation and increased differentiation of multiple retinal cell types. RNA-seq analysis not only confirmed the imbalance of proliferation and differentiation in the DKO retina but also revealed Zfp36l1 and Zfp36l2 interact with multiple signaling pathways including the sonic hedgehog pathway and the Notch pathway, to regulate this process.
2021-09-01 | GSE158718 | GEO
Project description:ZFP36L1 is a tandem zinc-finger RNA-binding protein that recognizes conserved Adenylate-Uridylate-rich Elements (AREs) located in 3' untranslated regions (UTRs) to mediate RNA decay. We hypothesized that ZFP36L1 is a negative regulator of a post-transcriptional hub involved in the RNA half-life regulation of cancer-related transcripts. Forced expression of ZFP36L1 in cancer cells markedly reduced cell proliferation in vitro and in vivo; whereas silencing of ZFP36L1 enhanced tumor cell growth. To identify direct downstream targets of ZFP36L1, systematic screening using RNA pull-down of wildtype and mutant ZFP36L1 as well as whole transcriptome sequencing of bladder cancer cells ± tet-on ZFP36L1, was performed. A network of 1,410 genes was identified as potential direct targets of ZFP36L1, including HIF1A, CCND1, and E2F1. ZFP36L1 specifically bound to the 3' UTRs of these targets for RNA degradation, thus suppressing their expression. Collectively, our findings reveal an indispensable role of ZFP36L1 as a post-transcriptional safeguard against aberrant hypoxic signaling and abnormal cell cycle progression.
2020-10-02 | GSE136181 | GEO
Project description:We expressed either a wt or a phosphomutant version of ZFP36L1 in IMR90 ER:RAS cells. 7 days upon RAS induction (when the cells reach a fully senescent phenotype) we collected the RNA. ZFP36L1 is a RNA binding protein that binds to AU-rich elements in the 3âUTR of mRNAs and triggers their degradation. Our previous experiments showed that the activity of ZFP36L1 was key in the regulation of the senescent phenotype.By performing RNAseq we have uncovered the effect of expressing a constitutively active mutant of ZFP36L1 within the senescent transcriptome. 4 samples examined: Non-senescent cells (EV - 4OHT), Senescent cells (EV + 4OHT), Senescent cells expressing ZFP36L1wt and Senescent cells expressing ZFP36L1mut
2015-07-07 | E-GEOD-61130 | biostudies-arrayexpress
Project description:Purpose: We aimed to identify the targets of the RNA binding protein ZFP36L1 in thymoctes. Methods: Total naïve thymocytes from control or DCKO mice were treated with UV light to crosslink RNA and proteins, then RNA-protein complexes were pulled down with anti-ZFP36L1. RNA was extracted and used to make cDNS libraries that were then sequenced by MiSeq 150bp single-end read (Sample 1) and HiSeq2500 RapidRun 50bp single-end read (sample 2, 3). Results: Sample demultiplexing was performed by identification of the 3 known bases of the 7 bases barcode introduced in the 5â end of the read by the RCLIP primer. The remaining four random bases were used to remove PCR duplicate reads. Reads were trimmed to remove any adaptor sequence and barcodes before mapping reads to genome GRCm38 using Bowtie. After read mapping, the single-nucleotide at position -1 was annotated as unique ZFP36L1 crosslink site. Identification of highly significant ZFP36L1 binding sites was performed using iCount to assign a FDR to each crosslink site. Conclusions: We identified ZFP36L1 binding sites in 8675 thymocyte mRNAs. Individual nucleotide resolution cross linking immunoprecipitation (iCLIP) of ZFP36L1-bound RNAs in total naive thymocytes from C57BL/6 mice.
2016-09-05 | E-GEOD-79178 | biostudies-arrayexpress