Coordinate regulation of ELF5 and EHF at the chr11p13 modifier region
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ABSTRACT:
PROVIDER: PRJNA542631 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9047570.fastq.gz | Fastqsanger.gz | |||
| SRR9047571.fastq.gz | Fastqsanger.gz | |||
| SRR9047572.fastq.gz | Fastqsanger.gz | |||
| SRR9047567.fastq.gz | Fastqsanger.gz | |||
| SRR9047568.fastq.gz | Fastqsanger.gz |
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Project description:E74-like factor 5 (ELF5) and ETS-homologous factor (EHF) are epithelial selective ETS family transcription factors (TFs) encoded by genes at chr11p13, a region associated with cystic fibrosis (CF) lung disease severity. EHF controls many key processes in lung epithelial function so its regulatory mechanisms are important. Using CRISPR/Cas9 technology, we removed three cis-regulatory elements (CREs) from the chr11p13 region in airway epithelial cells. Deletion of two enhancers and one CRE within a stretch enhancer at the EHF locus caused subtle changes in chromatin architecture, and though EHF expression did not change, ELF5 abundance increased. ELF5 is normally very low in airway cells so we next examined cell types that express more ELF5 (LNCaP and T47D). ATAC-seq experiments in these lines revealed novel peaks of open chromatin (potential CREs) at the 5’ end of chr11p13 that were associated with an expressed ELF5 gene. Furthermore, 4C-seq assays identified direct interactions between the active ELF5 promoter and sites within the EHF locus, suggesting coordinate regulation between these TFs. ChIP-seq for ELF5 in T47D cells revealed ELF5 occupancy within EHF introns 1 and 6 and siRNA-mediated depletion of ELF5 repressed EHF expression. These results define a new role for ELF5 in lung epithelial biology.
2021-05-11 | GSE131084 | GEO
Project description:E74-like factor 5 (ELF5) and ETS-homologous factor (EHF) are epithelial selective ETS family transcription factors (TFs) encoded by genes at chr11p13, a region associated with cystic fibrosis (CF) lung disease severity. EHF controls many key processes in lung epithelial function so its regulatory mechanisms are important. Using CRISPR/Cas9 technology, we removed three key cis-regulatory elements (CREs) from the chr11p13 region and also activated multiple open chromatin sites with CRISPRa in airway epithelial cells. Deletion of the CREs caused subtle changes in chromatin architecture and site-specific increases in EHF and ELF5. CRISPRa had most effect on ELF5 transcription. ELF5 levels are low in airway cells but higher in LNCaP (prostate) and T47D (breast) cancer cells. ATAC-seq in these lines revealed novel peaks of open chromatin at the 5' end of chr11p13 associated with an expressed ELF5 gene. Furthermore, 4C-seq assays identified direct interactions between the active ELF5 promoter and sites within the EHF locus, suggesting coordinate regulation between these TFs. ChIP-seq for ELF5 in T47D cells revealed ELF5 occupancy within EHF introns 1 and 6, and siRNA-mediated depletion of ELF5 enhanced EHF expression. These results define a new role for ELF5 in lung epithelial biology.
| S-EPMC6815777 | biostudies-literature
Project description:Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), but are not good predictors of lung disease phenotype. Genome-wide association studies (GWAS) previously identified additional regions of the genome associated with CF disease severity. One of these, at chromosome 11p13, is an intergenic region between Ets homologous factor (EHF) and Apaf-1 interacting protein (APIP). Our goal was to determine the functional significance of this region, which is predicted to be regulatory, since it lacks annotated genes. To identify cis-regulatory elements within the chr11p13 region in lung epithelial cells, we first mapped open chromatin, using DNase I digestion and deep sequencing (DNase-seq). Next, histone modifications associated with active chromatin, H3K4me1 and H3K27ac, were revealed by chromatin immunoprecipitation. Predicted enhancer elements were assayed in bronchial epithelial cells using luciferase reporter genes. Two elements showed strong enhancer activity for the promoters of both EHF and the 5’ adjacent gene E47 like ETS transcription factor 5 (ELF5). No enhancers of the APIP promoter were found. Next, to determine direct physical interactions between cis-regulatory elements and gene promoters within 11p13 we used circular chromosome conformation capture (4C-seq). 4C-seq confirmed the enhancer-promoter associations, identified additional interacting elements and defined the boundaries of the topologically associated domains (TADs) at 11p13, which are enriched for CTCF. No strong interactions were observed with the APIP promoter, which lies outside of the main TAD encompassing the GWAS signal. These results focus attention on the role of EHF in modifying CF lung disease severity.
2017-05-22 | GSE94726 | GEO
Project description:Elf5, an epithelial-specific Ets transcription factor, plays a crucial role in the pregnancy-associated development of the mammary gland. However, the molecular mechanisms employed by Elf5 to exert its effects on the mammary gland are largely unknown. Transcript profiling was used to investigate the transcriptional changes that occur as a result of Elf5 haploinsufficiency. We show that the development of the Elf5+/- gland is delayed at a transcriptional and morphological level, due to the delayed increase in Elf5 protein in these glands. We also identify a number of potential Elf5 target genes, including Mucin 4, whose expression, is directly regulated by the binding of Elf5 to an Ets-binding site within its promoter. We identify novel transcriptional targets of Elf5 and show that Muc4 is a direct target of Elf5, further elucidating the mechanisms through which Elf5 regulates proliferation and differentiation in the mammary gland.
2010-09-27 | GSE23373 | GEO
Project description:Elf5 induced transcriptional changes in MDA-MB-231 origin, control (mut Elf5) vs WT ELF5
2012-09-20 | GSE32144 | GEO
Project description:The data generated here shows increased interferon gamma gene signatures in Elf5- tumor cells in C3-T; Elf5-GFP reporter mice tumors
2020-02-15 | GSE122180 | GEO
Project description:Elf5 induced transcriptional changes in MDA-MB-231 origin, control (mut Elf5) vs WT ELF5 Two-condition experiment, control (mut-Elf5) vs WT-Elf5. Each has 3 biological repeats.
2012-09-20 | E-GEOD-32144 | biostudies-arrayexpress
Project description:Elf5, an epithelial-specific Ets transcription factor, plays a crucial role in the pregnancy-associated development of the mammary gland. However, the molecular mechanisms employed by Elf5 to exert its effects on the mammary gland are largely unknown. Transcript profiling was used to investigate the transcriptional changes that occur as a result of Elf5 haploinsufficiency. We show that the development of the Elf5+/- gland is delayed at a transcriptional and morphological level, due to the delayed increase in Elf5 protein in these glands. We also identify a number of potential Elf5 target genes, including Mucin 4, whose expression, is directly regulated by the binding of Elf5 to an Ets-binding site within its promoter. We identify novel transcriptional targets of Elf5 and show that Muc4 is a direct target of Elf5, further elucidating the mechanisms through which Elf5 regulates proliferation and differentiation in the mammary gland. We used Compugen 22,000 oligo arrays from the Adelaide Microarray Centre to determine the transcriptional effects of the loss of one Elf5 allele on mammary gland development. We examined Elf5+/+ and Elf5+/- mammary glands over 5 timepoints of mammary gland development in three experiments. Each experiment used the pooled RNA of 2 mice, resulting in a total of 6 individual mice at each timepoint per genotype. Replica 1 of each condition was labelled with the one fluorophore, and replicas 2 and 3 with the other fluorophore. A common reference design was used for this experiment. RNA extracted from eight pooled 17.5dpc C57BL/6 mouse embryos was used as the reference sample. In total, we performed 30 micraoarray hybridisations, examining 5 timepoints of mammary gland development in 2 genotypes (Elf5+/+ and Elf5+/-). This experiment was repeated with a total of three biological replicates.
2010-09-26 | E-GEOD-23373 | biostudies-arrayexpress
Project description:we found that EHF allowed colon tumor cells to escape p53-mediated apoptosis.We performed microarray analysis to find the target genes of EHF. A colorecal cancer cell line HCT116 was transfected with an siRNA targeting EHF or negative control.
2010-07-29 | E-GEOD-22265 | biostudies-arrayexpress