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| Status |
Public on May 08, 2019 |
| Title |
A distal super enhancer mediates estrogen-dependent mouse uterine–specific gene transcription of Insulin-like growth factor 1 (Igf1) |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Other
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| Summary |
Insulin-like growth factor 1 (IGF1) is primarily synthesized in and secreted from the liver; however, estrogen (E2), through E2 receptor α (ERα), increases uterine Igf1 mRNA levels. Previous ChIP-Seq analyses of the murine uterus have revealed a potential enhancer region distal from the Igf1 transcription start site (TSS) with multiple E2-dependent ERα-binding regions. Here, we show E2-dependent super enhancer–associated characteristics and suggest contact between the distal enhancer and the Igf1 TSS. We hypothesized that this distal super-enhancer region controls E2-responsive induction of uterine Igf1 transcripts. We deleted 430 bp, encompassing one of the ERα-binding sites, thereby disrupting interactions of the enhancer with gene-regulatory factors. As a result, E2-mediated induction of mouse uterine Igf1 mRNA is completely eliminated, whereas hepatic Igf1 expression remains unaffected. This highlights the central role of a distal enhancer in the assembly of the factors necessary for E2-dependent interaction with the Igf1 TSS and induction of uterus-specific Igf1 transcription. Of note, loss of the enhancer did not affect fertility or uterine growth responses. Deletion of uterine Igf1 in a PgrCre;Igf1f/f model decreased female fertility, but did not impact the E2-induced uterine growth response. Moreover, E2-dependent activation of uterine IGF1 signaling was not impaired by disrupting the distal enhancer or by deleting the coding transcript. This indicated a role for systemic IGF1, suggested that other growth mediators drive uterine response to E2, and that uterine-derived IGF1 is essential for reproductive success. Our findings elucidate the role of a super enhancer in Igf1 regulation and uterine growth.
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| Overall design |
ERa or Histone 3 modifications ChIP seq of pre-pubertal (21 days old) or ovariectomized adult uterine tissue treated for one hour with saline vehicle (V) or estradiol (E2); ERa ChIP seq of ovariectomized adult uterine tissue treated for 6, 8 or 12 hours with estradiol (E2); SMC1a ChIP seq or HiC of ovariectomized adult uterine tissue treated for one hour with saline vehicle (V) or estradiol (E2) or progesterone (P4); RNA seq of ovariectomized adult uterine tissue treated for two hours with saline vehicle (S) or for two, six or 24 hours with estradiol (E2)
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| Contributor(s) |
Hewitt SC, Lierz SL, Garcia M, Hamilton KJ, Gruzdev A, Grimm SA, Lydon JP, DeMayo FJ, Korach KS |
| Citation(s) |
31073032 |
| Submission date |
Jan 31, 2019 |
| Last update date |
Jul 15, 2019 |
| Contact name |
Sylvia C Hewitt |
| E-mail(s) |
sylvia.hewitt@nih.gov, curtiss@niehs.nih.gov
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| Phone |
9842874317
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| Organization name |
NIEHS
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| Department |
RDBL
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| Lab |
Pregnancy & Female Reproduction
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| Street address |
111 Alexander Dr
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| City |
Research Triangle Park |
| State/province |
NC |
| ZIP/Postal code |
27709 |
| Country |
USA |
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| Platforms (5)
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| GPL9250 |
Illumina Genome Analyzer II (Mus musculus) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (38)
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| Relations |
| BioProject |
PRJNA518135 |
| SRA |
SRP183089 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE125972_RAW.tar |
30.0 Gb |
(http)(custom) |
TAR (of BIGWIG, HIC, TXT) |
| GSE125972_counts_per_gene.RNAseq.txt.gz |
858.1 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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