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Series GSE125972 Query DataSets for GSE125972
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
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.
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)
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
Phone 9842874317
Organization name NIEHS
Department RDBL
Lab Pregnancy & Female Reproduction
Street address 111 Alexander Dr
City Research Triangle Park
State/province NC
ZIP/Postal code 27709
Country USA
Platforms (5)
GPL9250 Illumina Genome Analyzer II (Mus musculus)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
Samples (38)
GSM3587110 adult_E2-6h.ERa_ChIPseq
GSM3587111 adult_E2-8h.ERa_ChIPseq
GSM3587112 adult_E2-12h.ERa_ChIPseq
BioProject PRJNA518135
SRA SRP183089

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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
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Raw data are available in SRA
Processed data provided as supplementary file

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