A distal super enhancer mediates estrogen-dependent mouse uterine–specific gene transcription of Insulin-like growth factor 1 (Igf1)
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ABSTRACT:
PROVIDER: PRJNA518135 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8514660.fastq.gz | Fastqsanger.gz | |||
| SRR8514670.fastq.gz | Fastqsanger.gz | |||
| SRR8514680_1.fastq.gz | Fastqsanger.gz | |||
| SRR8514680_2.fastq.gz | Fastqsanger.gz | |||
| SRR8514690_1.fastq.gz | Fastqsanger.gz |
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Project description: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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Project description:Estrogen (E2) signaling through its nuclear receptor, estrogen receptor α (ERα) increases insulin-like growth factor 1 (IGF1) in the rodent uterus, which then initiates further signals via the IGF1 receptor (IGF1R). Directly administering IGF1 results in similar biological and transcriptional uterine responses. Our studies using global ERα-null mice demonstrated a loss of uterine biological responses of the uterus to E2 or IGF1 treatment, while maintaining transcriptional responses to IGF1. To address this discrepancy in the need for uterine ERα in mediating the IGF1 transcriptional vs. growth responses, we assessed the IGF1 transcriptional responses in PgrCre+Esr1f/f (called ERαUtcKO) mice, which selectively lack ERα in progesterone receptor (PGR) expressing cells, including all uterine cells, while maintaining ERα expression in other tissues and cells that do not express Pgr. Additionally, we profiled IGF1-induced ERα binding sites in uterine chromatin using ChIP-seq. Herein, we explore the transcriptional and molecular signaling that underlies our findings to refine our understanding of uterine IGF1 signaling and identify ERα-mediated and ERα-independent uterine transcriptional responses. Defining these mechanisms in vivo in whole tissue and animal contexts provides details of nuclear receptor mediated mechanisms that impact biological systems and have potential applicability to reproductive processes of humans, livestock and wildlife.
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Project description:Estrogen (E2) signaling through its nuclear receptor, estrogen receptor α (ERα) increases insulin-like growth factor 1 (IGF1) in the rodent uterus, which then initiates further signals via the IGF1 receptor (IGF1R). Directly administering IGF1 results in similar biological and transcriptional uterine responses. Our studies using global ERα-null mice demonstrated a loss of uterine biological responses of the uterus to E2 or IGF1 treatment, while maintaining transcriptional responses to IGF1. To address this discrepancy in the need for uterine ERα in mediating the IGF1 transcriptional vs. growth responses, we assessed the IGF1 transcriptional responses in PgrCre+Esr1f/f (called ERαUtcKO) mice, which selectively lack ERα in progesterone receptor (PGR) expressing cells, including all uterine cells, while maintaining ERα expression in other tissues and cells that do not express Pgr. Additionally, we profiled IGF1-induced ERα binding sites in uterine chromatin using ChIP-seq. Herein, we explore the transcriptional and molecular signaling that underlies our findings to refine our understanding of uterine IGF1 signaling and identify ERα-mediated and ERα-independent uterine transcriptional responses. Defining these mechanisms in vivo in whole tissue and animal contexts provides details of nuclear receptor mediated mechanisms that impact biological systems and have potential applicability to reproductive processes of humans, livestock and wildlife.
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Project description: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 suggested 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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