Reproducible specificity and efficiency of tamoxifen-mediated cre induction across ages
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1008727 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25748500_1.fastq.gz | Fastqsanger.gz | |||
| SRR25748500_2.fastq.gz | Fastqsanger.gz | |||
| SRR25748501_1.fastq.gz | Fastqsanger.gz | |||
| SRR25748501_2.fastq.gz | Fastqsanger.gz | |||
| SRR25748502_1.fastq.gz | Fastqsanger.gz |
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Project description:Temporally controlling cre recombinase through tamoxifen (TAM) induction has many advantages for biomedical research studies. While most projects use TAM induction of mice at early post-natal or adolescence (<2m.o.) ages, age-related neurodegeneration and aging studies can require experimental designs with cre induction in older mice (>12m.o.). While anecdotally reported to be problematic, there are no published comparisons of TAM mediated cre induction at young and older ages. Cx3cr1creERT2 mice for studying microglial were crossed to a floxed NuTRAP reporter to compare cre induction at young (3m.o.) and old (18m.o) ages. Specificity and efficiency microglial labeling was identical at 24m.o. in mice induced with TAM at 3m.o. or 18m.o. of age. Age-related microglial translatomic changes were nearly identical regardless of TAM induction age. While each cre and flox mouse line should be validated before use, these findings demonstrate that TAM induction of cres can be performed even into older mouse ages.
2023-12-14 | GSE241574 | GEO
Project description:Temporally controlling Cre recombination through tamoxifen (Tam) induction has many advantages for biomedical research. Most studies report early post-natal/juvenile (<2 m.o.) Tam induction, but age-related neurodegeneration and aging studies can require Cre induction in older mice (>12 m.o.). While anecdotally reported as problematic, there are no published comparisons of Tam-mediated Cre induction at early and late ages. Here, microglial-specific Cx3cr1creERT2 mice were crossed to a floxed NuTRAP reporter to compare Cre induction at early (3-6 m.o.) and late (20 m.o.) ages. Specificity and efficiency of microglial labeling at 21-22 m.o. were identical in mice induced with Tam at early and late ages. Age-related microglial translatomic changes were also similar regardless of Tam induction age. Each Cre and flox mouse line should be independently validated, however, these findings demonstrate that Tam-mediated Cre induction can be performed even into older mouse ages and should be generalizable to other inducible Cre models.
| S-EPMC10696116 | biostudies-literature
Project description:To directly examine the role of Foxe1 in the adult thyroid we generated a model of tamoxifen-inducible Cre mediated Foxe1 deletion in mice of C57BL/6J background (Foxe1flox/flox/Cre). Tamoxifen (0.05g/kg) was administered intraperitoneally to Foxe1flox/flox/Cre mice or Cre control mice aged 6-8 weeks, once daily for five consecutive days. Thyroids were harvested two weeks post-treatment, total RNA extracted and transcriptomic analysis performed using Clariom S Mouse arrays.
2022-10-01 | GSE193441 | GEO
Project description:The purpose of the study was to compare cortical transcript abundance between WT mice and Grin1 knockdown mice, and to determine whether transcript levels could be normalized in Grin1 Cre rescue mice (hemizygous for tamoxifen-inducible Rosa26 ERT2 Cre). All mice were treated with tamoxifen at 10 weeks of age until 12 weeks of age, and were euthanized at 15 weeks of age.
2020-05-02 | GSE98729 | GEO
Project description:Translational research on the Cre/loxP recombination system focuses on enhancing its specificity by modifying Cre/DNA interactions. Despite extensive efforts, the exact mechanisms governing how Cre distinguishes between substrates remains elusive. Cre recognizes 13 bp inverted repeats, initiating recombination in the 8 bp spacer region. While literature suggests that efficient recombination proceeds between lox sites with non-loxP spacer sequences when both lox sites have matching spacers, experimental validation for this assumption is lacking. To fill this gap, we investigated target site variations of identical pairs of the loxP 8 bp spacer region, screening 6,000 unique loxP-like sequences. Approximately 84% of these sites exhibited efficient recombination, affirming the flexibility of spacer sequences for catalysis. However, certain spacers negatively impacted recombination, emphasizing sequence dependence. Directed evolution of Cre on inefficiently recombined spacers not only yielded recombinases with enhanced activity but also mutants with reprogrammed selective activity. Mutations altering spacer specificity were identified, and molecular modelling and dynamics simulations elucidated the mechanism behind this specificity switch. These findings highlight the potential to fine-tune site-specific recombinases for spacer sequence specificity, offering a novel concept to enhance the applied properties of designer-recombinases for genome engineering applications.
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Project description:Tamoxifen, an antagonist to estrogen receptor (ER), is a first line drug used in breast cancer treatment. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying the resistance to tamoxifen, we established a tamoxifen-resistant cell line by treating the MCF7 breast cancer cell line with tamoxifen for over 6 months. We showed that this cell line exhibited resistance to tamoxifen both in vitro and in vivo. In order to quantify the phosphorylation alterations associated with tamoxifen resistance, we performed SILAC-based quantitative phosphoproteomic profiling on the resistant and vehicle-treated sensitive cell lines where we identified >5,600 unique phosphopeptides. We found phosphorylation levels of 1,529 peptides were increased (>2 fold) and 409 peptides were decreased (<0.5-fold) in tamoxifen resistant cells compared to tamoxifen sensitive cells. Gene set enrichment analysis revealed that focal adhesion pathway was the top enriched signaling pathway activated in tamoxifen resistant cells. We observed hyperphosphorylation of the focal adhesion kinases FAK1 and FAK2 in the tamoxifen resistant cells. Of note, FAK2 was not only hyperphosphorylated but also transcriptionally upregulated in tamoxifen resistant cells. Suppression of FAK2 by specific siRNA knockdown could sensitize the resistant cells to the treatment of tamoxifen. We further showed that inhibiting FAK activity using the small molecule inhibitor PF562271 repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 significantly associated with short metastasis-free survival of ER-positive breast cancer patients treated with tamoxifen-based hormone therapy. Our studies suggest that FAK2 is a great potential target for the development of therapy for the treatment of hormone refractory breast cancers.
2016-05-25 | PXD001812 | Pride
Project description:The primary objective is, first, the comparison of tamoxifen and anastrozole and, second, the comparison of zoledronate added to standard adjuvant therapy with controls according to disease-free survival (DFS) in premenopausal patients with non-metastatic breast cancer treated with tamoxifen or anastrozole. To assess whether zoledronate added to standard adjuvant therapy can decrease or even prevent bone loss in patients treated with hormonal blockade combined with an antiestrogen or aromatase inhibitor.
| 2026652 | ecrin-mdr-crc
Project description:We investigated the effects of tamoxifen, CreER recombination, and genetic manipulations to genes whose promoters are used to driving CreER expression on microglial gene expression across 4 different microglial inducible Cre lines.
2023-08-24 | GSE217062 | GEO
Project description:Interventions: No Group:No intervention
Primary outcome(s): CRE screening results
Study Design: Sequential
| 2699279 | ecrin-mdr-crc