Six1 and Six2 of the sine oculis homeobox subfamily are not functionally interchangeable in mouse nephron formation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA781611 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16975729.fastq.gz | Fastqsanger.gz | |||
| SRR16975730.fastq.gz | Fastqsanger.gz | |||
| SRR16975731.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 3 of 3 |
Similar Datasets
Project description:The vertebrate Six1 and Six2 arose by gene duplication from the Drosophila so (sine oculis) and have since diverged in their developmental expression patterns. Both genes are expressed in nephron progenitors of human fetal kidneys, and mutations in SIX1 or SIX2 cause branchio-oto-renal or renal hypodysplasia respectively. Since ~80% of SIX1 target sites are shared by SIX2, it is speculated that SIX1 and SIX2 may be functionally interchangeable by targeting common downstream genes. In contrast, in mouse kidneys, the expression of Six1 and Six2 only transiently overlaps in the metanephric mesenchyme before the onset of ureteric branching, and only Six2 expression is maintained in the nephron progenitors throughout development. This non-overlapping expression between Six1 and Six2 in mouse nephron progenitors promoted us to examine if Six1 can replace Six2. Surprisingly, forced expression of Six1 failed to rescue Six2-deficient kidney hypoplasia. We found that Six1 mediated Eya1 nuclear translocation and inhibited premature epithelialization of the progenitors but failed to rescue the proliferation defects and cell death caused by Six2-knockout. Genome-wide binding analyses showed that Six1 only bound to a small subset of Six2 target sites, but many Six2-bound loci that are crucial to the renewal and differentiation of nephron progenitors lacked Six1 occupancy. Thus, these data indicate that Six1 cannot substitute Six2 to drive nephrogenesis in mouse kidneys, demonstrating that these two transcription factors have not maintained equivalent biochemical properties since their divergence early in vertebrate evolution.
2022-01-27 | GSE189131 | GEO
Project description:Nephron endowment is determined by the self-renewal and induction of a nephron progenitor pool established at the onset of kidney development. In the mouse, the related transcriptional regulators Six1 and Six2 play non-overlapping roles in nephron progenitors. Transient Six1 activity prefigures, and is essential for, active nephrogenesis. In contrast, Six2 maintains later progenitor self-renewal from the onset of nephrogenesis. We compared Six2’s regulatory actions in mouse and human nephron progenitors by chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq). Surprisingly, SIX1 was identified as a SIX2 target unique to the human nephron progenitors. Further, RNA-seq and immunostaining revealed overlapping SIX1 and SIX2 progenitor activity in the 16 week human fetal kidney. Human SIX1 ChIP-seq revealed a similar set of targets to SIX2, and predicted both factors bind DNA through an identical recognition site. In contrast to the mouse where Six2 binds its own enhancers but doesn’t interact with DNA around Six1, both human SIX1 and SIX2 bind homologous SIX2 enhancers and putative enhancers positioned around SIX1. Transgenic analysis of a putative human SIX1 enhancer in the mouse revealed a transient, mouse-like, pre-nephrogenic, Six1 regulatory pattern. Together, these data demonstrate a divergence in SIX-factor regulation between mouse and human nephron progenitors. In the human, an auto/cross-regulatory loop drives continued SIX1 and SIX2 expression during active nephrogenesis. In contrast, the mouse establishes only an auto-regulatory Six2 loop. It is tempting to speculate that differential SIX-factor regulation may contribute to species differences in the duration of progenitor programs and nephron output.
2016-01-31 | GSE73865 | GEO
Project description:The vertebrate Six1 and Six2 arose by gene duplication from the Drosophila sine oculis and have since diverged in their developmental expression patterns. Both genes are expressed in nephron progenitors of human fetal kidneys, and mutations in SIX1 or SIX2 cause branchio-oto-renal syndrome or renal hypodysplasia respectively. Since ∼80% of SIX1 target sites are shared by SIX2, it is speculated that SIX1 and SIX2 may be functionally interchangeable by targeting common downstream genes. In contrast, in mouse kidneys, Six1 expression in the metanephric mesenchyme lineage overlaps with Six2 only transiently, while Six2 expression is maintained in the nephron progenitors throughout development. This non-overlapping expression between Six1 and Six2 in mouse nephron progenitors promoted us to examine if Six1 can replace Six2. Surprisingly, forced expression of Six1 failed to rescue Six2-deficient kidney phenotype. We found that Six1 mediated Eya1 nuclear translocation and inhibited premature epithelialization of the progenitors but failed to rescue the proliferation defects and cell death caused by Six2-knockout. Genome-wide binding analyses showed that Six1 selectively occupied a small subset of Six2 target sites, but many Six2-bound loci crucial to the renewal and differentiation of nephron progenitors lacked Six1 occupancy. Altogether, these data indicate that Six1 cannot substitute Six2 to drive nephrogenesis in mouse kidneys, thus demonstrating that the difference in physiological roles of Six1 and Six2 in kidney development stems from both transcriptional regulations of the genes and divergent biochemical properties of the proteins.
| S-EPMC8844495 | biostudies-literature
Project description:SIX2 is expressed by the self-renewing nephron progenitors in the human fetal kidney. We have also discovered that SIX1 is expressed in nephron progenitor population of the human fetal kidney, which is in contrast to the mouse. We performed ChIP-seq of SIX1 and SIX2 in order to identify the target genes of each factor and compare the role that each factor plays in transcriptional regulation of the nephron progenitors. We additionally performed ChIP-seq for p300 and H3K27ac in order to identify active loci and complement the transcription factor data.
2016-05-23 | GSE75948 | GEO
Project description:Identification of the gene targets of the SIX transcription factors in myogenic stem cells and in whole back muscles during murine fetal development Pax7 expression marks stem cells in developing skeletal muscles and adult satellite cells during homeostasis and muscle regeneration. The genetic determinants that control the entrance into the myogenic program and the appearance of PAX7+ cells during embryogenesis are poorly understood. SIX homeoproteins are encoded by the Sine oculis homeobox related Six1-Six6 genes in vertebrates. Six1, Six2, Six4 and Six5 are expressed in the muscle lineage. Here we tested the hypothesis that Six1 and Six4 could participate in the genesis of myogenic stem cells. We show that fewer PAX7+ cells occupy a satellite cell position between the myofiber and its associated basal lamina in Six1 and Six4 (s1s4KO) at E18. However, PAX7+ cells are detected in remaining muscle masses present in the epaxial region of the double mutant embryos and are able to divide and contribute to muscle growth. To further characterize the properties of s1s4KO PAX7+ cells, we analyzed their transcriptome and tested their properties after transplantation in adult regenerating tibialis anterior (TA) muscle. Mutant stem cells form hypotrophic myofibers that are not innervated but retain the ability to self-renew.
2020-10-07 | GSE159079 | GEO
Project description:Female mice exposed neonatally to the synthetic estrogen diethylstilbestrol (DES) develop metaplastic and neoplastic uterine changes as adults. Abnormal endometrial glands express the oncofetal protein sine oculis homeobox 1 (SIX1) and contain cells with basal (cytokeratin [CK]14+/18-) and poorly differentiated features (CK14+/18+), strongly associating SIX1 with aberrant differentiation and cancer. Here we tested whether SIX1 expression is necessary for abnormal endometrial differentiation and DES-induced carcinogenesis by using Pgr-cre to generate conditional knockout mice lacking uterine Six1 (Six1d/d). Interestingly, corn oil (CO) vehicle treated Six1d/d mice develop focal endometrial glandular dysplasia and features of carcinoma in situ as compared with CO wildtype Six1 (Six1+/+) mice. Furthermore, Six1d/d mice neonatally exposed to DES had a 42% higher incidence of endometrial cancer relative to DES Six1+/+ mice. While DES Six1d/d mice had >10-fold fewer CK14+/18- basal cells within the uterine horns as compared with DES Six1+/+ mice, the appearance of CK14+/18+ cells remained a feature of neoplastic lesions. We have employed whole genome microarray expression profiling as a discovery platform to identify genes associated with the phenotypic changes described above. Expression of three genes (Ihh, Krt14, and Trp63) were quantified by real-time PCR, confirming low variability between samples as well as the predicted response pattern.
2019-10-15 | GSE138501 | GEO
Project description:Purpose: The tumor microenvironment (TME), such as non-immune-infiltrated “cold” tumors, has been associated with immune suppression. However, the complex mechanisms regulating tumor immunogenicity have not been clearly elucidated. In this study, we investigated whether Transcription factor sine oculis homeobox 1 (SIX1) expression in the cancer cells regulated anti-tumor immunity by reshaping TME. Methods: The expression of SIX1 in human tumor tissues was analyzed based on TCGA data. Six1 knockout murine cell lines were generated to analyze the SIX1-associated tumor progression and anti-tumor immune response in tumor xenograft models. Immune cells and cytokines in TME were quantified by immunofluorescence, flow cytometry, quantitative reverse transcription-PCR, and ELISPOT assay. SIX1-associated differentially expressed genes were investigated in cancer cells and tissues with RNA-Seq. At the end, Correlation of SIX1 with TGFBR2 expression was assessed by Western blot and Dual-luciferase reporter assay. Results:SIX1 was highly upregulated in human tumor tissues, while rarely expressed in matched normal tissues. Deletion of the Six1 in cancer cells inhibited tumor growth, depending on adaptive immunity. Moreover, Six1 deficiency significantly enhanced CD8+ T cells infiltration, leading to eradication of poorly immunogenic tumors and maintaining a long-term protection from tumor re-challenge. Mechanistically, SIX1 as a transcription factor upregulated TGFBR2 expression, which induced collagen genes expression via the Smad2/3 phosphorylation, increased collagens deposition in TME and hampered CD8+ T cells infiltration. Conclusions: Six1 deletion in cancer cells improved tumor immunogenicity, leading to tumor destruction by enhancing anti-tumor immune responses. Our observations uncovered a crucial role of SIX1 on remodulating tumor immunogenicity and demonstrated a proof of concept for targeting SIX1 in cancer immunotherapy.
2021-09-09 | GSE183580 | GEO
Project description:The non-canonical NF-κB signaling cascade is essential for lymphoid organogenesis, B-cell maturation, osteoclast differentiation, and inflammation in mammals, whereas dysfunction of this system is associated with human diseases, including immunological disorders and cancer. While controlled expression of NF-κB Inducing Kinase (NIK) is the rate-limiting step in non-canonical NF-κB activation, mechanisms of inhibition remain largely unknown. Here, we report the identification of the sine oculis homeobox homolog family transcription factors SIX1 and SIX2 as essential inhibitory components of the non-canonical NF-κB signaling pathway. The developmentally silenced SIX-proteins are reactivated in differentiated macrophages by NIK-mediated suppression of the ubiquitin proteasome pathway. Consequently, SIX1 and SIX2 target a subset of inflammatory gene promoters and directly inhibit RelA and RelB trans-activation function in a negative feedback circuit. In support of a physiologically pivotal role for SIX-proteins in host immunity, human SIX1 transgene suppressed inflammation and promoted the recovery of mice from endotoxic shock. In addition, SIX1 and SIX2 protected RAS/p53-driven lung adenocarcinoma cells from inflammatory cell death induced by SMAC-mimetic chemotherapeutic agents, small-molecule activators of the non-canonical NF-κB pathway. Collectively, our study reveals a NIK-SIX signaling axis that fine-tunes inflammatory gene expression programs under both physiological and pathological conditions.
2019-03-22 | GSE126535 | GEO
Project description:Six1 is a critical transcription factor for specifying cell fates in multiple organs and shares common DNA-binding sites with Six2/4/5. However, its molecular function in defining the specificity of Six1-DNA interactions and in instructing cell fates is poorly understood. We performed Six1 ChIP-seq analyses in E10.5 mouse embryos and E13.5 cochleae to map genome-wide CRMs through which Six1 and its interacting TFs function in a combinatorial fashion to control the network of gene regulation necessary for proper development. Genome-wide characterization has identified a robust set of Six1 targets in embryos and auditory sensory epithelium, including genes participating in Wnt/Notch/Shh/Fgf signaling pathways and regulators critical for auditory hair cell formation. Our data provide insights into how Six1 acts in multiple regulatory networks operating in distinct cell types at different stages.
2020-04-17 | GSE108130 | GEO
Project description:Genome-wide map of SIX2 and SIX1 binding in human embryonic kidney cortex
| PRJNA298244 | ENA