A Sall1-NuRD interaction regulates multipotent nephron progenitors and is required for loop of Henle formation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE102583 | GEO | 2017/08/12
SECONDARY ACCESSION(S): PRJNA398077
REPOSITORIES: GEO
Similar Datasets
Project description:The formation of the proper number of nephrons requires a tightly regulated balance between renal progenitor cell self-renewal and differentiation. The molecular pathways that regulate the transition from renal progenitor to renal vesicle are not well understood. Here, we show that Sall1interacts with the nucleosome remodeling and deacetylase complex (NuRD) to inhibit premature differentiation of nephron progenitor cells. Disruption of Sall1-NuRD in vivo in knock-in mice (?SRM) resulted in accelerated differentiation of nephron progenitors and bilateral renal hypoplasia. Transcriptional profiling of mutant kidneys revealed a striking pattern in which genes of the glomerular and proximal tubule lineages were either unchanged or upregulated, and those in the loop of Henle and distal tubule lineages were downregulated. These global changes in gene expression were accompanied by a significant decrease in THP-, NKCC2- and AQP1-positive loop of Henle nephron segments in mutant ?SRM kidneys. These findings highlight an important function of Sall1-NuRD interaction in the regulation of Six2-positive multipotent renal progenitor cells and formation of the loop of Henle.
| S-EPMC5611954 | biostudies-literature
Project description:The mammalian kidney develops from reciprocal interactions between the metanephric mesenchyme and ureteric bud, the former of which contains nephron progenitors. The third lineage, the stroma, fills up the interstitial space and is derived from distinct progenitors that express the transcription factor Foxd1. We showed previously that deletion of the nuclear factor Sall1 in nephron progenitors leads to their depletion in mice. However, Sall1 is expressed not only in nephron progenitors but also in stromal progenitors. Here we report that specific Sall1 deletion in stromal progenitors leads to aberrant expansion of nephron progenitors, which is in sharp contrast with a nephron progenitor-specific deletion. The mutant mice also exhibited cystic kidneys after birth and died before adulthood. We found that Decorin, which inhibits Bmp-mediated nephron differentiation, was upregulated in the mutant stroma. In contrast, the expression of Fat4, which restricts nephron progenitor expansion, was reduced mildly. Furthermore, the Sall1 protein binds to many stroma-related gene loci, including Decorin and Fat4. Thus, the expression of Sall1 in stromal progenitors restricts the excessive expansion of nephron progenitors in a non-cell autonomous manner, and Sall1-mediated regulation of Decorin and Fat4 might at least partially underlie the pathogenesis.
| S-EPMC4625151 | biostudies-literature
Project description:The balanced self-renewal and differentiation of nephron progenitors are critical for kidney development and controlled, in part, by the transcription factor Six2, which antagonizes canonical Wnt signaling-mediated differentiation. A nuclear factor, Sall1, is expressed in Six2-positive progenitors as well as differentiating nascent nephrons, and it is essential for kidney formation. However, the molecular functions and targets of Sall1, especially the functions and targets in the nephron progenitors, remain unknown. Here, we report that Sall1 deletion in Six2-positive nephron progenitors results in severe progenitor depletion and apoptosis of the differentiating nephrons in mice. Analysis of mice with an inducible Sall1 deletion revealed that Sall1 activates genes expressed in progenitors while repressing genes expressed in differentiating nephrons. Sall1 and Six2 co-occupied many progenitor-related gene loci, and Sall1 bound to Six2 biochemically. In contrast, Sall1 did not bind to the Wnt4 locus suppressed by Six2. Sall1-mediated repression was also independent of its binding to DNA. Thus, Sall1 maintains nephron progenitors and their derivatives by a unique mechanism, which partly overlaps but is distinct from that of Six2: Sall1 activates progenitor-related genes in Six2-positive nephron progenitors and represses gene expression in Six2-negative differentiating nascent nephrons.
| S-EPMC4214521 | biostudies-literature
Project description:This experiment was carried to identify potential reprogramming factors that augment Sall1 and Nanog reprogramming efficiency either individually or in combination during co-expression. The intent of the experiment was to understand genes regulated by Sall1 and Nanog during mouse epiblast stem cell reprogramming. Empty: mock transfected cells. Nanog: Nanog gene expressing plasmid. Sall1: Sall1 gene expressing plasmid. Untransfected: Untransfected cells. Sall1Nanog: Sall1 and Nanog expressing plasmids (cotransfection).
2019-02-28 | E-MTAB-7692 | biostudies-arrayexpress
Project description:Sall1 is a multi-zinc finger transcription factor that regulates kidney organogenesis. It is considered to be a transcriptional repressor, preferentially localized on heterochromatin. Mutations or deletions of the human SALL1 gene are associated with the Townes-Brocks syndrome. Despite its high expression, no function was yet assigned for Sall1 in embryonic stem (ES) cells. In the present study we show that Sall1 is expressed in a differentiation-dependent manner and physically interacts with Nanog and Sox2, two components of the core pluripotency network. Genome-wide mapping of Sall1-binding loci has identified 591 genes, 80% of which are also targeted by Nanog. A large proportion of these genes are related to self-renewal and differentiation. Sall1 positively regulates and synergizes with Nanog for gene transcriptional regulation. In addition, our data show that Sall1 suppresses the ectodermal and mesodermal differentiation. Specifically, the induction of the gastrulation markers T brachyury, Goosecoid and Dkk1 and the neuroectodermal markers Otx2 and Hand1 was inhibited by Sall1 overexpression during embryoid body differentiation. These data demonstrate a novel role for Sall1 as a member of the transcriptional network that regulates stem cell pluripotency.
2010-11-23 | GSE25523 | GEO
Project description:Spalt-Like Transcription Factor 1 (Sall1) is a critical regulator of organogenesis and microglia identity. Despite its known biological importance, mechanisms that specify the cell-specific expression of Sall1 and its transcriptional functions remain poorly understood. Here, we demonstrate that targeted deletion of a conserved microglia-specific super enhancer interacting with the Sall1 promoter results in complete and specific loss of Sall1 expression in microglia, thereby identifying an essential regulatory element that transduces brain environmental signals required for microglia-specific gene expression. By determining the genomic binding sites of SALL1 and leveraging Sall1 enhancer knock out (EKO) mice to probe how SALL1 shapes the regulatory landscape of microglia, we provide evidence that SALL1 functions to both directly activate microglia-specific genes and repress genes that are associated with inflammation and aging. Unexpectedly, motifs for SMAD proteins that mediate transcriptional effects of TGFb signaling were enriched within the set of enhancers predicted to be directly activated by SALL1, suggesting that collaborative interactions between SALL1 and SMADs are required to establish microglia-specific gene expression. To test this hypothesis, we determined the transcriptional consequences of a conditional knockout of the common co-SMAD Smad4 and defined the genome-wide locations of SMAD4 in wild type and EKO microglia. These studies revealed two layers of functional interdependence. First, we found that SMAD4 binds directly to the Sall1 super enhancer and is required for Sall1 expression, consistent with the requirement of the TGFb and SMAD homologues Dpp and Mad for cell-specific expression of Spalt in the Drosophila wing. Second, we extend this paradigm by demonstrating that SALL1 in turn promotes binding and function of SMAD4 at microglia-specific enhancers while simultaneously suppressing binding of SMAD4 to enhancers of genes that become inappropriately activated in EKO microglia. Collectively, these results suggest molecular mechanisms by which SALL1 enforces microglia-specific functions of the TGFb-SMAD signaling axis that may be relevant to roles of SALL1 in other developmental contexts.
2023-05-01 | GSE226088 | GEO
Project description:Spalt-Like Transcription Factor 1 (Sall1) is a critical regulator of organogenesis and microglia identity. Despite its known biological importance, mechanisms that specify the cell-specific expression of Sall1 and its transcriptional functions remain poorly understood. Here, we demonstrate that targeted deletion of a conserved microglia-specific super enhancer interacting with the Sall1 promoter results in complete and specific loss of Sall1 expression in microglia, thereby identifying an essential regulatory element that transduces brain environmental signals required for microglia-specific gene expression. By determining the genomic binding sites of SALL1 and leveraging Sall1 enhancer knock out (EKO) mice to probe how SALL1 shapes the regulatory landscape of microglia, we provide evidence that SALL1 functions to both directly activate microglia-specific genes and repress genes that are associated with inflammation and aging. Unexpectedly, motifs for SMAD proteins that mediate transcriptional effects of TGFb signaling were enriched within the set of enhancers predicted to be directly activated by SALL1, suggesting that collaborative interactions between SALL1 and SMADs are required to establish microglia-specific gene expression. To test this hypothesis, we determined the transcriptional consequences of a conditional knockout of the common co-SMAD Smad4 and defined the genome-wide locations of SMAD4 in wild type and EKO microglia. These studies revealed two layers of functional interdependence. First, we found that SMAD4 binds directly to the Sall1 super enhancer and is required for Sall1 expression, consistent with the requirement of the TGFb and SMAD homologues Dpp and Mad for cell-specific expression of Spalt in the Drosophila wing. Second, we extend this paradigm by demonstrating that SALL1 in turn promotes binding and function of SMAD4 at microglia-specific enhancers while simultaneously suppressing binding of SMAD4 to enhancers of genes that become inappropriately activated in EKO microglia. Collectively, these results suggest molecular mechanisms by which SALL1 enforces microglia-specific functions of the TGFb-SMAD signaling axis that may be relevant to roles of SALL1 in other developmental contexts.
2023-05-01 | GSE226091 | GEO
Project description:Spalt-Like Transcription Factor 1 (Sall1) is a critical regulator of organogenesis and microglia identity. Despite its known biological importance, mechanisms that specify the cell-specific expression of Sall1 and its transcriptional functions remain poorly understood. Here, we demonstrate that targeted deletion of a conserved microglia-specific super enhancer interacting with the Sall1 promoter results in complete and specific loss of Sall1 expression in microglia, thereby identifying an essential regulatory element that transduces brain environmental signals required for microglia-specific gene expression. By determining the genomic binding sites of SALL1 and leveraging Sall1 enhancer knock out (EKO) mice to probe how SALL1 shapes the regulatory landscape of microglia, we provide evidence that SALL1 functions to both directly activate microglia-specific genes and repress genes that are associated with inflammation and aging. Unexpectedly, motifs for SMAD proteins that mediate transcriptional effects of TGFb signaling were enriched within the set of enhancers predicted to be directly activated by SALL1, suggesting that collaborative interactions between SALL1 and SMADs are required to establish microglia-specific gene expression. To test this hypothesis, we determined the transcriptional consequences of a conditional knockout of the common co-SMAD Smad4 and defined the genome-wide locations of SMAD4 in wild type and EKO microglia. These studies revealed two layers of functional interdependence. First, we found that SMAD4 binds directly to the Sall1 super enhancer and is required for Sall1 expression, consistent with the requirement of the TGFb and SMAD homologues Dpp and Mad for cell-specific expression of Spalt in the Drosophila wing. Second, we extend this paradigm by demonstrating that SALL1 in turn promotes binding and function of SMAD4 at microglia-specific enhancers while simultaneously suppressing binding of SMAD4 to enhancers of genes that become inappropriately activated in EKO microglia. Collectively, these results suggest molecular mechanisms by which SALL1 enforces microglia-specific functions of the TGFb-SMAD signaling axis that may be relevant to roles of SALL1 in other developmental contexts.
2023-05-01 | GSE226090 | GEO
Project description:Spalt-Like Transcription Factor 1 (Sall1) is a critical regulator of organogenesis and microglia identity. Despite its known biological importance, mechanisms that specify the cell-specific expression of Sall1 and its transcriptional functions remain poorly understood. Here, we demonstrate that targeted deletion of a conserved microglia-specific super enhancer interacting with the Sall1 promoter results in complete and specific loss of Sall1 expression in microglia, thereby identifying an essential regulatory element that transduces brain environmental signals required for microglia-specific gene expression. By determining the genomic binding sites of SALL1 and leveraging Sall1 enhancer knock out (EKO) mice to probe how SALL1 shapes the regulatory landscape of microglia, we provide evidence that SALL1 functions to both directly activate microglia-specific genes and repress genes that are associated with inflammation and aging. Unexpectedly, motifs for SMAD proteins that mediate transcriptional effects of TGFb signaling were enriched within the set of enhancers predicted to be directly activated by SALL1, suggesting that collaborative interactions between SALL1 and SMADs are required to establish microglia-specific gene expression. To test this hypothesis, we determined the transcriptional consequences of a conditional knockout of the common co-SMAD Smad4 and defined the genome-wide locations of SMAD4 in wild type and EKO microglia. These studies revealed two layers of functional interdependence. First, we found that SMAD4 binds directly to the Sall1 super enhancer and is required for Sall1 expression, consistent with the requirement of the TGFb and SMAD homologues Dpp and Mad for cell-specific expression of Spalt in the Drosophila wing. Second, we extend this paradigm by demonstrating that SALL1 in turn promotes binding and function of SMAD4 at microglia-specific enhancers while simultaneously suppressing binding of SMAD4 to enhancers of genes that become inappropriately activated in EKO microglia. Collectively, these results suggest molecular mechanisms by which SALL1 enforces microglia-specific functions of the TGFb-SMAD signaling axis that may be relevant to roles of SALL1 in other developmental contexts.
2023-05-01 | GSE226089 | GEO
Project description:Changes in gene expression represent an important source for phenotypical innovation. Yet, how such changes emerge and impact the evolution of traits remains elusive. Here, we explore the molecular mechanisms associated with the development of masculinizing ovotestes in female moles. By performing comparative analyses of epigenetic and transcriptional data in mole and mouse, we identified SALL1 as a co-opted gene for the formation of testicular tissue in mole ovotestes. Chromosome conformation capture analyses highlight a striking conservation of the 3D organization at the SALL1 locus, but a prominent evolutionary turnover of enhancer elements. Interspecies reporter assays support the capability of mole-specific enhancers to activate transcription in urogenital tissues. Through overexpression experiments in transgenic mice, we further demonstrate the capability of SALL1 to induce the ectopic gene expression programs that are a signature of mole ovotestes. Our results highlight the co-option of gene expression, through changes in enhancer activity, as a prominent mechanism for the evolution of traits. We performed RNAseq on mouse mutant ovaries overexpressing Sall1 and compared them to wildtype ovaries at E13.5
2022-11-23 | GSE218536 | GEO