Identification of downstream targets and pathways initiated by Sall1 and Nanog during reprogramming
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB31317 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR3163190_1.fastq.gz | Fastqsanger.gz | |||
| ERR3163190_2.fastq.gz | Fastqsanger.gz | |||
| ERR3163191_1.fastq.gz | Fastqsanger.gz | |||
| ERR3163191_2.fastq.gz | Fastqsanger.gz | |||
| ERR3163192_1.fastq.gz | Fastqsanger.gz |
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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).
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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.
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Project description:SALL1 is a critical regulator of embryonic development across a wide swath of tissues, including vital organs, but little is known about its function in adult tissues. Recent work from our group demonstrates that SALL1 is involved in urogenital development. This study delineates the role of SALL1 transcription factor in the adult reproductive system by demonstrating its requirement at multiple levels of uterine function during the implantation phase of early pregnancy. By generating a conditional knockout mouse model of Sall1 exclusively in female reproductive organs, it is demonstrated herein that SALL1 is independently required both in the uterine luminal epithelium for the attachment of competent blastocysts to the uterine wall, as well as in the uterine stroma for the process of decidualization, another prerequisite for pregnancy success. This robust, multi-tissue-layer requirement for SALL1 across multiple stages in the process of implantation makes it a newly identified regulator of early pregnancy. Herein it isshown that loss of SALL1 causes misexpression of estrogen receptor alpha (ESR1) during the window of implantation, and subsequent pathological deregulation of multiple estrogen response genes whose tight titrations are prerequisites of pregnancy. RNA sequencing of independent knockout uterine compartments at multiple timepoints, and ChIP sequencing to identify direct transcriptional targets, elucidated multiple powerful regulatory pathways downstream of SALL1. Importantly, the use of a selective estrogen receptor antagonist, fulvestrant, at a precise timepoint and dose, offers a partial rescue of embryo attachment to the uterine luminal epithelium, further demonstrating that SALL1 is upstream of ESR1 during implantation phase signaling.
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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.
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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.
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