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Sall4 regulates distinct transcription circuitries in different blastocyst-derived stem cell lineages

ABSTRACT: Stem cells self-renew or differentiate under the governance of a stem cell-specific transcriptional program with each transcription factor orchestrating the activities of a particular set of genes. Here we demonstrate that a single transcription factor is able to regulate distinct core circuitries in two different blastocyst-derived stem cell lines, embryonic stem (ES) and extra-embryonic endoderm (XEN) cells. The transcription factor, Sall4, is required for early embryonic development and for ES cell pluripotency. Sall4 is also expressed in XEN cells and depletion of Sall4 disrupts self-renewal and induces differentiation. Genome-wide analysis reveals Sall4 is regulating different gene sets in ES and XEN cells, and depletion of Sall4 targets in the respective cell types induces differentiation. With Oct4, Sox2 and Nanog, Sall4 forms a crucial interconnected auto-regulatory network in ES cells. In XEN cells, Sall4 regulates key XEN lineageassociated genes, Gata4, Gata6, Sox7 and Sox17. Our findings demonstrate how Sall4 functions as an essential stemness factor for two different stem cell lines. Keywords: ES/XEN comparison, ES Sall4 KD/control KD comparison, and XEN Sall4 KD/control KD comparison

ORGANISM(S): Mus musculus

PROVIDER: GSE12482 | GEO | 2008/08/19

SECONDARY ACCESSION(S): PRJNA112961

REPOSITORIES: GEO

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Project description:Embryonic stem cells have potential utility in regenerative medicine due to their pluripotent characteristics. Sall4, a zinc-finger transcription factor, is expressed very early in embryonic development with Oct4 and Nanog, two well characterized pluripotency regulators. Sall4 plays an important role in governing the fate of stem cells through transcriptional regulation of both Oct4 and Nanog. Using chromatin immunoprecipitation coupled to microarray hybridization (ChIP on Chip), we have mapped global gene targets of Sall4 unveiling possible regulation of broad ES cell functions. Approximately 5,000 genes were identified that were bound by the Sall4 protein and many of these have major functions in developmental and regulatory pathways. Sall4 bound more than six times as many annotated genes within promoter regions as Oct4 and twice as many as Nanog. Immunoprecipitation revealed a heterotrimeric protein complex between Sall4, Oct4, and Nanog, consistent with binding site co-occupancies. Further, Sall4 bound many genes that are regulated in part by the chromatin-based epigenetic events mediated by polycomb-repressive complexes and bivalent domains. This suggests that Sall4 plays a central and diverse role in regulating stem cell pluripotency during early embryonic development that involves integration of transcriptional and epigenetic control processes. Keywords: ChIP-chip We used ChIP-chip to map global promoter bound by Sall4, a zinc finger transcription factor. Growing evidence has suggested that Sall4 plays a vital role in ES cell pluripotency maintenance. Evidence for this includes its recent use as a marker for somatic cell reprogramming, in a genetic signature for ES cells, and evidence that Sall4 enhances reprogramming. These recent findings and two previously described interactions with Oct4 and Nanog strongly support the role of Sall4 in ES cells. This hypothesis was furthered here as we show that Sall4 plays important roles through transcriptional regulation of vital ES cell genes.

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Sall4 regulates distinct transcription circuitries in different blastocyst-derived stem cell lineages

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