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HUES cells: control and overexpressing OCT4

ABSTRACT: HUES24 cell line was nucleofected with POU5f1 cDNA to overexpress OCT4; This leads to the formation of mesendodermal cells Short- and Long-scales intra- and inter-chromosomal interactions are linked to gene transcription, but the molecular event underlying these structures and how it affects cell fate decision during embryonic development are poorly understood. One of the first embryonic cell fate decisions (i.e mesendoderm determination) is driven by the POU factor OCT4, acting in concert with the high mobility group genes SOX-2 and SOX-17. Here, we identify novel chromatin remodelling mechanism and enhancer function driven by both OCT4 and SALL4 that mediate cell fate switching. We found that OCT4 alters the higher-order chromatin structure at both Sox-2 and Sox-17 loci. OCT4 titrates out cohesin and switches the Sox-17 enhancer from a locked (within an inter-chromosomal Sox-2 enhancer/CTCF/cohesin loop) to an active (within an intra-chromosomal Sox-17 promoter/enhancer/cohesin loop) state. SALL4 concomitantly mobilizes the polycomb complexes at the Soxs loci. Thus, OCT4/SALL4-driven cohesin-and polycombs-mediated changes in higher order chromatin structure mediate instruction of early cell fate in embryonic cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58125 | GEO | 2015/04/02

SECONDARY ACCESSION(S): PRJNA249067

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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HUES cells: control and overexpressing OCT4

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