SALL4 controls cell fate in response to DNA base composition

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Structure of SALL4 zinc-finger domain reveals link between AT-rich DNA binding and Okihiro syndrome

Spalt-like 4 (SALL4) maintains vertebrate embryonic stem cell identity and is required for the development of multiple organs, including limbs. Mutations in SALL4 are associated with Okihiro syndrome and SALL4 is also a known target of thalidomide. SALL4 protein has a distinct preference for AT-rich sequences, recognised by a pair of zinc fingers at the C-terminus. However, unlike many characterised zinc finger proteins, SALL4 shows flexible recognition with many different combinations of AT-rich sequences being targeted. SALL4 interacts with the NuRD corepressor complex which potentially mediates repression of AT-rich genes. We present a crystal structure of SALL4 C-terminal zinc fingers with an AT-rich DNA sequence, which shows that SALL4 uses small hydrophobic and polar side chains to provide flexible recognition in the major groove. Missense mutations reported in patients that lie within the C-terminal zinc fingers reduced overall binding to DNA but not the preference for AT-rich sequences. Furthermore, these mutations altered association of SALL4 with AT-rich genomic sites, providing evidence that these mutations are likely pathogenic. ## Complementary datasets ## Datasets in this repository complement additional datasets that are deposited in public databases: * Coordinates and structure factors are deposited in the Protein Data Bank: accession 8A4I; * SAXS data are deposited in the small angle scattering database (SASDB): accessions SASDP64 (SALL4 ZFC4); SASDP74 (DNA); SASDP84 (SALL4 ZFC4 + DNA); * HT-SELEX data are deposited at Array express: accession E-MTAB-11519

Role of Sox2 in preimplantation and postimplantation pluripotency

Microarray gene expression analysis of mouse embryonic stem cells in different culture conditions. 4 conditions: AFN=Activin/FGF/N2B27 (unsorted (All) or sorted by Sox2 expression into High or Low), PCLN=LIF/2i/N2B27, LBN=LIF/BMP/N2B27 (sorted by Sox2 expression into High and Low) and FCSL=LIF/FCS/GMEM (sorted by Sox2 expression into High and Low). 3 replicates per group. 24 samples total.Sox2 is a key transcription factor directing embryonic stem cell (ESC) pluripotency. However, the role of SoxB1 proteins in epiblast stem cell (EpiSC) pluripotency is unknown. Here we compare the transcriptomes of pluripotent cells cultured in different conditions that express different levels of Sox2. While highest Sox2 level in ESCs are enriched for naive pluripotency markers, ESCs and EpiSCs expressing the same Sox2 level were transcriptionally distinct. Thus Sox2 levels do not dictate the distinction between ESC and EpiSC states.Corsinotti A, Wong FC, Tatar T, Szczerbinska I et al. Distinct SoxB1 networks are required for naïve and primed pluripotency. Elife 2017 Dec 19;6. PMID: 2925686