SALL4 recruits BAF to activate enhancers required for cranial neural crest cell specification
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ABSTRACT:
PROVIDER: PRJNA1246518 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR32981508_1.fastq.gz | Fastqsanger.gz | |||
| SRR32981508_2.fastq.gz | Fastqsanger.gz | |||
| SRR32981510_1.fastq.gz | Fastqsanger.gz | |||
| SRR32981510_2.fastq.gz | Fastqsanger.gz |
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Project description:SALL4 is a critical transcription factor involved in early embryonic development. While its role in pluripotency remains debated, SALL4 has been implicated in various lineage specification processes. The neural crest-derived anomalies observed in individuals with SALL4 haploinsufficiency, combined with high SALL4 expression observed in mouse cranial neural crest cells (CNCCs), suggest a role for this transcription factor in CNCC specification and craniofacial development, however, this has not yet been investigated. Moreover, while SALL4 is an established interactor of the NuRD chromatin remodeling complex, recent mass-spectrometry studies from our group have suggested a novel interaction between SALL4 and the BAF complex during human CNCC specification. Here, we investigate the functional significance of this interaction and the broader role of SALL4 in CNCC development. We generated a human iPSC line with SALL4 heterozygous knock-out to model the haploinsufficient variants observed in SALL4-associated human developmental syndromes. Our findings reveal that the SALL4A isoform directly interacts with the BAF subunit DPF2 via its zinc-finger-cluster-3 and -4 domain. During early CNCC specification, SALL4A is required for BAF-mediated chromatin remodeling at enhancers essential for CNCC fate. In the absence of SALL4A, cells progress normally through the neuroectodermal stage but fail to specify into CNCCs, as CNCC lineage-specific enhancers remain repressed. Moreover, we demonstrate that the SALL4B isoform cannot compensate for SALL4A loss, as it lacks the zinc-finger-3 domain necessary for BAF interaction. These findings establish a novel role for SALL4A in CNCC specification by regulating BAF-mediated enhancer activation, shedding light on the molecular mechanisms underlying SALL4-associated craniofacial anomalies.
2025-04-08 | GSE293821 | GEO
Project description:The BAF chromatin remodeler regulates lineage commitment including cranial neural crest cell (CNCC) specification. BAF subunit mutations cause Coffin-Siris Syndrome (CSS), a congenital disorder characterized by distinct craniofacial features and intellectual disability. Approximately 50% of CSS patients carry mutations in one of the mutually exclusive BAF subunits, ARID1A/ARID1B. While Arid1a deletion in mouse neural crest causes severe craniofacial phenotypes, little is known about the role of ARID1A in CNCC specification. Using CSS patient-derived ARID1A+/- iPSCs to model CNCC specification, we discovered that ARID1A-haploinsufficency impairs epithelial to mesenchymal transition (EMT), a process necessary for CNCC delamination and migration from the neural tube. Furthermore, wild-type ARID1A-BAF regulates enhancers associated with EMT genes. ARID1A-BAF binding at these enhancers is impaired in heterozygotes, while binding at promoters is unaffected. At the sequence level, these EMT enhancers contain binding motifs for ZIC2, and ZIC2 binding at these sites is ARID1A-dependent. When excluded from EMT enhancers, ZIC2 relocates to neuronal enhancers, triggering aberrant neuronal gene activation. In mice, deletion of Zic2 impairs NCC delamination, while ZIC2 overexpression in chick embryos at pre-migratory neural crest stages elicits abnormal cell delamination from the neural tube. These findings reveal a novel ARID1A-ZIC2 axis essential for EMT and CNCC delamination.
2024-07-23 | GSE261846 | GEO
Project description:Sall4 is a transcription factor essential for early mammalian development. Though it is reported to play an important role in embryonic stem (ES) cell self-renewal, whether it is an essential pluripotency factor has been disputed. Though Sall4 is known to associate with the Nucleosome Remodeling and Deacetylase (NuRD) complex, the nature of this interaction is unclear as NuRD and Sall4 serve opposing functions in ES cells. Here we use defined culture conditions and single-cell gene expression analyses to show that Sall4 prevents activation of the neural gene expression programme in ES cells but is dispensable for maintaining the pluripotency gene regulatory network. We further show using genome-wide analyses that while Sall4 interacts with NuRD, it neither recruits NuRD to chromatin nor influences transcription via NuRD. Rather we propose a model where, by titrating Sall4 protein, NuRD limits the differentiation-inhibiting activity of Sall4 in ES cells to enable lineage commitment.
2016-08-02 | PXD003614 | Pride
Project description:The BAF complex modulates chromatin accessibility. Specific BAF configurations have functional consequences, and subunit switches are essential for cell differentiation. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause a neurodevelopmental disorder spectrum, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we reprogrammed ARID1B+/- Coffin-Siris patient-derived skin fibroblasts into iPSCs, and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF), including SMARCA4, and nine additional subunits. ARID1B-BAF acts as a gate-keeper, ensuring exit from pluripotency and lineage commitment, by attenuating NANOG, SOX2 and the thousands of enhancers directly regulated by these two pluripotency factors at the iPSC stage. In iPSCs, these enhancers are maintained active by an ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A-BAF to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks, and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at pluripotency enhancers throughout all stages of CNCC formation. This leads to a persistent and aberrant SOX2 and NANOG activity, which impairs CNCC formation. In fact, despite showing the typical neural crest signature (TFAP2A+, SOX9+), the ARID1B-haploinsufficient CNCCs are also NANOG-positive, in stark contrast with the ARID1B-wt CNCCs, which are NANOG-negative. These findings suggest a connection between ARID1B mutations, neuroectoderm formation, and a pathogenic mechanism for Coffin-Siris syndrome.
2021-10-12 | PXD028557 | Pride
Project description:Sall4 is a mouse homolog of a causative gene of the autosomal dominant disorder known as Okihiro syndrome. We previously showed that Sall4 absence leads to lethality during peri-implantation and that Sall4-null embryonic stem (ES) cells proliferate poorly with intact pluripotency when cultured on feeder cells. However, a subsequent report indicated that shRNA-mediated Sall4 inhibition in ES cells led to a severe reduction in Oct3/4 and a secondary increase in Cdx2, which resulted in complete differentiation into the trophectoderm when cultured in the feeder-free condition. So we profiled gene expression changes when Sall4 is deleted in ES cells in the presence or absence of feeder cells. key word: embryonic stem (ES) cell, Sall4, feeder
2009-04-01 | GSE14219 | GEO
Project description:Craniofacial microsomia (CFM) is a congenital defect that usually results from aberrant development of embryonic pharyngeal arches. However, the molecular basis of CFM pathogenesis is largely unknown. Here, we employ the zebrafish model to investigate mechanisms of CFM pathogenesis. In early embryos, tet2 and tet3 are essential for pharyngeal cartilage development. Single-cell RNA sequencing reveals that loss of Tet2/3 impairs chondrocyte differentiation due to insufficient BMP signaling. Moreover, biochemical and genetic evidence reveals that the sequence-specific 5mC/5hmC-binding protein, Sall4, binds the promoter of bmp4 to activate bmp4 expression and control pharyngeal cartilage development. Mechanistically, Sall4 directs co-phase separation of Tet2/3 with Sall4 to form condensates that mediate 5mC oxidation on the bmp4 promoter, thereby promoting bmp4 expression and enabling sufficient BMP signaling. These findings suggest the TET-BMP-Sall4 regulatory axis is critical for pharyngeal cartilage development. Collectively, our study provides insights into understanding craniofacial development and CFM pathogenesis.
2024-03-04 | GSE226184 | GEO
Project description:High confidence SALL4 targets were identified in mESCs by performing Cut&Run on SALL4 Flox/Flox and SALL4 -/- cells. We validated a commercially available antibody that specifically recognizes SALL4 protein.
2022-12-08 | GSE203303 | GEO
Project description:SALL4 is a nuclear factor central to the maintenance of stem cell pluripotency and is a key component in HCC, a malignancy with no effective treatment. In cancer cells, SALL4 associates with NuRD to silence tumor suppressor genes such as PTEN. Here, we design a potent therapeutic SALL4 peptide (FFW) capable of antagonizing the SALL4-NURD interaction using systematic truncation and amino acid substitution studies. To understand the pathways affected by the peptide treatment, we performed RNA sequencing on cells treated with different peptides. Furthermore, to identify SALL4 DNA binding targets, we have performed CRUD-ChIP sequencing with SALL4 and H2K27Ac antibodies on HCC cell line SNU398.
2018-07-05 | GSE112729 | GEO
Project description:Sall genes are expressed early in development and in diversity of embryonic and adult structures. Sall4 plays a crucial role during the development of a number of systems. Mutations in the SALL4 gene have been linked to Okihiro/acro-renal-ocular syndrome, in which patients exhibit forearm malformations and eye movement deficits. Homozygote and heterozygote Sall4 cells from mouse blastocysts were collected and used to design a genetrap mouse mutant line. The homozygote Sall4 ES cells form mouse blastocyst were hybridizised versus TBV wildtype cells to detect changes in gene expression. Three biological samples of different passages of the same clone of NT1 and TBV were analyzed in 13 chip hybridizations; each sample was analyzed in 2-5 experimental replicates including dye swap experiments. Keywords: others
2006-08-02 | GSE4322 | GEO
Project description:Sall4 is a mouse homolog of a causative gene of the autosomal dominant disorder known as Okihiro syndrome. We previously showed that Sall4 absence leads to lethality during peri-implantation and that Sall4-null embryonic stem (ES) cells proliferate poorly with intact pluripotency when cultured on feeder cells. However, a subsequent report indicated that shRNA-mediated Sall4 inhibition in ES cells led to a severe reduction in Oct3/4 and a secondary increase in Cdx2, which resulted in complete differentiation into the trophectoderm when cultured in the feeder-free condition. So we profiled gene expression changes when Sall4 is deleted in ES cells in the presence or absence of feeder cells. key word: embryonic stem (ES) cell, Sall4, feeder ES cells were cultured with or without mouse embryonic fibroblast (MEF) feeder cells in LIF-supplemented medium as described. To maintain the expression of Oct3/4, all ES cells were cultured in the presence of Blasticidin. Four samples were analyzed. GSM356329, GSM356330 : cultured in the absence of feeders GSM356331, GSM356332 : cultured on the feeders
2009-04-01 | E-GEOD-14219 | biostudies-arrayexpress