SALL4 controls cell fate in response to DNA base composition

Pantier, Raphaël; Chhatbar, Kashyap; Quante, Timo; Skourti-Stathaki, Konstantina; Cholewa-Waclaw, Justyna; Alston, Grace; Alexander-Howden, Beatrice; Lee, Heng Yang; Cook, Atlanta G.; Spruijt, Cornelia G.; Vermeulen, Michiel; Selfridge, Jim; Bird, Adrian

doi:10.1016/j.molcel.2020.11.046

Cited by 33 publications

(42 citation statements)

References 90 publications

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“…Although Nanog seems relatively density-insensitive during self-renewal, once mESCs are committed to differentiation in -LIF, Nanog protein levels decrease more at LD compared to HD ( Figure 1 I). We also observe more rapid loss of protein expression of pluripotency-related factors Sall4 and Zfp281 ( Luo et al., 2019 ; Pantier et al., 2021 ) at LD. Interestingly, Oct4, Sox2, and Klf5 were downregulated in a density-independent manner, and protein levels of E-cadherin and Zfp57 expression were maintained better in LD compared to HD.…”

Section: Resultsmentioning

confidence: 72%

β-catenin links cell seeding density to global gene expression during mouse embryonic stem cell differentiation

et al. 2022

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Summary Although cell density is known to affect numerous biological processes including gene expression and cell fate specification, mechanistic understanding of what factors link cell density to global gene regulation is lacking. Here, we reveal that the expression of thousands of genes in mouse embryonic stem cells (mESCs) is affected by cell seeding density and that low cell density enhances the efficiency of differentiation. Mechanistically, β-catenin is localized primarily to adherens junctions during both self-renewal and differentiation at high density. However, when mESCs differentiate at low density, β-catenin translocates to the nucleus and associates with Tcf7l1, inducing co-occupied lineage markers. Meanwhile, Esrrb sustains the expression of pluripotency-associated genes while repressing lineage markers at high density, and its association with DNA decreases at low density. Our results provide new insights into the previously neglected but pervasive phenomenon of density-dependent gene regulation.

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Section: Resultsmentioning

confidence: 72%

β-catenin links cell seeding density to global gene expression during mouse embryonic stem cell differentiation

et al. 2022

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“…SALL4 was previously shown to interact with the NuRD repressive complex 46 , while interactions with BAF have been largely unexplored. It was recently demonstrated that this transcription factor has an affinity for AT-rich regions 49 , thus providing further support to the ARID1B-SALL4 interaction. SALL4 mutations are also associated with developmental syndromes, including Okihiro syndrome, Holt-Oram syndrome, and Townes-Brocks Syndrome 50 .…”

Section: Resultsmentioning

confidence: 78%

Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation in ARID1B-related neurodevelopmental disorders

et al. 2021

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Subunit switches in the BAF chromatin remodeler are essential during development. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause neurodevelopmental disorders, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we leveraged ARID1B+/− Coffin-Siris patient-derived 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). ARID1B-BAF regulates exit from pluripotency and lineage commitment by attenuating thousands of enhancers and genes of the NANOG and SOX2 networks. In iPSCs, these enhancers are maintained active by ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A- 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 the pluripotency enhancers throughout all stages of CNCC formation. This leads to persistent NANOG/SOX2 activity which impairs CNCC formation. Despite showing the typical neural crest signature (TFAP2A/SOX9-positive), ARID1B-haploinsufficient CNCCs are also aberrantly NANOG-positive. These findings suggest a connection between ARID1B mutations, neuroectoderm specification and a pathogenic mechanism for Coffin-Siris syndrome.

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“…SALL4 was previously shown to interact with the NuRD repressive complex 46 , while interactions with BAF have been largely unexplored. It was recently demonstrated that this transcription factor has affinity for ATrich regions 49 , thus providing further support to the ARID1B-SALL4 interaction. SALL4 mutations are also associated with developmental syndromes, including Okihiro syndrome, Holt-Oram syndrome, and Townes-Brocks Syndrome 50 .…”

Section: The Arid1b-baf Complex Exclusively Incorporates Smarca4 As An Atpase Subunitmentioning

confidence: 76%

Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation inARID1B-related neurodevelopmental disorders

Pagliaroli

Porazzi

Curtis

et al. 2021

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The BAF complex modulates genome-wide chromatin accessibility. Specific BAF configurations have been shown to 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 investigated cranial neural crest cell (CNCC) differentiation. We discovered a novel BAF configuration (ARID1B-BAF), which includes ARID1B, SMARCA4, and eight additional subunits. This novel version of BAF acts as a gate-keeper which ensures exit from pluripotency and commitment towards neural crest differentiation, by attenuating pluripotency enhancers of the SOX2 network. At the iPSC stage, these enhancers are maintained in active state by an ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A-BAF to ARID1B-BAF, eliciting attenuation of SOX2 enhancers and pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at pluripotency enhancers throughout CNCC differentiation. This correlates with aberrant SOX2 binding at pluripotency enhancers, and failure to reposition SOX2 at developmental enhancers. SOX2 dysregulation promotes upregulation of the NANOG network, impairing CNCC differentiation. ARID1B-BAF directly modulates NANOG expression upon differentiation cues. Intriguingly, the cells with the most prominent molecular phenotype in multiple experimental assays are derived from a patient with a more severe clinical impairment. These findings suggest a direct connection between ARID1B mutations, CNCC differentiation, and a pathogenic mechanism for Coffin-Siris syndrome.

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SALL4 controls cell fate in response to DNA base composition

Cited by 33 publications

References 90 publications

β-catenin links cell seeding density to global gene expression during mouse embryonic stem cell differentiation

β-catenin links cell seeding density to global gene expression during mouse embryonic stem cell differentiation

Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation in ARID1B-related neurodevelopmental disorders

Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation inARID1B-related neurodevelopmental disorders

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