Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation in ARID1B-related neurodevelopmental disorders.
Luca Pagliaroli,Patrizia Porazzi,Alyxandra T. Curtis,Chiara Scopa,Harald Mikkers,Christian Freund,Lucia Daxinger,Sandra Deliard,Sarah A. Welsh,Sarah Offley,Connor A. Ott,Bruno Calabretta,Samantha A. Brugmann,Gijs W. E. Santen,Marco Trizzino +14 more
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In this paper, the authors leveraged ARID1B+/− Coffin-Siris patient-derived iPSCs and modeled cranial neural crest cell (CNCC) formation.Abstract:
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. Mutations in the ARID1B subunit of the BAF chromatin remodeling complex are associated with the neurodevelopmental Coffin-Siris syndrome. Here the authors reveal that there is a transition from ARID1A-containing complexes to ARID1B during cranial neural crest cell differentiation that is impaired in Coffin-Siris patient-derived cells, which is important for exit from pluripotency.read more
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Young transposable elements rewired gene regulatory networks in human and chimpanzee hippocampal intermediate progenitors
TL;DR: In this paper, the authors investigated the evolution of gene regulatory networks underpinning hippocampal neurogenesis in apes, and leveraged the differentiation of human and chimpanzee induced Pluripotent Stem Cells into TBR2-positive hippocampal intermediate progenitors (hpIPCs).
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Paraspeckles interact with SWI/SNF subunit ARID1B to regulate transcription and splicing
Divya Reddy,Saikat Bhattacharya,Michaella J. Levy,Jing Zhang,Madelaine Gogol,Hua Li,Laurence Florens,Jerry L. Workman +7 more
TL;DR: In this paper , the authors show that paraspeckles interact with the SWI/SNF chromatin remodeling complex, specifically mediated by the direct interaction of the long-non-coding RNA NEAT1 of the paraspecks with ARID1B of the cBAF•type SWI•SNF complex.
Journal ArticleDOI
Young transposable elements rewired gene regulatory networks in human and chimpanzee hippocampal intermediate progenitors
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Evidence for an association between Coffin‐Siris syndrome and congenital diaphragmatic hernia
Yoel Gofin,Xiao-li Zhao,Amanda Gerard,Fernando Scaglia,Michael F. Wangler,Samantha A. Schrier Vergano,Daryl A. Scott +6 more
TL;DR: Evidence is provided that deleterious variants in ARID1B, ARID2, DPF2, and SMARCC2, which are associated with CSS types 1–8, respectively, areassociated with the development of CDH, and that the mSWI/SNF (BAF) complex may play an important role in diaphragm development.
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T. S. Vital,Aminah Wali,Kyle V. Butler,Yan Xiong,Joseph P. Foster,S. Marcel,Andrew W. McFadden,Valerie Nguyen,B. M. Bailey,Kelsey N. Lamb,Lindsey I. James,Stephen V. Frye,Amber L. Mosely,Jian Jin,Samantha G. Pattenden,Ian J. Davis +15 more
TL;DR: In this paper , a small molecule called MS0621 was identified as a modulator of chromatin state at sites of aberrant chromatin accessibility at EWSR1::FLI1-bound loci.
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