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 in ARID1B-related neurodevelopmental disorders.
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DOI：
10.1038/s41467-021-26810-x
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发表时间：
2021-11-09
影响因子：
16.6
通讯作者：
Trizzino M
中科院分区：
文献类型：
--
作者：
Pagliaroli L;Porazzi P;Curtis AT;Scopa C;Mikkers HMM;Freund C;Daxinger L;Deliard S;Welsh SA;Offley S;Ott CA;Calabretta B;Brugmann SA;Santen GWE;Trizzino M
BAF染色质重塑中的亚基转换在发育过程中是必不可少的。ARID 1B和它的副产物ARID 1A编码互斥的BAF亚基。从头ARID 1B单倍不足突变导致神经发育障碍，包括Coffin-Siris综合征，其特征在于神经和颅面特征。在这里，我们利用ARID 1B +/− Coffin-Siris患者来源的iPSC和模拟颅神经嵴细胞（CNCC）形成。我们发现，ARID 1B仅在该过程的第一阶段是活跃的，与神经外胚层特化相一致，在那里它是谱系特异性BAF构型（ARID 1B-BAF）的一部分。ARID 1B-BAF通过减弱NANOG和SOX 2网络的数千个增强子和基因来调节退出多能性和谱系定型。在iPSC中，这些增强子通过含有ARID 1A的BAF保持活性。在分化开始时，细胞从ARID 1A-转变为ARID 1B-BAF，引起NANOG/SOX 2网络的衰减并触发多能性退出。Coffin-Siris患者细胞不能进行ARID 1A/ARID 1B转换，并在CNCC形成的所有阶段将ARID 1A-BAF维持在多能性增强子处。这导致持续的NANOG/S 0X 2活性，其损害CNCC形成。尽管显示出典型的神经嵴特征（TFAP 2A/SOX 9阳性），但ARID 1B单倍体不足的CNCC也是异常的NANOG阳性。这些发现表明ARID 1B突变，神经外胚层特化和Coffin-Siris综合征的致病机制之间存在联系。BAF染色质重塑复合物ARID 1B亚基突变与神经发育Coffin-Siris综合征相关在这里，作者揭示了在Coffin-Siris患者来源的细胞中受损的颅神经嵴细胞分化期间存在从含ARID 1A的复合物到ARID 1B的过渡，这对于退出多能性很重要。
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.
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影响因子：
16.6
作者：
Gatchalian J;Malik S;Ho J;Lee DS;Kelso TWR;Shokhirev MN;Dixon JR;Hargreaves DC
通讯作者：
Hargreaves DC
影响因子：
10.5
作者：
Braun SMG;Petrova R;Tang J;Krokhotin A;Miller EL;Tang Y;Panagiotakos G;Crabtree GR
通讯作者：
Crabtree GR
DOI：
10.1073/pnas.1610612114
发表时间：
2017-06-06
影响因子：
11.1
作者：
De Kumar, Bony;Parker, Hugo J.;Krumlauf, Robb
通讯作者：
Krumlauf, Robb
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS