BAF subunit switching regulates chromatin accessibility to control cell cycle exit in the developing mammalian cortex.
BAF subunit switching regulates chromatin accessibility to control cell cycle exit in the developing mammalian cortex.
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BAF亚基转换调节染色质可及性以控制发育中的哺乳动物皮层的细胞周期退出。
DOI：
10.1101/gad.342345.120
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发表时间：
2021-03-01
影响因子：
10.5
通讯作者：
Crabtree GR
中科院分区：
文献类型：
--
作者：
Braun SMG;Petrova R;Tang J;Krokhotin A;Miller EL;Tang Y;Panagiotakos G;Crabtree GR
在这里，Braun等人研究了胚胎脑中细胞周期退出和同步分化的发生是如何被调节的，这伴随着BAF亚基转换，在神经干/祖细胞中产生神经元特异性的nBAF复合物。他们在体内操纵了BAF亚基交换的时间，发现npBAF亚基BAF53a的早期缺失会阻碍细胞周期退出，从而破坏神经发生，并且Wnt、EGF、FGF、Sox2、myc和Pax6在缺乏BAF53a的情况下都无法维持增殖，这为在持续存在外源性增殖线索的情况下神经祖细胞周期退出的新机制提供了见解。mSWI/SNF或BAF染色质调控复合物是人类神经发育的剂量敏感调节剂，在自闭症谱系障碍和智力残疾中经常发生突变。神经干细胞/祖细胞的细胞周期退出和分化伴随着BAF亚基转换，从而产生神经元特异性的nBAF复合物。我们在体内操纵了BAF亚基交换的时间，发现npBAF亚基BAF53a的早期丢失会延缓细胞周期，从而破坏神经发生。由于Polycomb积累，BAF53a的缺失导致特定神经转录因子结合位点的染色质可及性降低，包括先驱因子SOX2和ASCL1。这导致细胞周期基因的抑制，从而阻断细胞周期的进展和分化。Baf53a缺失后的细胞周期阻滞可以通过过早表达nBAF亚基BAF53b来修复，但不能通过其他主要的增殖或分化驱动因素来修复。WNT、EGF、bFGF、SOX2、c-MYC或PAX6在缺乏BAF53a的情况下都不能维持增殖，这突出了在持续存在外源性增殖线索时神经祖细胞周期退出的新机制。
Here, Braun et al. investigated how cell cycle exit and synchronous differentiation onset are regulated in the embryonic brain, which is accompanied by BAF subunit switching to generate neuron-specific nBAF complexes in neural stem/progenitor cells. They manipulated the timing of BAF subunit exchange in vivo and found that early loss of the npBAF subunit BAF53a stalls cell cycle exit to disrupt neurogenesis and that Wnt, EGF, FGF, Sox2, myc, and Pax6 all fail to maintain proliferation in the absence of BAF53a, providing insight into a novel mechanism underlying neural progenitor cell cycle exit in the continued presence of extrinsic proliferative cues. mSWI/SNF or BAF chromatin regulatory complexes are dosage-sensitive regulators of human neural development frequently mutated in autism spectrum disorders and intellectual disability. Cell cycle exit and differentiation of neural stem/progenitor cells is accompanied by BAF subunit switching to generate neuron-specific nBAF complexes. We manipulated the timing of BAF subunit exchange in vivo and found that early loss of the npBAF subunit BAF53a stalls the cell cycle to disrupt neurogenesis. Loss of BAF53a results in decreased chromatin accessibility at specific neural transcription factor binding sites, including the pioneer factors SOX2 and ASCL1, due to Polycomb accumulation. This results in repression of cell cycle genes, thereby blocking cell cycle progression and differentiation. Cell cycle block upon Baf53a deletion could be rescued by premature expression of the nBAF subunit BAF53b but not by other major drivers of proliferation or differentiation. WNT, EGF, bFGF, SOX2, c-MYC, or PAX6 all fail to maintain proliferation in the absence of BAF53a, highlighting a novel mechanism underlying neural progenitor cell cycle exit in the continued presence of extrinsic proliferative cues.
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影响因子：
16.6
作者：
Braun SMG;Kirkland JG;Chory EJ;Husmann D;Calarco JP;Crabtree GR
通讯作者：
Crabtree GR
影响因子：
8.8
作者：
Baek S;Goldstein I;Hager GL
通讯作者：
Hager GL
影响因子：
64.8
作者：
DOWNES, CS;CLARKE, DJ;JOHNSON, RT
通讯作者：
JOHNSON, RT
影响因子：
64.5
作者：
Eroglu, Elif;Burkard, Thomas R.;Knoblich, Juergen A.
通讯作者：
Knoblich, Juergen A.
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