TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish
TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish
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DOI：
10.1038/s41598-019-46632-8
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发表时间：
2019-07-24
影响因子：
4.6
通讯作者：
Bondeson, Marie-Louise
中科院分区：
文献类型：
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作者：
Gudmundsson, Sanna;Wilbe, Maria;Bondeson, Marie-Louise
TATA盒结合蛋白相关因子1（TAF1）蛋白是转录因子II D复合物的关键单元，其在转录起始期间起重要作用。TAF1的变体与神经发育障碍有关，但TAF1的分子功能仍然难以捉摸。在这项研究中，我们提出了一个五代家庭的影响与X连锁的智力残疾，共隔离与TAF1 c。1998，p.（Arg1190Cys）变体。所有受影响的男性表现为智力残疾和畸形特征，而杂合子女性无症状，并有完全偏斜的X染色体失活。我们通过在斑马鱼中建立TAF1直系同源物的第一个完全敲除模型，研究了TAF1的作用及其与神经发育的关系。从该模型中可以推断出人类TAF1在胚胎发生过程中的重要功能，表明完整的TAF1对胚胎发育至关重要。taf1基因敲除斑马鱼的转录组分析揭示了与神经发育过程相关的基因的富集。总之，我们认为功能性TAF1对胚胎发育，特别是神经发育过程至关重要。
The TATA-box binding protein associated factor 1 (TAF1) protein is a key unit of the transcription factor II D complex that serves a vital function during transcription initiation. Variants of TAF1 have been associated with neurodevelopmental disorders, but TAF1's molecular functions remain elusive. In this study, we present a five-generation family affected with X-linked intellectual disability that co-segregated with a TAF1 c. 3568C>T, p.(Arg1190Cys) variant. All affected males presented with intellectual disability and dysmorphic features, while heterozygous females were asymptomatic and had completely skewed X-chromosome inactivation. We investigated the role of TAF1 and its association to neurodevelopment by creating the first complete knockout model of the TAF1 orthologue in zebrafish. A crucial function of human TAF1 during embryogenesis can be inferred from the model, demonstrating that intact taf1 is essential for embryonic development. Transcriptome analysis of taf1 zebrafish knockout revealed enrichment for genes associated with neurodevelopmental processes. In conclusion, we propose that functional TAF1 is essential for embryonic development and specifically neurodevelopmental processes.