A neuron-specific microexon ablates the novel DNA-binding function of a histone H3K4me0 reader PHF21A.
A neuron-specific microexon ablates the novel DNA-binding function of a histone H3K4me0 reader PHF21A.
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神经元特异性微外显子消除了组蛋白 H3K4me0 阅读器 PHF21A 的新型 DNA 结合功能。
DOI：
10.1101/2023.10.20.563357
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Iwase,Shigeki
中科院分区：
文献类型：
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作者：
Porter,RobertS;Nagai,Masayoshi;An,Sojin;Gavilan,MariaC;Murata-Nakamura,Yumie;Bonefas,KatherineM;Zhou,Bo;Dionne,Olivier;Manuel,JeruManoj;St-Germain,Joannie;Browning,Liam;Laurent,Benoit;Cho,Uhn-Soo;Iwase,Shigeki
细胞类型特异性染色质景观如何在后生动物个体发育过程中出现和发展仍然是一个重要的问题。转录因子以细胞类型特异性的方式表达，并将染色质调节机制募集到特定的基因组位点。相反，染色质调节蛋白广泛表达，并被认为在不同细胞类型中发挥相同的内在功能。然而，人类遗传学研究揭示了神经发育对染色质因子突变的意外脆弱性，其机制未知。在这里，我们报告说，14染色质调节器进行进化保守的神经元特异性剪接事件涉及微外显子。在14种染色质调节剂中，有两种是组蛋白H3 K4去甲基化酶复合物的组成部分;催化亚基LSD 1和H3 K4 me 0阅读蛋白PHF 21 A采用神经元特异性形式。我们发现典型的PHF 21 A（PHF 21 A-c）通过AT-钩基序与DNA结合，而神经元对应物PHF 21 A-n缺乏这种DNA结合功能，但保持H3 K4 me 0识别完整。体外重建的典型和神经元PHF 21 A-LSD 1复合物鉴定的神经元复合物作为一个亚纯型H3 K4去甲基化机制与减少核小体参与。此外，与自闭症相关的PHF 21 A错义突变，1285 G>A，位于神经元微外显子上游的共同外显子的最后一个核苷酸，导致PHF 21 A-n的剪接受损。因此，无处不在的染色质调控复合物通过其亚基的选择性剪接在神经元中发挥独特的内在功能，并可能有助于忠实的人脑发育。
How cell-type-specific chromatin landscapes emerge and progress during metazoan ontogenesis remains an important question. Transcription factors are expressed in a cell-type-specific manner and recruit chromatin-regulatory machinery to specific genomic loci. In contrast, chromatin-regulatory proteins are expressed broadly and are assumed to exert the same intrinsic function across cell types. However, human genetics studies have revealed an unexpected vulnerability of neurodevelopment to chromatin factor mutations with unknown mechanisms. Here, we report that 14 chromatin regulators undergo evolutionary-conserved neuron-specific splicing events involving microexons. Of the 14 chromatin regulators, two are integral components of a histone H3K4 demethylase complex; the catalytic subunit LSD1 and an H3K4me0-reader protein PHF21A adopt neuron-specific forms. We found that canonical PHF21A (PHF21A-c) binds to DNA by AT-hook motif, and the neuronal counterpart PHF21A-n lacks this DNA-binding function yet maintains H3K4me0 recognition intact. In-vitro reconstitution of the canonical and neuronal PHF21A-LSD1 complexes identified the neuronal complex as a hypomorphic H3K4 demethylating machinery with reduced nucleosome engagement. Furthermore, an autism-associatedPHF21Amissense mutation, 1285 G>A, at the last nucleotide of the common exon immediately upstream of the neuronal microexon led to impaired splicing ofPHF21A-n. Thus, ubiquitous chromatin regulatory complexes exert unique intrinsic functions in neurons via alternative splicing of their subunits and potentially contribute to faithful human brain development.