Lineage-specific splicing regulation of MAPT gene in the primate brain.

IF 11.1 Q1 CELL BIOLOGY Cell genomics Pub Date : 2024-06-12 Epub Date: 2024-05-20 DOI:10.1016/j.xgen.2024.100563
Yocelyn Recinos, Suying Bao, Xiaojian Wang, Brittany L Phillips, Yow-Tyng Yeh, Sebastien M Weyn-Vanhentenryck, Maurice S Swanson, Chaolin Zhang
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Abstract

Divergence of precursor messenger RNA (pre-mRNA) alternative splicing (AS) is widespread in mammals, including primates, but the underlying mechanisms and functional impact are poorly understood. Here, we modeled cassette exon inclusion in primate brains as a quantitative trait and identified 1,170 (∼3%) exons with lineage-specific splicing shifts under stabilizing selection. Among them, microtubule-associated protein tau (MAPT) exons 2 and 10 underwent anticorrelated, two-step evolutionary shifts in the catarrhine and hominoid lineages, leading to their present inclusion levels in humans. The developmental-stage-specific divergence of exon 10 splicing, whose dysregulation can cause frontotemporal lobar degeneration (FTLD), is mediated by divergent distal intronic MBNL-binding sites. Competitive binding of these sites by CRISPR-dCas13d/gRNAs effectively reduces exon 10 inclusion, potentially providing a therapeutically compatible approach to modulate tau isoform expression. Our data suggest adaptation of MAPT function and, more generally, a role for AS in the evolutionary expansion of the primate brain.

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灵长类动物大脑中 MAPT 基因的特异性剪接调控。
前体信使 RNA(pre-mRNA)替代剪接(AS)的分化在哺乳动物(包括灵长类动物)中很普遍,但对其潜在机制和功能影响却知之甚少。在这里,我们将灵长类动物大脑中的盒式外显子包含作为一种数量性状建模,并鉴定出1170个(∼3%)外显子在稳定选择下具有品系特异性剪接转变。其中,微管相关蛋白 tau(MAPT)外显子 2 和 10 在猫科动物和同系动物中经历了反相关的两步进化转变,导致了它们在人类中目前的内含水平。第 10 号外显子剪接的发育阶段特异性分化(其失调可导致额颞叶变性(FTLD))是由不同的远端内含子 MBNL 结合位点介导的。CRISPR-dCas13d/gRNA 与这些位点的竞争性结合可有效减少第 10 号外显子的包含,从而为调节 tau 异构体的表达提供了一种潜在的治疗方法。我们的数据表明了 MAPT 功能的适应性,更广泛地说,AS 在灵长类动物大脑的进化扩张中扮演着重要角色。
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