自闭症患者L1反转录转座子表达的探索性分析

IF 6.3 1区 医学 Q1 GENETICS & HEREDITY Molecular Autism Pub Date : 2023-06-28 DOI:10.1186/s13229-023-00554-5
Giovanni Spirito, Michele Filosi, Enrico Domenici, Damiano Mangoni, Stefano Gustincich, Remo Sanges
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引用次数: 0

摘要

背景:自闭症谱系障碍(ASD)是一组高度异质性的神经发育疾病,其遗传病因尚不完全清楚。一些研究依赖于外周组织的转录组分析,将ASD分解为均匀的分子表型。最近,对死后脑组织基因表达变化的分析已经确定了一组基因,这些基因参与了以前与ASD病因相关的途径。除了蛋白质编码转录物外,人类转录组还由大量非编码rna和转座因子(te)组成。测序技术的进步已经证明te可以以一种受调节的方式转录,并且它们的失调可能在脑部疾病中起作用。方法:我们利用已发表的数据集,包括来自(1)ASD受试者死后大脑的RNA-seq数据,(2)在体外细胞培养中敲除10种不同的ASD相关基因,(3)不一致兄弟姐妹的血液。我们测量了进化年轻的全长转座L1元件的表达水平,并表征了失调控L1的基因组位置,评估了它们对asd相关基因转录的潜在影响。我们独立分析了每个样本,避免将疾病受试者聚集在一起以揭示分子表型的异质性。结果:我们在死后脑样本的一个子集中检测到内含子全长L1s的强烈上调,并在体外分化的iPSC神经元中检测到ATRX敲除。L1上调与大量解除调控的基因和保留的内含子相关。在1例受试者的前扣带皮层中,少量显著上调的L1与显著下调的asd相关基因重叠,提示L1转录可能对宿主转录物存在负面影响。局限性:我们的分析必须被认为是探索性的,需要在更大的队列中进行验证。主要的限制是样本量小,并且缺乏对死后脑样本的重复。由于其序列的重复性,测量位点特异性te的转录是复杂的,这降低了将测序读数定位到正确基因组位点的准确性。结论:ASD中的L1上调似乎仅限于一部分受试者,这些受试者的特征还包括典型基因表达的普遍失调和内含子保留的增加。在一些来自前扣带皮层的样本中,L1s的上调似乎直接损害了一些asd相关基因的表达,其机制尚不清楚。因此,L1s上调可能会识别出一组具有共同分子特征的ASD受试者,并有助于对个体进行分层,以制定新的治疗干预策略。
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Exploratory analysis of L1 retrotransposons expression in autism.

Background: Autism spectrum disorder (ASD) is a set of highly heterogeneous neurodevelopmental diseases whose genetic etiology is not completely understood. Several investigations have relied on transcriptome analysis from peripheral tissues to dissect ASD into homogenous molecular phenotypes. Recently, analysis of changes in gene expression from postmortem brain tissues has identified sets of genes that are involved in pathways previously associated with ASD etiology. In addition to protein-coding transcripts, the human transcriptome is composed by a large set of non-coding RNAs and transposable elements (TEs). Advancements in sequencing technologies have proven that TEs can be transcribed in a regulated fashion, and their dysregulation might have a role in brain diseases.

Methods: We exploited published datasets comprising RNA-seq data from (1) postmortem brain of ASD subjects, (2) in vitro cell cultures where ten different ASD-relevant genes were knocked out and (3) blood of discordant siblings. We measured the expression levels of evolutionarily young full-length transposable L1 elements and characterized the genomic location of deregulated L1s assessing their potential impact on the transcription of ASD-relevant genes. We analyzed every sample independently, avoiding to pool together the disease subjects to unmask the heterogeneity of the molecular phenotypes.

Results: We detected a strong upregulation of intronic full-length L1s in a subset of postmortem brain samples and in in vitro differentiated neurons from iPSC knocked out for ATRX. L1 upregulation correlated with an high number of deregulated genes and retained introns. In the anterior cingulate cortex of one subject, a small number of significantly upregulated L1s overlapped with ASD-relevant genes that were significantly downregulated, suggesting the possible existence of a negative effect of L1 transcription on host transcripts.

Limitations: Our analyses must be considered exploratory and will need to be validated in bigger cohorts. The main limitation is given by the small sample size and by the lack of replicates for postmortem brain samples. Measuring the transcription of locus-specific TEs is complicated by the repetitive nature of their sequence, which reduces the accuracy in mapping sequencing reads to the correct genomic locus.

Conclusions: L1 upregulation in ASD appears to be limited to a subset of subjects that are also characterized by a general deregulation of the expression of canonical genes and an increase in intron retention. In some samples from the anterior cingulate cortex, L1s upregulation seems to directly impair the expression of some ASD-relevant genes by a still unknown mechanism. L1s upregulation may therefore identify a group of ASD subjects with common molecular features and helps stratifying individuals for novel strategies of therapeutic intervention.

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来源期刊
Molecular Autism
Molecular Autism GENETICS & HEREDITY-NEUROSCIENCES
CiteScore
12.10
自引率
1.60%
发文量
44
审稿时长
17 weeks
期刊介绍: Molecular Autism is a peer-reviewed, open access journal that publishes high-quality basic, translational and clinical research that has relevance to the etiology, pathobiology, or treatment of autism and related neurodevelopmental conditions. Research that includes integration across levels is encouraged. Molecular Autism publishes empirical studies, reviews, and brief communications.
期刊最新文献
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