Splicing activates transcription from weak promoters upstream of alternative exons.
Splicing activates transcription from weak promoters upstream of alternative exons.
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DOI：
10.1038/s41467-023-39200-2
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发表时间：
2023-06-10
影响因子：
16.6
通讯作者：
Fiszbein, Ana
中科院分区：
文献类型：
--
作者：
Uriostegui-Arcos, Maritere;Mick, Steven T. T.;Shi, Zhuo;Rahman, Rufuto;Fiszbein, Ana
转录和剪接是内在耦合的。内部外显子的选择性剪接可以通过最近描述的外显子介导的转录启动激活（EMATS）现象来微调基因表达。然而，这种现象与人类疾病的关系尚不清楚。在这里，我们开发了一种通过EMATS激活基因表达的策略，并证明了其治疗由必需基因表达缺失引起的遗传疾病的潜力。我们首先确定了人类EMATS基因的目录，并提供了其病理变异的列表。为了验证EMATS是否可以激活基因表达，我们构建了表达基于运动神经元2 （SMN2）基因选择性剪接的剪接报告基因的稳定细胞系。利用目前用于治疗脊髓性肌萎缩症的小分子和反义寡核苷酸（ASOs），我们证明了增加选择性外显子的包含可以通过增强emats样基因的转录而激活基因表达高达45倍。我们观察到，在位于高度包含的跳过外显子近端的弱人类启动子调控下的基因中，效果最强。很少有治疗策略能够上调基因表达。在这里，作者开发了一种通过调节剪接的小分子和反义寡核苷酸激活人类基因表达的方法。
Transcription and splicing are intrinsically coupled. Alternative splicing of internal exons can fine-tune gene expression through a recently described phenomenon called exon-mediated activation of transcription starts (EMATS). However, the association of this phenomenon with human diseases remains unknown. Here, we develop a strategy to activate gene expression through EMATS and demonstrate its potential for treatment of genetic diseases caused by loss of expression of essential genes. We first identified a catalog of human EMATS genes and provide a list of their pathological variants. To test if EMATS can be used to activate gene expression, we constructed stable cell lines expressing a splicing reporter based on the alternative splicing of motor neuron 2 (SMN2) gene. Using small molecules and antisense oligonucleotides (ASOs) currently used for treatment of spinal muscular atrophy, we demonstrated that increase of inclusion of alternative exons can trigger an activation of gene expression up to 45-fold by enhancing transcription in EMATS-like genes. We observed the strongest effects in genes under the regulation of weak human promoters located proximal to highly included skipped exons. Few therapeutic strategies are able to upregulate gene expression. Here, the authors developed an approach to activate expression of human genes through small molecules and antisense oligonucleotides that modulate splicing.
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影响因子：
16
作者：
Dujardin, Gwendal;Lafaille, Celina;Kornblihtt, Alberto R.
通讯作者：
Kornblihtt, Alberto R.
影响因子：
9.8
作者：
Hua, Yimin;Vickers, Timothy A;Baker, Brenda F;Bennett, C Frank;Krainer, Adrian R
通讯作者：
Krainer, Adrian R
影响因子：
46.9
作者：
Bray, Nicolas L.;Pimentel, Harold;Pachter, Lior
通讯作者：
Pachter, Lior
影响因子：
46.9
作者：
Goraczniak, Rafal;Behlke, Mark A.;Gunderson, Samuel I.
通讯作者：
Gunderson, Samuel I.
DOI：
10.1016/b978-0-12-803685-3.00018-5
发表时间：
2017-01-01
期刊：
SPINAL MUSCULAR ATROPHY: DISEASE MECHANISMS AND THERAPY
影响因子：
--
作者：
Hua, Y.;Krainer, A. R.
通讯作者：
Krainer, A. R.