There is more than meet the eye: reconstruction of isoform level regulatory networks in the human brain

许多潜在的可治疗的遗传疾病的治疗仍然脱节，因为我们仍然没有一个完整的图片如何基因在细胞和组织之间的不同调节。许多基因，包括一些与性状和疾病直接相关的基因，在细胞和组织中广泛表达，如果盲目地用药物靶向，会导致潜在的不良副作用。然而，几乎所有的人类基因都经历了选择性剪接，通过这个过程，不同的转录本从一个单一的基因产生。最近的工作由我们和其他人证明，选择性剪接的转录本产生的许多这些基因往往有一个更具体的表达，打开了机会，以确定特定的异构体作为药物开发的潜在目标。为了进一步鉴定感兴趣的异构体，通过重建整合相关组织中剪接信息的调控网络来充分阐明其调控变得越来越重要。该项目的主要目的是开发在人脑转录水平重建调控网络的方法，评估候选基因的转录调控，并评估遗传变异对转录调控的影响。

Therapies for many potentially treatable genetic diseases remain out of touch because we still don't have a full picture of how genes are regulated differently between cells and tissues. Many genes, including some directly associated with traits and disorders, are widely expressed across cells and tissues, leading to potential unwanted secondary effects if blindly targeted with medications. However, nearly all genes in humans undergo alternative splicing, the process through which different transcripts are generated from a single gene.Recent work by us and others demonstrated that alternatively spliced transcripts arising from many of these genes tend to have a much more specific expression, opening the opportunity to identify specific isoforms as potential targets for drug development. To further the identification of isoforms of interest it is becoming increasingly important to fully characterise their regulation through the reconstruction of regulatory networks integrating splicing information in relevant tissues.The main aim of the project is to develop approaches to reconstruct regulatory networks at the transcript level in the human brain, assess the transcript regulation for candidate genes, and assess the impact of genetic variation on transcript regulation.