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

许多潜在可治疗的遗传疾病的治疗方法仍然遥不可及，因为我们仍然没有完全了解细胞和组织之间基因是如何被不同地调节的。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，可能会导致不必要的继发性效应。然而，人类中几乎所有的基因都经历了选择性剪接，通过这一过程，单个基因产生了不同的转录本。我们和其他人最近的工作表明，由许多这些基因产生的选择性剪接转录物往往具有更特异性的表达，这为鉴定作为药物开发潜在靶点的特定同种异构体提供了机会。为了进一步鉴定感兴趣的同工异构体，通过整合相关组织中的剪接信息的调节网络的重建来充分表征它们的调节变得越来越重要。该项目的主要目的是开发在人脑转录水平上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.