Computational Methods for Predicting Changes in 3-D Chromosome Re- arrangement and Gene Deregulation in Human Diseases

预测人类疾病中 3-D 染色体重排和基因失调变化的计算方法

• 批准号: 2105929
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2105929
• 关键词: Computational; Methods; Predicting; Changes; Chromosome

The aim of this project is to develop computational models in order to predict the 3-D chromatin organization. This could be achieved by starting from the HiP-HoP model which allowed to reproduce the conformation of the Pax6 locus obtained through 3C and FISH experiments. The basic idea of HiP-HoP simulations is to represent the chromatin fibre as a bead- spring polymer where each bead corresponds to 1 kb. To understand how genomic loci fold, it is necessary to include proteins (i.e. transcription factors) which can bind particular sites along the chromatin chain forming molecular bridges. The polymer is so composed by beads of different types having a stronger or weaker interaction with transcription factors. Data from the ENCODE project allow to assign a specific type to each bead as they give information about epigenetic marks (e.g. H3K27ac regions), but also about chromatin accessibility (e.g. by using ATAC-seq). This model embeds also possible post-translational modifications or active protein degradation by considering transcription factors as beads which can switch back and forth between a binding and a non-binding state.Chromatin fibre folding is influenced by CTCF/cohesin loops too: to include this loop-extrusion (LE) mechanism, additional springs between non-adjacent beads are introduced in the HiP-HoP model. The springs move during simulations forming loops, and they can bind and unbind to the filament. This last mechanism intends to reproduce interactions between cohesin and CTCF binding sites, since the LE process driven by cohesin stops when this encounters a CTCF site with a motif oriented towards the direction of the extruder. Lastly it is important to depict chromatin as a heteromorphic fibre in order to accu- rately predict the 3-D loci folding within cells with different levels of transcriptional activity. The heteromorphic chromatin is obtained by including additional springs between beads without acetylation mark, leaving H3K27ac regions less compact. All previous features characterize the HiP-HoP model which correctly reproduces the folding of the Pax6 locus, but also of the globin loci, without requiring any fitting to experimental data (e.g. HiC data). The aim of this PhD project is therefore to start from this model to predict confor- mations of loci in other cell types and different organisms.

这个项目的目的是开发计算模型，以预测3-D染色质组织。这可以通过从允许再现通过3C和FISH实验获得的Pax 6基因座的构象的HiP-HoP模型开始来实现。HiP-HoP模拟的基本思想是将染色质纤维表示为珠-弹簧聚合物，其中每个珠对应于Ikb。为了理解基因组基因座如何折叠，有必要包括能够结合沿着染色质链形成分子桥的特定位点的蛋白质（即转录因子）。聚合物由不同类型的珠粒组成，这些珠粒与转录因子具有更强或更弱的相互作用。来自ENCODE项目的数据允许为每个珠子分配特定类型，因为它们提供了关于表观遗传标记（例如H3 K27 ac区域）的信息，而且还提供了关于染色质可及性（例如通过使用ATAC-seq）的信息。该模型还将转录因子视为可以在结合和非结合状态之间来回切换的珠子，从而嵌入了可能的翻译后修饰或活性蛋白降解。染色质纤维折叠也受到CTCF/粘蛋白环的影响：为了包括这种环挤出（LE）机制，在HiP-HoP模型中引入了非相邻珠子之间的额外弹簧。弹簧在模拟过程中移动，形成循环，并且可以绑定和取消绑定到细丝。这最后一种机制旨在再现粘附素和CTCF结合位点之间的相互作用，因为当粘附素遇到具有朝向挤出机方向的基序的CTCF位点时，由粘附素驱动的LE过程停止。最后，为了准确预测具有不同水平转录活性的细胞内的3-D位点折叠，将染色质描绘为异形纤维是重要的。通过在没有乙酰化标记的珠子之间包括额外的弹簧，使H3 K27 ac区域不那么紧凑，获得异形染色质。所有先前的特征表征了HiP-HoP模型，其正确地再现了Pax 6基因座的折叠，而且还再现了珠蛋白基因座的折叠，而不需要对实验数据（例如HiC数据）进行任何拟合。因此，本博士项目的目的是从该模型开始预测其他细胞类型和不同生物体中基因座的构象。