Computation Analysis of RPE Specific Transcription

描述(申请人提供)：RPE细胞在光感受器外节(POS)下面形成一个单细胞层，负责光感受器外节(POS)的光色素再生和吞噬功能。RPE细胞损伤是老年性黄斑变性(AMD)的主要原因，AMD是工业化国家老年人失明的主要原因。AMD中RPE功能障碍的原因尚不清楚，但由于AMD是一种发病较晚的多因素疾病，RPE转录机制的慢性紊乱可能是导致各种RPE异常的主要机制之一。因此，更好地了解RPE特异性转录将有助于揭示AMD的病因。该项目的总体目标是开发能够系统地识别与RPE特异性有关的假定DNA基序的计算方法和算法。假说是，在其他因素中，RPE特异性表达受与特定DNA序列结合的转录因子以及这些位点在RPE特异性基因附近的可及性的调节。这种机制应该在哺乳动物身上进化保守。为了识别RPE特有的基因，将通过对基因表达实验的深入分析来建立数据库。有了这个数据库，我们将开发基于数学定律的计算算法，以找到富含RPE特定基因的DNA k-mer模式的组合。此外，进入细胞核的调节信号首先遇到染色质，而不是DNA，组蛋白也以序列特异性的方式与DNA结合。因此，我们只将那些与相对“自由”的染色体区域相容且与测试数据集中的基因一致的位点定性为潜在的顺式调控候选位点。计算预测将在合作者的实验室进行实验验证。综上所述，这些方法将使我们能够确定导致RPE特异性的关键监管要素。它将使眼科研究人员能够解决目前难以回答的问题。还预计，由此产生的计算方法将适用范围更广。

DESCRIPTION (provided by applicant): RPE cells form a single cell layer underneath the photoreceptor outer segments (POS) and are responsible for regeneration of photopigments and phagocytosis in growing POS. Impairment of RPE cells is the primary cause of age-related macular degeneration (AMD), the leading cause of blindness among the elderly in industrialized countries. The cause of RPE dysfunction in AMD is not known; however, since AMD is a late onset and multifactorial disease, chronic disruption of the transcriptional machinery of RPE is likely one major mechanism underlying various RPE abnormalities. Thus better understanding RPE-specific transcription will help uncover the etiology of AMD. The overall goal of the project is to develop computational methods and algorithms that can systematically identify putative DNA motifs responsible for RPE specificity. The hypothesis is that, among other factors, RPE-specific expression is regulated by transcription factors binding to specific DNA sequences and the accessibility of these sites in the neighborhood of RPE-specific genes. Such mechanisms should be evolutionarily conserved in mammals. To identify RPE-specific genes, a data library will be created through thorough analysis of gene expression experiments. With this data library, we will then develop computational algorithms based on mathematical laws to find a combination of DNA k-mer patterns enriched in RPE-specific genes. Moreover, regulatory signals entering the nucleus first encounter chromatin, not DNA, and histones binding to DNA were also found in a sequence-specific manner. We thus characterize only those sites compatible with relatively "free" chromosomal regions and consistent with genes in the test dataset as potential candidate sites of cis-regulation. Computational predictions will be verified experimentally in the laboratories of collaborators. Taken together, these approaches will allow us to identify key regulatory elements leading to RPE specificity. It will allow eye researchers to address questions that are currently not easily answered. It is also anticipated that the resulting computational approaches would be applicable much more broadly.