Mapping the genomic landscape of developmental competence in retina

描述(由申请人提供)：项目摘要：视网膜细胞类型是在神经发生过程中一系列离散的时间间隔中产生的。视网膜前体细胞连续获得和失去产生特定细胞类型的能力的分子机制在很大程度上是未知的。然而，对ES细胞分化的研究已经为这种情况的发生提供了洞察力。在谱系承诺之前，许多细胞特异性基因的调控序列都以组蛋白修饰为标志，组蛋白修饰具有转录活性和抑制染色质的特征。二价染色质的这些结构域被认为既促进了指导细胞命运指定的转录因子的招募，又为这些基因在谱系承诺后的快速激活做好了准备。我们假设，类似的机制可能控制视网膜前体细胞的发育能力。为了解决这个问题，我们建议使用CHIP-SEQ来绘制早期和晚期视网膜前体细胞中与转录调控相关的组蛋白修饰的基因组分布。同时，我们将确定组蛋白修饰的变化是否与CHX10和LHX2基因组分布的变化直接相关，这两个前体特异性转录因子调节早期祖细胞的增殖和晚期出生细胞类型的谱系承诺。我们预计这项工作将提供视网膜前体细胞中活性增强子和启动子的全面图谱，并作为未来表观遗传过程在调节视网膜细胞脂肪规格中作用的功能研究的基础。这些研究还可能有助于为旨在生产基于CCell的失明障碍疗法的研究提供信息，并有助于确保高效地产生在疾病中丢失的特定细胞类型。

DESCRIPTION (provided by applicant): Project summary: Retinal cell types are generated during a series of discrete temporal intervals during the course of neurogenesis. The molecular mechanism by which retinal progenitors successively acquire and lose competence to generate specific cell types is largely unknown. Studies of ES cell differentiation, however, have provided insights into how this might occur. Prior to lineage commitment, the regulatory sequences of many cell-specific genes are marked by histone modifications characteristic of both transcriptionally active and repressed chromatin. These domains of bivalent chromatin are proposed to both facilitate recruitment of transcription factors that direct cell fate specificatio and to prime these genes for rapid activation following lineage commitment. We hypothesize that similar mechanisms may control the developmental competence of retinal progenitors. To address this question, we propose to use ChIP-Seq to map the genomic distribution of histone modifications associated with transcriptional regulation in both early and late-stage retinal progenitors. In parallel, we will determine whether changes in histone modifications directly correlate with changes in the genomic distribution of CHX10 and LHX2, two progenitor-specific transcription factors that regulate proliferation of early-stage progenitors and lineage commitment of late-born cell types. We anticipate that this work will provide a comprehensive map of active enhancers and promoters in retinal progenitor cells, and serve as the basis for future functional studies of the role of epigenetic processes in the regulation of retinal cell fat specification. These studies may also help inform research aimed at producing ccell-based therapies for blinding disorders, and help ensure the efficient generation of specific cell types that have been lost in disease.