Epigenetic Regulation of Retinal Development by BCOR

BCOR 对视网膜发育的表观遗传调控

• 批准号: 10367943
• 负责人: Michelle Zhang
• 金额: $ 5.18万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367943
• 关键词: 5' Untranslated Regions; Address; Affect; Anophthalmos; Binding; Cell Differentiation process; Cell Extracts; Cell Line; Cells; ChIP-seq; Childhood; Chromatin; Chromatin Remodeling Factor; Complex; Congenital Disorders; Data; Defect; Dental Pulp; Development; Disease; Embryo; Epigenetic Process; Eye Development; Eye diseases; Frameshift Mutation; Gatekeeping; Gene Mutation; Generations; Genes; Genetic Transcription; Global Change; HDAC1 gene; Histone H2A; Human; Immunofluorescence Immunologic; In Situ Hybridization; Knowledge; LHX2 gene; Link; Lysine; Mass Spectrum Analysis; Mediating; Microdissection; Microphthalmos; Modeling; Modification; Mutate; Mutation; Neurodegenerative Disorders; Optic vesicle; Organoids; PRC1 Protein; Patients; Persons; Phenotype; Play; Polycomb; Process; Proteins; Quality of life; RB1 gene; RNA; Rana; Regenerative Medicine; Regulation; Retina; Retinal Degeneration; Retinal Diseases; Retinoblastoma; Role; Stains; Syndrome; Testing; Time; Tissues; Transcript; Variant; Vision; Visual Fields; Xenopus; Zebrafish; base; cell type; chromatin remodeling; design; epigenetic regulation; experimental study; gene network; histone modification; improved; in vitro Model; in vivo; induced pluripotent stem cell; knock-down; malignant neoplasm of eye; neurogenesis; novel; optic cup; recruit; regenerative approach; retinal progenitor cell; stem cells; transcription factor; transcriptome sequencing

Project Summary Normal vision depends on the balanced generation and homeostatic regulation of major retinal cell types, and the disruption of these processes may result in congenital retinal disorders and retinal degeneration, affecting millions of people around the world each year. Regenerative medicine depends on our understanding of retinal development for informing retinal cell reprogramming and manufacturing. While there have been significant advances in unravelling the roles of transcription factors, a major gap exists in our knowledge of how these tightly regulated gene networks are governed by epigenetic mechanisms. Polycomb-group complexes are evolutionarily conserved epigenetic machineries that remodel chromatin through histone modifications for silencing targeted genes and have been recently shown to affect retinal neurogenesis and lineage decisions. BCOR is a component of the Polycomb Repressive Complex 1 variant that ubiquitinates lysine 119 on histone H2A (H2AK119Ub). Dysregulation of BCOR is clearly associated with eye and retinal disorders, including Lenz microphthalmia, Oculofaciocardiodental Syndrome, and retinoblastoma, but its role in retinal neurogenesis is still not well understood. In preliminary studies, I performed coimmunoprecipitation-mass spectrometry and validated BCOR’s interaction with other PcG proteins in retinal cells. I then performed BCOR chromatin immunoprecipitation sequencing (ChIP-seq) and identified strong peaks at retinal progenitor genes LHX2, PAX6, SIX3, and SIX6, all of which are significant in optic vesicle development and later play distinct roles in retinal cell fate decisions. Thus, I propose to investigate the role of BCOR in retinal neurogenesis. I hypothesize that BCOR mediates the switch from retinal progenitors to differentiated cell types by recruiting PcG proteins to regulate H2AK119Ub on the chromatin to repress multipotency genes. I will test this hypothesis with the following aims: (1) Identify the epigenetic mechanism of BCOR for regulating retinal progenitor genes, and (2) Determine how BCOR affects the generation of major retinal cell types in vivo. My overall objective is to characterize BCOR-ncPRC1.1’s role in retinal development as an avenue to discovering new epigenetic targets for regenerative strategies in the retina.

项目摘要 正常视力取决于主要残留细胞类型的平衡产生和稳态调节，以及 这些过程的破坏可能导致先天性残留障碍和残留变性，从而影响 每年世界各地数百万人。再生医学取决于我们对残留的理解 开发用于视网膜细胞重编程和制造的开发。虽然有重要的 揭示转录因素的作用的进步，我们了解这些方面的主要差距 严格调节的基因网络受表观遗传机制的控制。多肉液组合物为 进化配置的表观遗传机通过组蛋白修饰重塑染色质 沉默的靶向基因，最近已证明会影响残留的神经发生和谱系决策。 BCOR是Polycomb抑制复合物1变体的组成部分，可在组蛋白上泛素赖氨酸119 H2A（H2AK119UB）。 BCOR的失调显然与包括Lenz在内的眼睛和残留障碍有关 微观心脏病，眼球性心动过性综合征和视网膜母细胞瘤，但其在视网膜神经发生中的作用是 仍然不太了解。在初步研究中，我进行了共免疫沉淀 - 质谱法和 验证了BCOR与残留细胞中其他PCG蛋白的相互作用。然后我进行了Bcor染色质 免疫沉淀测序（CHIP-SEQ），并确定了视网膜祖细胞基因LHX2的强峰， PAX6，SIX3和SIX6，所有这些在视囊发育中都很重要，后来在 视网膜细胞脂肪决策。我建议研究BCOR在视网膜神经发生中的作用。我 假设BCOR通过招募从残余祖细胞到分化细胞类型的转换介导 PCG蛋白在染色质上调节H2AK119UB，以反映多能基因。我会测试这个 假设的以下目的：（1）确定BCOR的表观遗传机制用于调节永久性 祖细胞基因和（2）确定BCOR如何影响体内主要残留细胞类型的产生。我的 总体目标是将BCOR-NCPRC1.1在视网膜发展中的作用描述为发现的途径 视网膜再生策略的新表观遗传靶标。