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Homeotic hotspot in the human genome for eye and brain disease

人类眼部和脑部疾病基因组中的同源异型热点

基本信息

批准号：
10416324
负责人：
Thomas M. Glaser
金额：
$ 39.26万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10416324
关键词：
3-Dimensional 9q21 Affect Alleles Anatomy Anophthalmos Anterior Apoptosis Architecture Bilateral Biological Assay Blindness Brain Brain Diseases CRISPR/Cas technology Cell Differentiation process Cells Cerebellar Ataxia Cerebellum Childhood Choroid Plexus Epithelium Chromatin Chromosome Fragile Sites Chromosomes Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coloboma Constitutional Cornea Cre driver DNA DNA Binding Defect Development Disease Drosophila genus Ectoderm Electroporation Embryonic Development Enhancers Epithelial Evolution Exhibits Exons Eye Eye diseases Female Genetic Transcription Genome Gonadal structure Heterogeneity Hi-C Human Human Genetics Human Genome In Vitro Inheritance Patterns Iris Kinetics Lens Placodes Life Light Link Meiosis Methods Microphthalmos Modeling Molecular Mosaicism Mus Mutation Neural tube Nucleotides Optic vesicle Organ Pathogenesis Pathogenicity Patients Pattern Phenotype Pigments Pluripotent Stem Cells Positioning Attribute Prevalence Purkinje Cells Retina Retinal Photoreceptors Retinitis Pigmentosa Rod Running Series Signal Transduction Site Specific qualifier value Specificity Spinocerebellar Ataxias Structure of retinal pigment epithelium Surface Syndrome System Techniques Testing Testis Tissues Transcriptional Regulation Transgenes Visual Fields X Inactivation arm brain malformation cell type embryo tissue gain of function histogenesis in utero induced pluripotent stem cell male malformation mouse model nerve stem cell novel optic cup photoreceptor degeneration prenatal proband promoter relating to nervous system retinal neuron sex sex determination single-cell RNA sequencing stem cells transcription factor

项目摘要

PROJECT SUMMARY Classical homeotic mutations (e.g. Drosophila Ubx) disrupt embryonic development, transforming one tissue type into another. We have discovered the molecular basis of four human X-linked disorders affecting the eye or brain – BASR syndrome, foveal dysgenesis, retinitis pigmentosa and spinocerebellar ataxia, which have a homeotic or degenerative basis. Each disorder is caused by insertion of a large autosomal DNA segment at the same Xq27 palindromic site near SOX3, which encodes a potent trans- cription factor homologous to SRY (testis determinant). The Xq insertions are predicted to disrupt chromatin architecture, activating SOX3 ectopically in tissues defined by newly juxtaposed enhancers, and altering cell fate (homeosis) via a gain-of-function (GOF). We propose that SOX3 changes retinal pigment epithelia (RPE) into neuroretina in BASR, reprograms cerebellar Purkinje cells in SCAX5, and triggers photoreceptor degeneration in RP24. Using a novel palinsert PCR assay, we defined the breakpoints and candidate enhancers for each insertion. We also identified >10 further Xq27 disorders affecting the eye, brain or other organs – including unsolved cases with a likely similar mechanism. We will define new Xq27 palindrome insertions and test our hypothesis for disease pathogenesis at chromatin and developmental levels, using [1] patient-derived iPSCs, 3D chromatin interaction assays (Hi-C), in vitro differentiation, serial scRNA-seq profiles; and [2] (homol informative mouse transgenes, including the binary CRISPR/Cas9 Hprt HoP-In ogy promoted integration) GOF system we pioneered – with Sox3HA expression activated in RPE, rods, Purkinje cells, or other tissues via established Cre drivers, in a constitutional (XY) or mosaic (XX) pattern, and in a sustained or Dox-inducible manner.

项目总结