Genomic analysis of ribosomal DNA and its application to the investigation of disease pathogenesis
Year: 2011
Type: article
Abstract: Background and Significance Overview Structure and transcription of rDNA Organization of the mammalian rDNA repeat Cytological features and chromatin structure of rDNA Nucleosome occupancy of rDNA Transcription of rRNA Cell type-specific regulation of rRNA transcription Epigenetic regulation of rDNA CpG methylation Core histone modifications H1: the linker histone weighs in on rRNA transcription Histone variants H2A.Z H3.3 Nucleosome positioning TTF-I sets the stage for epigenetic regulation of rDNA Formation of heterochromatin at rDNA Noncoding RNA transcripts epigenetically regulate rDNA Establishment of active rDNA chromatin Replication timing of rDNA repeats Consequences of dysregulated ribosome biogenesis Crosstalk between ribosome biogenesis and p53 Ribopathies: human diseases of ribosome biogenesis The Minute mutations General phenomena related to impaired ribosome biogenesis CHD proteins, CHD7, and CHARGE syndrome CHD proteins CHD7 and CHARGE syndrome Summary and research aims Chapter 2: Integrative genomic analysis of human ribosomal DNA Abstract Introduction Results Alignment of high-throughput sequencing data to rDNA Distribution of histone modifications at rDNA Cell type-specificity of histone marks at rDNA Chromatin accessibility and transcription at rDNA Nucleosome occupancy of rDNA ChIP-seq analysis of Pol I chromatin association ChIP-seq analysis of UBF chromatin association The insulator-binding protein CTCF associates with rDNA Discussion Materials and methods Chapter 3: CHD7 functions in the nucleolus as a positive regulator of rRNA biogenesis Abstract Introduction Results CHD7 associates with rDNA CHD7 is dually localized to the nucleoplasm and nucleolus CHD7 influences the levels of the 45S pre-rRNA transcript Depletion of CHD7 reduces cell proliferation and protein synthesis CHD7 antagonizes DNA methylation at active rDNA repeats CHARGE-relevant tissues from Chd7 gene-trap mice show reduced pre-rRNA levels CHD7 promotes rDNA association of the Treacher Collins syndrome protein, treacle Discussion Materials and methods Chapter 4: Investigation into dysregulated ribosome biogenesis as a shared pathogenic component of human haploinsufficiency syndromes Abstract Introduction Results Discussion Chapter 5: Discussion and Future Directions Summary Genomic analysis of rDNA CHD7 positively regulates rRNA synthesis Discussion and future directions How does CHD7 promote rRNA biogenesis?Is dysregulated rRNA transcription a pathogenic component of CHARGE syndrome?Relevance of dysregulated rRNA transcription to CHARGE syndrome Relevance of dysregulated nucleoplasmic transcription to CHARGE syndrome A dual-function model for CHD7 and its relevance to CHARGE syndrome rDNA copy number, CpG methylation, and phenotypic variability in CHARGE syndrome rDNA copy number variation CpG methylation Implications of variable rDNA copy number and CpG methylation for phenotypic variability in CHARGE syndrome Dissecting nucleoplasmic and nucleolar functions of CHD7 Testing the requirements for a nucleoplasmic function of CHD7 in the mouse Separating the functions of CHD7 using patientspecific iPSCs Investigating CHD7 nucleolar targeting via nucleolar protein interactions CHD7 and rRNA biogenesis: a connection to cancer?Further applications of rDNA genomics Condition-dependent alterations in rDNA chromatin structure Distinguishing active and inactive rDNA repeats Large-scale analysis of protein occupancy at rDNA Appendix: Detailed chromatin immunoprecipitation protocol Bibliography List of abbreviations ac acetyl ActD actinomycin D ATP adenosine triphosphate bp base pairs BrdU BSA bovine serum albumin 5-bromo-2'-deoxyuridine CHARGE coloboma of the eye, heart malformations, atresia of the choanae, retardation of growth and development, genital hypoplasia, and ear abnormalities including deafness CHD chromodomain helicase DNA binding protein ChIP chromatin immunoprecipitation ChIP-chip chromatin immunoprecipitation with microarray analysis ChIP-chop chromatin immunoprecipitation with methylation-sensitive restriction digest ChIP-PCR chromatin immunoprecipitation with quantitative PCR ChIP-seq chromatin immunoprecipitation with high-throughput sequencing co-IP co-immunoprecipitation
Author: Gabriel E. Zentner
Institution: Case Western Reserve University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: Strong
OpenAlex ID: W2595081790