CTCF regulates global chromatin accessibility and transcription during rod photoreceptor development

• 成果类型: Article
• 署名作者: Chen, Dahong; Keremane, Saumya; Wang, Silu; Lei, Elissa P.
• 署名单位: National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); State University of New York (SUNY) System; University at Buffalo, SUNY; State University of New York (SUNY) System; University at Buffalo, SUNY
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11763
• DOI: 10.1073/pnas.2416384122
• 发表日期: 2025-03-04
• 关键词: enhancers; expression; genes; cells

摘要

Chromatin architecture facilitates accurate transcription at a number of loci, but it remains unclear how much chromatin architecture is involved in global transcriptional regulation. Previous work has shown that rapid depletion of the architectural protein CTCF in cell culture alters global chromatin organization but results in surprisingly limited gene expression changes. This discrepancy has also been observed when other architectural proteins are depleted, and one possible explanation is that full transcriptional changes are masked by cellular heterogeneity. We tested this idea by performing multiomics analyses with sorted juvenile postmitotic mouse rods, which undergo synchronized development, and we identified CTCF- dependent regulation of global chromatin accessibility and gene expression. CTCF depletion leads to dysregulation of similar to 20% of the entire transcriptome (>3,000 genes) and similar to 41% of genome accessibility (>27,000 sites) before any prominent cellular or physiological phenotypes arise. Importantly, these changes are highly enriched for CTCF occupancy at euchromatin, suggesting direct CTCF binding and transcriptional regulation at these active loci. CTCF mainly promotes chromatin accessibility and frequently inhibits expression of these direct binding targets, which are enriched for binding motifs of transcription repressors. These findings provide different and sometimes opposite conclusions from previous studies, emphasizing the need to consider cellular heterogeneity and cell- type specificity when performing multiomics analyses. CTCF knockout rods undergo complete degeneration by adulthood, indicating an essential role for their viability. We conclude that the architectural protein CTCF binds chromatin and regulates global chromatin accessibility and transcription during rod development.