CTCF Regulates Global Chromatin Accessibility and Transcription During Rod Photoreceptor Development

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2025 Feb 24

PMID 39993185

Authors

Dahong Chen

Saumya Keremane

Silu Wang

Elissa P Lei

Affiliations

Soon will be listed here.

Abstract

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 ~20% of the entire transcriptome (>3,000 genes) and ~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.

Citing Articles

CTCF regulates global chromatin accessibility and transcription during rod photoreceptor development.

Chen D, Keremane S, Wang S, Lei E Proc Natl Acad Sci U S A. 2025; 122(9):e2416384122.

PMID: 39993185 PMC: 11892594. DOI: 10.1073/pnas.2416384122.

References

Zhang H, Lam J, Zhang D, Lan Y, Vermunt M, Keller C . CTCF and transcription influence chromatin structure re-configuration after mitosis. Nat Commun. 2021; 12(1):5157. PMC: 8397779. DOI: 10.1038/s41467-021-25418-5. View

McGill B, Barve R, Maloney S, Strickland A, Rensing N, Wang P . Abnormal Microglia and Enhanced Inflammation-Related Gene Transcription in Mice with Conditional Deletion of in -Expressing Neurons. J Neurosci. 2017; 38(1):200-219. PMC: 5761433. DOI: 10.1523/JNEUROSCI.0936-17.2017. View

Benchorin G, Calton M, Beaulieu M, Vollrath D . Assessment of Murine Retinal Function by Electroretinography. Bio Protoc. 2017; 7(7). PMC: 5698848. DOI: 10.21769/BioProtoc.2218. View

Feodorova Y, Koch M, Bultman S, Michalakis S, Solovei I . Quick and reliable method for retina dissociation and separation of rod photoreceptor perikarya from adult mice. MethodsX. 2015; 2:39-46. PMC: 4487332. DOI: 10.1016/j.mex.2015.01.002. View

Nora E, Goloborodko A, Valton A, Gibcus J, Uebersohn A, Abdennur N . Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization. Cell. 2017; 169(5):930-944.e22. PMC: 5538188. DOI: 10.1016/j.cell.2017.05.004. View

Pero R, Lembo F, Palmieri E, Vitiello C, Fedele M, Fusco A . PATZ attenuates the RNF4-mediated enhancement of androgen receptor-dependent transcription. J Biol Chem. 2001; 277(5):3280-5. DOI: 10.1074/jbc.M109491200. View

Zhang S, Ubelmesser N, Barbieri M, Papantonis A . Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion. Nat Genet. 2023; 55(5):832-840. DOI: 10.1038/s41588-023-01364-4. View

Corces M, Trevino A, Hamilton E, Greenside P, Sinnott-Armstrong N, Vesuna S . An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nat Methods. 2017; 14(10):959-962. PMC: 5623106. DOI: 10.1038/nmeth.4396. View

Kim S, Yu N, Shim K, Kim J, Kim H, Han D . Remote Memory and Cortical Synaptic Plasticity Require Neuronal CCCTC-Binding Factor (CTCF). J Neurosci. 2018; 38(22):5042-5052. PMC: 6705941. DOI: 10.1523/JNEUROSCI.2738-17.2018. View

10.

Frank C, Liu F, Wijayatunge R, Song L, Biegler M, Yang M . Regulation of chromatin accessibility and Zic binding at enhancers in the developing cerebellum. Nat Neurosci. 2015; 18(5):647-56. PMC: 4414887. DOI: 10.1038/nn.3995. View

11.

Sams D, Nardone S, Getselter D, Raz D, Tal M, Rayi P . Neuronal CTCF Is Necessary for Basal and Experience-Dependent Gene Regulation, Memory Formation, and Genomic Structure of BDNF and Arc. Cell Rep. 2016; 17(9):2418-2430. DOI: 10.1016/j.celrep.2016.11.004. View

12.

Golan-Mashiach M, Grunspan M, Emmanuel R, Gibbs-Bar L, Dikstein R, Shapiro E . Identification of CTCF as a master regulator of the clustered protocadherin genes. Nucleic Acids Res. 2012; 40(8):3378-91. PMC: 3333863. DOI: 10.1093/nar/gkr1260. View

13.

Hsieh T, Cattoglio C, Slobodyanyuk E, Hansen A, Darzacq X, Tjian R . Enhancer-promoter interactions and transcription are largely maintained upon acute loss of CTCF, cohesin, WAPL or YY1. Nat Genet. 2022; 54(12):1919-1932. PMC: 9729117. DOI: 10.1038/s41588-022-01223-8. View

14.

Kubo N, Ishii H, Xiong X, Bianco S, Meitinger F, Hu R . Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation. Nat Struct Mol Biol. 2021; 28(2):152-161. PMC: 7913465. DOI: 10.1038/s41594-020-00539-5. View

15.

Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C . Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020; 588(7836):124-129. PMC: 7752134. DOI: 10.1038/s41586-020-2975-4. View

16.

Liu Y, Dekker J . CTCF-CTCF loops and intra-TAD interactions show differential dependence on cohesin ring integrity. Nat Cell Biol. 2022; 24(10):1516-1527. PMC: 10174090. DOI: 10.1038/s41556-022-00992-y. View

17.

Creyghton M, Cheng A, Welstead G, Kooistra T, Carey B, Steine E . Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010; 107(50):21931-6. PMC: 3003124. DOI: 10.1073/pnas.1016071107. View

18.

Madisen L, Zwingman T, Sunkin S, Oh S, Zariwala H, Gu H . A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2009; 13(1):133-40. PMC: 2840225. DOI: 10.1038/nn.2467. View

19.

Solovei I, Kreysing M, Lanctot C, Kosem S, Peichl L, Cremer T . Nuclear architecture of rod photoreceptor cells adapts to vision in mammalian evolution. Cell. 2009; 137(2):356-68. DOI: 10.1016/j.cell.2009.01.052. View

20.

Kaczynski J, Cook T, Urrutia R . Sp1- and Krüppel-like transcription factors. Genome Biol. 2003; 4(2):206. PMC: 151296. DOI: 10.1186/gb-2003-4-2-206. View