Deletion of a single CTCF motif at the boundary of a chromatin domain with three FGF genes disrupts gene expression and embryonic development

Author:

Chakraborty, Shreeta

Wenzlitschke, Nina

Anderson,Matthew

Eraso, Ariel

Baudic, Manon

Thompson, Joyce J

Evans, Alicia A

Shatford-Adams, Lilly M

Chari,Raj

Awasthi,Roackie

Dale, Ryan K

Lewandoski,Mark

Petros, Timothy J

Rocha, Pedro P
Author Address

Unit on Genome Structure and Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA., Genetics of Vertebrate Development Section, Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA., Bioinformatics and Scientific Programming Core, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA., Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Unit on Cellular and Molecular Neurodevelopment, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA., Unit on Genome Structure and Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA; National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: pedrorocha@nih.gov.,

Abstract:

Chromatin domains delimited by CTCF can restrict the range of enhancer action. However, disruption of some domain boundaries results in mild gene dysregulation and phenotypes. We tested whether perturbing a domain with multiple developmental regulators would lead to more severe outcomes. We chose a domain with three FGF ligand genes-Fgf3, Fgf4, and Fgf15-that control different murine developmental processes. Heterozygous deletion of a 23.9-kb boundary defined by four CTCF sites led to ectopic interactions of the FGF genes with enhancers active in the brain and induced FGF expression. This caused orofacial clefts, encephalocele, and fully penetrant perinatal lethality. Loss of the single CTCF motif oriented toward the enhancers-but not the three toward the FGF genes-recapitulated these phenotypes. Our works shows that small sequence variants at particular domain boundaries can have a surprisingly outsized effect and must be considered as potential sources of gene dysregulation in development and disease. Published by Elsevier Inc.

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