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Local chromatin interactions contribute to expression of the fibrinogen gene cluster
Author(s): ,
C. Espitia Jaimes
Affiliations:
Department of Genetic Medicine and Development, University of Geneva, Faculty of Medicine, Geneva, Switzerland
,
R. J. Fish
Affiliations:
Department of Genetic Medicine and Development, University of Geneva, Faculty of Medicine, Geneva, Switzerland
M. Neerman‐Arbez
Affiliations:
Department of Genetic Medicine and Development, University of Geneva, Faculty of Medicine, Geneva, Switzerland. Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland
Correspondence: Marguerite Neerman‐Arbez, Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, 1, rue Michel Servet, 1211 Geneva, Switzerland|Tel: +41 22 379 5655|E‐mail: marguerite.neerman-arbez@unige.ch
ISTH Academy. Neerman-Arbez M. Oct 4, 2018; 234162
Marguerite Neerman-Arbez
Marguerite Neerman-Arbez

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Background
The coordinately regulated genes encoding human fibrinogen are clustered. This evolutionarily conserved configuration provides a possible mechanism for co‐regulation whereby regulatory elements influence gene expression locally. The cluster is flanked by CCCTC‐binding factor (CTCF) interaction sites that are candidate insulator regions mediating chromatin looping.
Objectives
To further our understanding of fibrinogen gene regulation, we aimed to investigate whether interactions exist between parts of the fibrinogen locus and how these contacts contribute to fibrinogen expression.
Methods
We used chromosome conformation capture in cultured cell lines to detect chromatin interactions at the fibrinogen gene cluster. We generated clonal cell lines where two CTCF interaction sites at one end of the locus were deleted using CRISPR‐Cas9‐mediated genome editing. Fibrinogen expression and protein production were measured using qRT‐PCR and ELISA, respectively.
Results
We detected proximity between the ends of the fibrinogen locus, regardless of whether cells express fibrinogen. An interaction between the FGA promoter and the edge of the locus was more frequent in fibrinogen‐expressing cells. Deletion of a CTCF site at one edge of the cluster altered chromatin interactions, reduced steady‐state expression of FGB and FGG mRNA, and led to a halving of secreted fibrinogen. These phenotypes were completely restored by reintroduction of the CTCF interaction motif in previously motif‐deleted clones.
Conclusions
Chromatin interactions are important for the coordinated regulation of the human fibrinogen genes. This finding furthers our comprehension of how fibrinogen is produced and identifies a possible source of variability in plasma fibrinogen levels seen in populations.
Keyword(s)
CCCTC‐binding factor, CRISPR‐cas systems, fibrinogen, gene expression regulation, multigene family
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