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Cloning and functional characterization of the human fractalkine receptor promoter regions
Alexandre Garin1, Philippe Pellet, Philippe Deterre
1Laboratoire d'Immunologie Cellulaire et Tissulaire, INSERM U543, Hôpital Pitié-Salpêtrière, 91 Boulevard de l'Hôpital, AP-HP, 75634 Paris cedex 13, France.
Insights
Reduced expression of the fractalkine receptor, CX3CR1, impacts HIV and heart disease. This study reveals CX3CR1 gene regulation involves three promoters and alternative splicing, allowing precise cell-specific expression.
Area of Science:
- Molecular Biology
- Immunology
- Genetics
Background:
- Reduced fractalkine receptor (CX3CR1) expression correlates with faster HIV progression and lower acute coronary event risk.
- Understanding CX3CR1 transcriptional regulation is crucial for elucidating its role in disease.
Purpose of the Study:
- To structurally and functionally characterize the CX3CR1 gene.
- To elucidate the mechanisms of CX3CR1 transcriptional regulation.
Main Methods:
- Gene structure and functional analysis of the CX3CR1 gene.
- Identification and characterization of promoter activities and transcript variants.
- Analysis of alternative splicing in different cell types.
Main Results:
- The CX3CR1 gene comprises four exons and three introns, spanning over 18 kb.
- Three distinct mature messenger transcripts are generated through alternative splicing of untranslated exons with exon 4.
- Constitutive promoter activity upstream of exons 1 and 2 was identified, with cell-specific enhancement by these exons.
Conclusions:
- The CX3CR1 gene exhibits complex transcriptional regulation involving three distinct promoter regions.
- Alternative splicing and promoter usage allow for versatile and precise CX3CR1 expression in various cell types.
- This intricate regulation likely contributes to CX3CR1's diverse roles in health and disease.
Abstract:
We have previously shown that reduced expression of the fractalkine receptor, CX3CR1, is correlated with rapid HIV disease progression and with reduced susceptibility to acute coronary events. In order to elucidate the mechanisms underlying transcriptional regulation of CX3CR1 expression, we structurally and functionally characterized the CX3CR1 gene. It consists of four exons and three introns spanning over 18 kb. Three transcripts are produced by splicing the three untranslated exons with exon 4, which contains the complete open reading frame. The transcript predominantly found in leucocytes corresponds to the splicing of exon 2 with exon 4. Transcripts corresponding to splicing of exons 1 and 4 are less abundant in leucocytes and splicing of exons 3 and 4 are rare longer transcripts. A constitutive promoter activity was found in the regions extending upstream from untranslated exons 1 and 2. Interestingly, exons 1 and 2 enhanced the activity of their respective promoters in a cell-specific manner. These data show that the CX3CR1 gene is controlled by three distinct promoter regions, which are regulated by their respective untranslated exons and that lead to the transcription of three mature messengers. This highly complex regulation may allow versatile and precise expression of CX3CR1 in various cell types.
