CCCTC-binding factor: the specific transcription factor of β-galactoside α-2,6-sialyltransferase 1 which up-regulates the sialylation of anti-citrullinated protein antibodies in rheumatoid arthritis.

OBJECTIVE: Sialylation on the crystallizable fragment (Fc) of anti-citrullinated protein antibodies (ACPAs), which is catalysed by β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) could attenuate inflammation of rheumatoid arthritis (RA). In this study, we screened the transcription factor of ST6GAL1 and elucidated the mechanism of transcriptionally up-regulating sialylation of ACPAs in B cells to explore its role in the progression of rheumatoid arthritis (RA).

METHODS: Transcription factors interacting with the P2 promoter of ST6GAL1 were screened by DNA pull-down and LC-MS/MS, and verified by chromatin immunoprecipitation (ChIP), Dual luciferase reporter assay and Electrophoretic mobility shift assay (EMSA). The function of the CCCTC-binding factor (CTCF) on the expression of ST6GAL1 and the inflammatory effect of ACPAs were verified by knocking down and overexpressing CTCF in B cells. Collagen-induced arthritis (CIA) model was constructed from B cells-specific CTCF knockout mice to explore the effect of CTCF on arthritis progression.

RESULTS: We observed that the level of ST6GAL1 and ACPAs sialylation decreased in serum of RA patients and were negatively correlated with DAS28 scores. Subsequently, CTCF was screened and verified as the transcription factor interacting with the P2 promoter of ST6GAL1, which enhances the sialylation of ACPAs, thus weakening the inflammatory activity of ACPAs. Furthermore, the above results were also verified in the CIA model constructed from B cell-specific CTCF knockout mice.

CONCLUSION: CTCF is the specific transcription factor of ST6GAL1 in B cells which up-regulates the sialylation of ACPAs in RA and attenuates the disease progression.