Background/Purpose: Understanding the genetic and epigenetic background of rheumatoid arthritis (RA) is complex since multiple genes and environmental factors are involved. By conducting congenic mapping in mice and genome-wide association studies (GWAS) in humans a number of arthritis risk loci were explored. One of the arthritis loci was identified on human chromosome 9 that is syntenic with mouse chromosome 2. Transcriptome analyses identified the PHD finger protein 19 (PHF19) gene in this chromosomal region that showed differential expression in arthritic samples. PHF19 is a component of a multiprotein complex, which is responsible of heritable silencing of genes. To understand the molecular function of PHF19 in autoimmune arthritis, Phf19^-/- KO animals were generated and investigated in a murine model of RA.

Methods: Phf19 gene was ablated from the mouse genome by conventional KO methodology. Human proteoglycan (PG)-induced arthritis (PGIA) model was used to investigate Phf19 function in arthritis. Since PGIA is MHC-controlled autoimmune disease, speed congenic approach was employed to put the ablated Phf19 region into full BALB/c genetic background. PGIA susceptibility was tested in Phf19^-/- KO and wild type BALB/c mice. Flow cytometry was used to identify the affected cell types in bone marrow and secondary lymphoid organs. Phf19 ablation provoked gene expression profile change was explored using gene expression microarray platforms. Quantitative reverse transcription PCR was employed to verify microarray data.

Results: Phf19-ablated adult mice had normal body weight, and no visible skeletal malformation was observed. Genetic deletion of Phf19 did not affect fertility and embryogenesis and normal pups of normal litter size was born from Phf19^-/- KO animals. However, Phf19^-/- KO female mice were more susceptible for PGIA. We detected altered B cell development in bone marrow and secondary lymphoid organs. The genetic ablation triggered gene expression profile changes are under investigation.

Conclusion: Our studies provide the first experimental evidence that Phf19, an epigenetic factor, is directly involved in arthritis pathogenesis and can be considered as a risk factor in autoimmune arthritis. The exact role of Phf19 in arthritis must be explored by investigating the associated gene regulatory network, which might reveal some additional druggable genes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-ablation-of-phd-finger-protein-19-gene-promotes-autoimmune-arthritis-in-mice/