Background/Purpose: Chromatin modification enzymes regulate gene expression by altering the accessibility of promoters to transcription factors. Several of these enzymes are dysregulated in rheumatoid arthritis, suggesting a role for epigenetic factors in inflammatory arthritis. We sought to determine whether they are dysregulated in psoriatic arthritis (PsA), a seronegative inflammatory arthritis that develops in 30% of patients with cutaneous psoriasis (PsC).

Methods: Total RNA was isolated from peripheral blood of psoriatic disease (PsD) patients (PsA & PsC) and controls. Quantitative RT-PCR arrays were used to profile mRNA expression of 84 genes encoding DNA and histone modification enzymes. Significant fold changes were calculated using the ΔΔCt method and Student’s t-test. Univariate regressions were performed to examine correlations between gene expression (ΔCt) and clinical data.

Results: Gene expression profiling was performed on 20 PsA patients satisfying CASPAR criteria (mean age 48 years, males 45%, age at psoriasis 25 years, age at PsA 32 years, PASI 5.0, active joint count 11, axial disease 35%, treated with methotrexate 35% and prednisone 25%), 18 PsC patients (mean age 45 years, males 50%, age at psoriasis 25 years, PASI 5.2), and 19 controls (mean age 43 years, males 53%). Significantly dysregulated genes (fold change >1.5 or <0.68, p<0.05) are summarized in Table 1. Two genes were significantly dysregulated in PsD vs. controls. In PsC vs. controls, no genes were significantly dysregulated >1.5 or <0.68-fold, but 6 genes were dysregulated >1.2 or <0.84-fold. Eleven genes were significantly dysregulated in PsA vs. controls: HAT1, RPS6KA3, AURKC, HDAC11 (upregulated), and ASH1L, KDM6B, EHMT2, SETD1A, MLL, HDAC9, MLL3 (downregulated). In PsA vs. PsC, 3 genes were significantly dysregulated: HAT1, PRMT8, and HDAC11. In PsA patients, SETD1A expression was positively correlated with methotrexate therapy (p=0.008, r=0.58) but negatively correlated with prednisone therapy (p=0.038, r=-0.47), active joint count (p=0.017, r=-0.53), and axial disease (p=0.014, r=-0.54).

Conclusion: We identified several dysregulated chromatin modification enzymes in psoriatic disease, including histone methyltransferase complex component SETD1A which was downregulated in PsA and correlated with disease expression and therapy. SETD1A is located in a PsA susceptibility region on 16p11.2 that harbors genes involved in IL-23/IL-17/NF-κB signaling. HDAC11, a histone deacetylase involved in inflammation by influencing immune activation versus tolerance was downregulated in PsA compared with PsC. Future studies will seek to validate these results, examine the role of these enzymes in the epigenetic basis of PsA, and determine whether they can serve as biomarkers of PsA susceptibility and disease expression.

 Table 1. Significantly dysregulated genes (p<0.05, fold change >1.5 or <0.68).

Comparison	Gene	Description	Fold Change	95% CI	P-value
PsD vs. Controls	HAT1	Histone acetyltransferase 1	1.54	(1.03,2.04)	0.017
	RPS6KA3	Ribosomal protein S6 kinase, 90kDa, polypeptide 3	1.50	(1.15,1.81)	0.002
PsC vs. Controls†	AURKC	Aurora kinase C	1.39	(0.81,1.97)	0.049
	HDAC11	Histone deacetylase 11	1.30	(0.78,1.82)	0.022
	UBE2A	Ubiquitin-conjugating enzyme E2A	1.24	(1.01,1.47)	0.041
	ASH1L	Ash1 (absent, small, or homeotic)-like	0.84	(0.67,1.01)	0.022
	SETD1A	SET domain containing 1A	0.83	(0.66,0.99)	0.035
	MLL3	Myeloid/lymphoid or mixed-lineage leukemia 3	0.82	(0.64,0.99)	0.034
PsA vs. Controls	HAT1	Histone acetyltransferase 1	2.13	(1.38,2.89)	1.0E-04
	RPS6KA3	Ribosomal protein S6 kinase, 90kDa, polypeptide 3	1.65	(1.24,2.07)	3.0E-04
	ESCO1	Establishment of cohesion 1 homolog 1	1.56	(1.17,1.94)	0.001
	USP16	Ubiquitin specific peptidase 16	1.54	(1.20,1.89)	2.0E-04
	ASH1L	Ash1 (absent, small, or homeotic)-like	0.68	(0.52,0.85)	0.001
	KDM6B	Lysine (K)-specific demethylase 6B	0.68	(0.49,0.86)	0.011
	EHMT2	Euchromatic histone-lysine N-methyltransferase 2	0.68	(0.54,0.82)	0.001
	SETD1A	SET domain containing 1A	0.63	(0.51,0.76)	4.2E-05
	MLL	Myeloid/lymphoid or mixed-lineage leukemia	0.62	(0.46,0.79)	0.001
	HDAC9	Histone deacetylase 9	0.61	(0.31,0.91)	0.018
	MLL3	Myeloid/lymphoid or mixed-lineage leukemia 3	0.61	(0.47,0.74)	6.8E-05
PsA vs. PsC	HAT1	Histone acetyltransferase 1	2.00	(1.39,2.61)	1.0E-04
	PRMT8	Protein arginine methyltransferase 8	1.57	(1.21,1.93)	3.0E-4
	HDAC11	Histone deacetylase 11	0.62	(0.31,0.94)	0.017

^† Fold change > 1.2 or < 0.83.

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