Varying expression of four genes sharing a common regulatory sequence may differentiate rheumatoid arthritis from ageing effects on the CD4+ lymphocytes

Abstract

Summary The CD28 gene is similarly down‐regulated in CD4+ lymphocytes from both healthy elderly people and patients with rheumatoid arthritis (RA) because of impaired protein‐binding activity of the ‘α’ sequence in its promoter region. Other genes important for the CD4+ cell function may share that sequence and may be similarly regulated and affected. We searched GenBank for possible ‘α’ homologues and then compared transcriptional activities of the respective genes in the CD4+ cells of young and older healthy individuals and those with RA by real‐time PCR. We show here that genes encoding one of the zinc finger proteins (ZNF334), the ‘aging hormone’ Klotho, the retinoid acid receptor β2 (RARβ2) and the T‐cell adapter protein GRAP‐2, contain sequences with various (exceeding 70%) degrees of homology to the ‘α’ sequence near their promoters. These genes are transcribed in human CD4+ lymphocytes; the expressions of RARβ2, KLOTHO and ZNF334 are significantly decreased in a correlated manner in the cells of patients with RA compared with those of healthy individuals. In RA patients, the extremely reduced expression of ZNF334 does not depend on the individual’s age, apparently constituting a disease‐related phenomenon; whereas that of RARβ2 and KLOTHO occurs mostly in the cells of relatively younger patients, making them similar to the lymphocytes of healthy elderly in this aspect.

Klotho locus, metabolic traits, and serum hemoglobin in hospitalized older patients: a genetic association analysis

“…Gendersegregated analyses with the GRS-tagged approach also confirmed the association of KL variants with LC in males. The present findings confirmed recent studies that have shown that the expression of the KL gene is extremely reduced in the CD4+ lymphocytes of patients with rheumatoid arthritis (Witkowski et al 2007), mostly in the cells of relatively younger patients (Soroczyńska-Cybula et al 2011), making them similar to the lymphocytes of healthy elderly in this aspect. Moreover, an impairment of B lymphopoiesis was demonstrated in mice homozygous for hypomorphic KL alleles and attributed to a defect in the "microenvironment" in the bone marrow (Okada et al 2000).…”

The in vitro modulatory effect of TNFα on the mRNA expression and protein levels of zinc finger protein ZNF334 in CD4+lymphocytes of healthy people

“…It is hypothesized that modified in vitro proliferation dynamics of these cells may be associated with their reduced levels of CD28 expression, earlier proven to be due to an indirect effect of TNFα on the CD28 gene promoter (Bryl et al, 2001). We have demonstrated that the ZNF334 gene promoter contains a sequence closely homologous to the TN-Fα-responsive sequence in the promoter of CD28 gene (Soroczynska-Cybula et al, 2011). These observations led to the hypothesis that also the expression of ZNF334 is controlled by TNFα.…”

“…Zinc finger proteins are thought to function as either positive or negative regulators of expression of other genes (Urrutia, 2003;Soroczynska-Cybula et al, 2011). Recently, a novel function has been proposed for two related zinc finger proteins, ZNF91 and ZNF93, suggested to have evolved to suppress retrotransposons (Jacobs et al, 2014).…”

“…Zinc finger proteins are thought to play an important role as positive or negative regulators of expression of multiple genes, including those involved in the regulation of cell proliferation (Urrutia, 2003;Ghaleb et al, 2005). With the exception of our paper cited above (Soroczynska-Cybula et al, 2011), there are so far (February 2015) no reports about specific function of ZNF334, nor about its disease-associated expression disorders in human T cells.…”

“…We have recently demonstrated that expression of the ZNF334 gene, encoding one of the recently discovered and as yet very poorly characterized members of the family of zinc finger proteins (ZNFs) of is greatly reduced in peripheral blood CD4 + lymphocytes derived from rheumatoid arthritis (RA) patients (Soroczynska-Cybula et al, 2011). Zinc finger proteins are thought to play an important role as positive or negative regulators of expression of multiple genes, including those involved in the regulation of cell proliferation (Urrutia, 2003;Ghaleb et al, 2005).…”