Publication Date:
2014-09-13
Description:
In addition to osteoblast lineage cells, the TNF-like factor Receptor Activator of NF-ΚB ligand (RANKL) is expressed in both B and T cells and may play a role in bone resorption. Rankl expression in mouse T cells is mediated through multiple distal elements marked by increased transcription factor occupancy, histone tail acetylation and RNA polymerase II recruitment. Little is known, however, of the regulation of human RANKL in T cells. Accordingly, we examined the consequence of T cell receptor (TCR) activation on expression of this factor in both Jurkat cells and in primary human T cells. We then explored the mechanism of this regulation by scanning over 400 kb of DNA surrounding the RANKL locus for regulatory enhancers using ChIP-chip analysis. Histone H3/H4 acetylation enrichment identified putative regulatory regions located between -170 and -220 kb upstream of the human RANKL TSS that we designated the human T cell control region (hTCCR). This region showed high sequence conservation with the mouse TCCR. Inhibition of MEK1/2 by U0126 resulted in decreased RANKL expression suggesting that stimulation through MEK1/2 was a prerequisite. ChIP-chip analysis also revealed that c-FOS was recruited to the hTCCR as well. Importantly, both the human RLD5a/b enhancer and segments of the hTCCR mediated robust inducible reporter activity following TCR activation. Finally, SNPs implicated in diseases characterized by dysregulated BMD co-localized to the hTCCR region. We conclude that the hTCCR region contains a cell-selective set of enhancers that plays an integral role in the transcriptional regulation of the TNFSF11 gene in human T cells. J. Cell. Biochem. © 2014 Wiley Periodicals, Inc.
Electronic ISSN:
0091-7419
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
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