Abstract
Mast cell tryptases have crucial roles in allergic and inflammatory diseases. The mouse tryptase genes represent a cluster of loci on chromosome 16p3.3. While their functional studies have been extensively performed, transcriptional regulation of tryptase genes is poorly understood. In this study, we examined the molecular basis of the tryptase gene expression in bone marrow-derived mast cells (BMMCs) of C57BL/6 mice and in MEDMC-BRC6 mast cells. The expression of the Tpsb2 and Tpsg1 genes, which reside at the 3′-end of the tryptase locus, is significantly decreased by the reduction of the GATA transcription factors GATA1 or GATA2. Chromatin immunoprecipitation assays have shown that the GATA factors bind at multiple regions within the locus, including 1.0 and 72.8 kb upstream of the Tpsb2 gene, and that GATA1 and GATA2 facilitate each other’s DNA binding activity to these regions. Deletion of the −72.8 kb region by genome editing significantly reduced the Tpsb2 and Tpsg1 mRNA levels in MEDMC-BRC6 cells. Furthermore, binding of CTCF and the cohesin subunit Rad21 was found upstream of the −72.8 kb region and was significantly reduced in the absence of GATA1. These results suggest that mouse tryptase gene expression is coordinately regulated by GATA1 and GATA2 in BMMCs.
Highlights
Mast cell tryptases are expressed abundantly and are the major component in secretory granules
We showed that conditional ablation of GATA2 in bone marrow-derived mast cells (BMMCs) resulted in the reduced expression of a number of mast cell-specific genes, including the mast cell tryptase genes Tpsb2 and Tpsg1 [18]
The Introduction of Small Interfering RNA (siRNA) Targeting Either GATA1 or GATA2 into BMMCs Leads to a Significant Reduction in Mast Cell Tryptase Gene Expression
Summary
Mast cell tryptases are expressed abundantly and are the major component in secretory granules. Mice lacking mast cell tryptase mMCP6 show impaired immunoprotective activity against bacteria [3] and parasite [4] infection, suggesting its important role in host defense. The genes encoding mast cell tryptase form a cluster of loci on chromosome 16p3.3 and 17A3.3 in humans and mice, respectively. Human tryptase loci contain four genes expressed in mast cells: TPSG1, TPSB2, TPSAB1 and TPSD1. TPSG1 encodes γ-tryptase, the only membrane-anchored member of the family. There are three soluble tryptases—α-, β- (βI, βII and βIII) and δ-tryptase—that are transcribed from three genes, TPSB2, TPSAB1 and TPSD1. The transcripts from the Tpsg, Tpsb and Tpsab genes are mTMT, mMCP6 and mMCP7, respectively. The mTMT is membrane-anchored, whereas mMCP6 and mMCP7 are soluble tryptases
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