Architecture and expression of the nfatc1 gene in lymphocytes

Abstract

In lymphocytes, the three NFAT factors NFATc1 (also designated as NFAT2), NFATc2 (NFAT1), and NFATc3 (NFAT4 or NFATx) are expressed and are the targets of immune receptor signals, which lead to a rapid rise of intracellular Ca(++), the activation of phosphatase calcineurin, and to the activation of cytosolic NFATc proteins. In addition to rapid activation of NFAT factors, immune receptor signals lead to accumulation of the short NFATc1/αA isoform in lymphocytes which controls their proliferation and survival. In this mini-review, we summarize our current knowledge on the structure and transcription of the Nfatc1 gene in lymphocytes, which is controlled by two promoters, two poly A addition sites and a remote downstream enhancer. The Nfatc1 gene resembles numerous primary response genes (PRGs) induced by LPS in macrophages. Similar to the PRG promoters, the Nfatc1 promoter region is organized in CpG islands, forms DNase I hypersensitive sites, and is marked by histone tail modifications before induction. By studying gene induction in lymphocytes in detail, it will be important to elucidate whether the properties of the Nfatc1 induction are not only typical for the Nfatc1 gene but also for other transcription factor genes expressed in lymphocytes.

Keywords: chromatin; induction; lymphocytes, Nfatc1; transcription.

Figure 1

Molecular organization and epigenetic marks of the Nfatc1 gene. (A) Exon–intron structure of the murine Nfatc1 gene. The two promoters P1 (red) and P2 (blue) and the two poly A addition sites pA1 and pA2 (both in green) are indicated. In intron 10, an enhancer for the Nfatc1 induction in lymphocytes is located, and at the 3′ end of intron 1, an enhancer was described for controlling Nfatc1 transcription in endocardial cells of the developing heart (13). (B) Occurrence of DNase I hypersensitive sites in the human NFATC1 gene in CD34⁺ hematopoietic progenitor cells and CD3⁺ T cells (see http://nihroadmap.nih.gov/epigenomics (14). Note the existence of DNase I hypersensitivity over the promoter region and the intron 10 in which we identified an enhancer for the induction of Nfatc1 gene (Patra et al., in preparation; see below). (C) Epigenetic H3K4me3 marks – as indicator for regulatory elements, which are either poised for or active in transcription (15) – at the promoter region and intron 10 sites in Th1 and Th2 cells (16). Note the appearance of H3K4me3 mark around the P1 and P2 promoters in all types of T cells, whereas the occurrence of H3K4me3 mark in intron 10 is restricted to Th1 and Th2 in which we observed a strong Nfatc1 induction upon cellular activation (17). (D) Accumulation of RNA polymerase II (pol II) and of epigenetic marks on the Nfatc1 gene in DP thymocytes (18). Note the appearance of pol II at promoter P2 and of enhancer mark H3K4me1 in the promoter region and intron 10.