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Down syndrome critical region-1 is a transcriptional target of nuclear factor of activated T cells-c1 within the endocardium during heart development.

ABSTRACT: Patients with Down syndrome have characteristic heart valve lesions resulting from endocardial cushion defects. The Down syndrome critical region 1 (DSCR1) gene, identified at the conserved trisomic 21 region in those patients, encodes a calcineurin inhibitor that inactivates nuclear factor of activated T cells (NFATc) activity. Here, we identify a regulatory sequence in the promoter region of human DSCR1 that dictates specific expression of a reporter gene in the endocardium, defined by the temporal and spatial expression of Nfatc1 during heart valve development. Activation of this evolutionally conserved DSCR1 regulatory sequence requires calcineurin and NFATc1 signaling in the endocardium. NFATc1 proteins bind to the regulatory sequence and trigger its enhancer activity. NFATc1 is sufficient to induce the expression of Dscr1 in cells that normally have undetectable or minimal NFATc1 or DSCR1. Pharmacologic inhibition of calcineurin or genetic Nfatc1 null mutation in mice abolishes the endocardial activity of this DSCR1 enhancer. Furthermore, in mice lacking endocardial NFATc1, the endogenous Dscr1 expression is specifically inhibited in the endocardium but not in the myocardium. Thus, our studies indicate that the DSCR1 gene is a direct transcriptional target of NFATc1 proteins within the endocardium during a critical window of heart valve formation.

SUBMITTER: Wu H

PROVIDER: S-EPMC2366997 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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Down syndrome critical region-1 is a transcriptional target of nuclear factor of activated T cells-c1 within the endocardium during heart development.

Wu Hai H Kao Shih-chu SC Barrientos Tomasa T Baldwin Scott H SH Olson Eric N EN Crabtree Gerald R GR Zhou Bin B Chang Ching-Pin CP

The Journal of biological chemistry 20070810 42

Patients with Down syndrome have characteristic heart valve lesions resulting from endocardial cushion defects. The Down syndrome critical region 1 (DSCR1) gene, identified at the conserved trisomic 21 region in those patients, encodes a calcineurin inhibitor that inactivates nuclear factor of activated T cells (NFATc) activity. Here, we identify a regulatory sequence in the promoter region of human DSCR1 that dictates specific expression of a reporter gene in the endocardium, defined by the tem ...[more]

PMID: 17693409

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Project description:The LH surge triggers dramatic transcriptional changes in genes associated with ovulation and luteinization. The present study investigated the spatiotemporal expression of nuclear factor IL-3 (NFIL3), a transcriptional regulator of the basic leucine zipper transcription factor superfamily, and its potential role in the ovary during the periovulatory period. Immature female rats were injected with pregnant mare's serum gonadotropin, treated with human chorionic gonadotropin (hCG), and ovaries or granulosa cells were collected at various times after hCG. Nfil3 mRNA was highly induced both in intact ovaries and granulosa cells after hCG treatment. In situ hybridization demonstrated that Nfil3 mRNA was highly induced in theca-interstitial cells at 4-8 h after hCG, localized to granulosa cells at 12 h, and decreased at 24 h. Overexpression of NFIL3 in granulosa cells inhibited the induction of prostaglandin-endoperoxide synthase 2 (Ptgs2), progesterone receptor (Pgr), epiregulin (Ereg), and amphiregulin (Areg) and down-regulated levels of prostaglandin E2. The inhibitory effect on Ptgs2 induction was reversed by NFIL3 small interfering RNA treatment. In theca-interstitial cells the expression of hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (Hpgd) was also inhibited by NFIL3 overexpression. Data from luciferase assays demonstrated that NFIL3 overexpression decreased the induction of the Ptgs2 and Areg promoter activity. EMSA and chromatin immunoprecipitation analyses indicated that NFIL3 binds to the promoter region containing the DNA-binding sites of cAMP response element binding protein and CCAAT enhancer binding protein-β. In summary, hCG induction of NFIL3 expression may modulate the process of ovulation and theca-interstitial and granulosa cell differentiation by regulating expression of PTGS2, PGR, AREG, EREG, and HPGD, potentially through interactions with cAMP response element binding protein and CCAAT enhancer binding protein-β on their target gene promoters.

Dataset Information

Down syndrome critical region-1 is a transcriptional target of nuclear factor of activated T cells-c1 within the endocardium during heart development.

Publications

Down syndrome critical region-1 is a transcriptional target of nuclear factor of activated T cells-c1 within the endocardium during heart development.

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