Yong Chen1, Xinmin Cao. 1. Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Singapore City 138673, Singapore.
Abstract
BACKGROUND INFORMATION: The transcription factor NFAT (nuclear factor of activated T-cell) family comprises important regulators in immuno-responses and mouse embryonic development, including early cardiovascular and heart valve development. The mechanism involved, however, is not fully understood. Nkx2-5 (NK2 transcription factor related, locus 5) is one of the earliest genes expressed in early cardiac progenitor cells and is essential for heart tube development by control of a subset of cardiac muscle-specific genes. Previously we found that downregulation of mitochondrial respiratory chain complex I caused severe cardiac deficiencies during heart tube development in Xenopus embryos associated with compromised Nkx2-5 expression. However, the heart defects and Nkx2-5 expression could be rescued by a constitutively activated NFAT, suggesting a possible link between NFAT and Nkx2-5 during early heart development. RESULTS: In the present study, we demonstrate that NFAT regulates Nkx2-5 expression in both mouse ES (embryonic stem) cells and P19 cells, a mouse model for embryonic differentiation. We found that there are six core NFAT-binding elements in the 5' regulatory region of the Nkx2-5 gene. Although NFAT is able to bind directly to all but one of these elements, it activates Nkx2-5 transcription only via a specific binding site in the distal enhancer region. Interestingly, the transcriptional activity of NFAT is largely dependent on the co-factor GATA (GATA-binding transcription factor), which binds to an element adjacent to this key NFAT-binding site. Furthermore, binding of the endogenous NFAT to this particular site was observed during cardiac differentiation in mouse ES and P19 cells. CONCLUSIONS: The results suggest that Nkx2-5 is a direct target of NFAT that co-ordinates with other transcription factors such as GATA4 to regulate Nkx2-5 during cardiogenesis.
BACKGROUND INFORMATION: The transcription factor NFAT (nuclear factor of activated T-cell) family comprises important regulators in immuno-responses and mouse embryonic development, including early cardiovascular and heart valve development. The mechanism involved, however, is not fully understood. Nkx2-5 (NK2 transcription factor related, locus 5) is one of the earliest genes expressed in early cardiac progenitor cells and is essential for heart tube development by control of a subset of cardiac muscle-specific genes. Previously we found that downregulation of mitochondrial respiratory chain complex I caused severe cardiac deficiencies during heart tube development in Xenopus embryos associated with compromised Nkx2-5 expression. However, the heart defects and Nkx2-5 expression could be rescued by a constitutively activated NFAT, suggesting a possible link between NFAT and Nkx2-5 during early heart development. RESULTS: In the present study, we demonstrate that NFAT regulates Nkx2-5 expression in both mouse ES (embryonic stem) cells and P19 cells, a mouse model for embryonic differentiation. We found that there are six core NFAT-binding elements in the 5' regulatory region of the Nkx2-5 gene. Although NFAT is able to bind directly to all but one of these elements, it activates Nkx2-5 transcription only via a specific binding site in the distal enhancer region. Interestingly, the transcriptional activity of NFAT is largely dependent on the co-factor GATA (GATA-binding transcription factor), which binds to an element adjacent to this key NFAT-binding site. Furthermore, binding of the endogenous NFAT to this particular site was observed during cardiac differentiation in mouse ES and P19 cells. CONCLUSIONS: The results suggest that Nkx2-5 is a direct target of NFAT that co-ordinates with other transcription factors such as GATA4 to regulate Nkx2-5 during cardiogenesis.
Authors: Patrick van Vliet; Teun P de Boer; Marcel A G van der Heyden; Mazen K El Tamer; Joost P G Sluijter; Pieter A Doevendans; Marie-José Goumans Journal: Stem Cell Rev Rep Date: 2010-06 Impact factor: 5.739
Authors: Nai-Ming Chen; Garima Singh; Alexander Koenig; Geou-Yarh Liou; Peter Storz; Jin-San Zhang; Lisanne Regul; Sankari Nagarajan; Benjamin Kühnemuth; Steven A Johnsen; Matthias Hebrok; Jens Siveke; Daniel D Billadeau; Volker Ellenrieder; Elisabeth Hessmann Journal: Gastroenterology Date: 2015-01-23 Impact factor: 22.682