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Journal of RNAi and Gene Silencing : An International Journal of RNA and Gene Targeting Research (1)
Mechanisms of Development (1)
Molecular and Cellular Biology (1)
Gallagher, Joseph M. (2)
Latinkić, Branko V. (2)
Nemer, Mona (2)
Black, Sarah (1)
Bochtler, Matthias (1)
Gallagher, Joseph M (1)
Joyce, Peter I (1)
Kirilenko, Pavel (1)
Komati, Hiba (1)
Kuwabara, Patricia E (1)
Lefebvre, Chantal (1)
Roy, Emmanuel (1)
Yamak, Abir (1)
Year of Publication
Carboxy terminus of GATA4 transcription factor is required for its cardiogenic activity and interaction with CDK4
Latinkić, Branko V.
Mechanisms of Development
•Carboxy terminal region of GATA4 is required for cardiogenesis in Xenopus pluripotent explants and in embryos.•Carboxy terminus of GATA4 interacts with CDK4.•CDK4 enhances transcriptional and cardiogenic activity of GATA4.•GATA4-Tbx5 and GATA4-FOG2 interactions are not required for cardiogenesis.
GATA4-6 transcription factors regulate numerous aspects of development and homeostasis in multiple tissues of mesodermal and endodermal origin. In the heart, the best studied of these factors, GATA4, has multiple distinct roles in cardiac specification, differentiation, morphogenesis, hypertrophy and survival. To improve understanding of how GATA4 achieves its numerous roles in the heart, here we have focused on the carboxy-terminal domain and the residues required for interaction with cofactors FOG2 and Tbx5. We present evidence that the carboxy terminal region composed of amino acids 362–400 is essential for mediating cardiogenesis in Xenopus pluripotent explants and embryos. In contrast, the same region is not required for endoderm-inducing activity of GATA4. Further evidence is presented that the carboxy terminal cardiogenic region of GATA4 does not operate as a generic transcriptional activator. Potential mechanism of action of the carboxy terminal end of GATA4 is provided by the results showing physical and functional interaction with CDK4, including the enhancement of cardiogenic activity of GATA4 by CDK4. These results establish CDK4 as a GATA4 partner in cardiogenesis. The interactions of GATA4 with its other well described cofactors Tbx5 and FOG2 are known to be involved in heart morphogenesis, but their requirement for cardiac differentiation is unknown. We report that the mutations that disrupt interactions of GATA4 with Tbx5 and FOG2, G295S and V217G, respectively, do not impair cardiogenic activity of GATA4. These findings add support to the view that distinct roles of GATA4 in the heart are mediated by different determinants of the protein. Finally, we show that the rat GATA4 likely induces cardiogenesis cell autonomously or directly as it does not require activity of endodermal transcription factor Sox17, a GATA4 target gene that induces cardiogenesis non-cell autonomously.
GATA4; Cardiogenesis; CDK4
Dissociation of Cardiogenic and Postnatal Myocardial Activities of GATA4
Latinkić, Branko V.
Molecular and Cellular Biology
Transcription factor GATA4 is a critical regulator of the embryonic and postnatal heart, but the mechanisms and cofactors required for its diverse functions are not fully understood. Here, we show that whereas the N-terminal domain of GATA4 is required for inducing cardiogenesis and for promoting postnatal cardiomyocyte survival, distinct residues and domains therein are necessary to mediate these effects. Cardiogenic activity of GATA4 requires a 24-amino-acid (aa) region (aa 129 to 152) which is needed for transcriptional synergy and physical interaction with BAF60c. The same region is not essential for induction of endoderm or blood cell markers by GATA4, suggesting that it acts as a cell-type-specific transcriptional activation domain. On the other hand, a serine residue at position 105, which is a known target for mitogen-activated protein kinase (MAPK) phosphorylation, is necessary for GATA4-dependent cardiac myocyte survival and hypertrophy but is entirely dispensable for GATA4-induced cardiogenesis. We find that S105 is differentially required for transcriptional synergy between GATA4 and serum response factor (SRF) but not other cardiac cofactors such as TBX5 and NKX2.5. The findings provide new insight into GATA4 mechanisms of action and suggest that distinct regulatory pathways regulate activities of GATA4 in embryonic development and postnatal hearts.
Manipulating and enhancing the RNAi response
Joyce, Peter I
Kuwabara, Patricia E
Journal of RNAi and Gene Silencing : An International Journal of RNA and Gene Targeting Research
The phenomenon that is known as RNA mediated interference (RNAi) was first observed in the nematode C. elegans. The application of RNAi has now been widely disseminated and the mechanisms underlying the pathway have been uncovered using both genetics and biochemistry. In the worm, it has been demonstrated that RNAi is easily adapted to high throughput analysis and screening protocols. Hence, given the availability of whole genome sequences, RNAi has been used extensively as a tool for annotating gene function. Genetic screens performed with C. elegans have also led to the identification of genes that are essential for RNAi or that modulate the RNAi process. The identification of such genes has made it possible to manipulate and enhance the RNAi response. Moreover, many of the genes identified in C. elegans have been conserved in other organisms. Thus, opportunities are available for researchers to take advantage of the insights gained from the worm and apply them to their own systems in order to improve the efficiency and potency of the RNAi response.
C. elegans; RdRP; RNA interference; siRNA; systemic RNAi
Results 1-3 (3)
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