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Cardiovascular biology

How genes know their place

Credit: J. R. WALLS

Embryonic development is largely a matter of switching on the right genes, in the right place, and at the right time — it's no use activating heart-manufacturing genes in the limbs, for instance. Elsewhere in this issue (Nature 432, 107–112; 2004), Benoit G. Bruneau and colleagues describe a protein that keeps heart-specific genes in their place.

Using mice, the authors first discovered that the protein in question, named Baf60c, is initially expressed only in the developing heart. Investigating further, they found that completely eliminating Baf60c from mouse embryos led to major cardiac defects (and early death). Knocking out about 50% of the protein led to somewhat milder, although still ultimately fatal, problems, such as an abnormally straight and split outflow tract (the yellow area in this picture).

Why do these problems occur? Baf60c is part of a complex that controls the accessibility of genes by interacting with transcription factors — proteins that regulate gene expression. So perhaps,without Baf60c, heart-specific genes cannot gain access to the transcriptional machinery and therefore remain inactive. Indeed, Bruneau and colleagues found that many genes that are characteristic of different aspects of heart development are not expressed when Baf60c is eliminated, including various genes involved in the formation of the outflow tract. Moreover, in in vitro studies, the authors showed that Baf60c enhances the interaction between Brg1, a key component of the complex in which Baf60c is found, and certain heart-specific transcription factors.

So, at early stages of development, Baf60c seems to ensure that a complex that alters the structure of DNA — and hence its accessibility to proteins that activate genes — is targeted specifically to genes that are needed for heart development. This mechanism might also work in other tissues, with proteins other than Baf60c providing the necessary specificity. And the findings might bear on human disease: the defects caused by a partial lack of Baf60c are somewhat similar to those seen in some people with congenital heart defects. It remains to be seen, however, how the heart-specific expression of Baf60c is achieved in the first place.

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Tromans, A. How genes know their place. Nature 432, 29 (2004). https://doi.org/10.1038/432029a

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