ATP-dependent chromatin remodeling in neural development

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Recent advances have revealed that modification of chromatin structure is an important determinant of cell fate and function. DNA methylation and covalent modifications of histone tails contribute to changes in chromatin architectures, either enhancing or repressing gene expression. Another mechanism underlying the modification of chromatin structure relies on the activity of the SWI/SNF-related ATP-dependent chromatin remodeling complexes that control the accessibility of DNA sequences to transcription factors. There is increasing evidence that ATP-dependent chromatin remodeling complexes based on the alternative DNA-dependent ATPases, Brg1 and Brm, plays essential roles during neural development in both vertebrates and invertebrates. This remodeling complex has dedicated functions at different stages of neural development that appear to arise by combinatorial assembly of its subunits.

Introduction

Vertebrate genomes contain about 30 genes encoding ATP-dependent chromatin remodeling enzymes that are often subunits of large polymorphic complexes resembling the yeast SWI/SNF complex [1••]. Recent studies have revealed that one family of complexes based on the Brg1 and Brm ATPases (BAF complexes) has particularly crucial dosage-dependent roles in the development of the nervous system [2, 3••, 4••]. Exchanges of subunits within BAF complexes accompany the transitions, from pluripotent to multipotent stem cells and finally to post-mitotic neurons, and appear to be crucial for these transitions [5••, 6••].

Section snippets

ATP-dependent chromatin remodeling and the development of the invertebrate nervous system

As summarized in Table 1, screens for genes involved in neurogenesis or morphogenesis of dendrites of neurons in invertebrate systems identified subunits of BAF complexes to be important for various aspects of neural development. Recently, Parrish et al. performed an RNAi screen to identify transcription factors that influenced dendrite formation of class I da neurons in the peripheral nervous system (PNS) in Drosophila embryos [7••]. Close examination of defects in dendrite morphogenesis

Genetics and biochemical features of BAF complexes in mammals

In mammals, the composition of BAF complexes is polymorphic with subunits encoded by homologous gene families, members of which assume mutually exclusive occupancy in the complex [14, 15, 16]. The core ATPase subunit is encoded by Brg1 and Brm in mammals. Although genome wide mapping in neurons has not been done, studies in embryonic stem (ES) cells indicate that there are about 10 000 BAF binding sites per genome and about half of these occur near genes most commonly near the transcription

Physical interactors with BAF complex

Numerous studies identified proteins that interact with BAF complexes, and in this review, we focus on a number of the interacting proteins important for neural development. The variety of interactions appears to arise from the different subunit compositions of the complexes such that the chromatin remodeler is tailored to the needs of a specific cell type (Figure 1). Neural restrictive silencing factor (NRSF or REST) is a zinc finger domain transcription factor that binds to its target sites

BAF subunit switching during neural development

In mammals, the composition of BAF complexes is highly polymorphic owing to multiple gene families that encode the subunits. The resulting combinatorial assembly of BAF complexes plays an essential role during neural development. Two subunits, BAF45a and BAF53a, are assembled into BAF complexes in neural progenitors (designated as npBAF complex). During neuronal differentiation, the expression of BAF45a and BAF53a diminishes, and their places are replaced by homologous members, BAF45b and

Conclusion

ATP-dependent chromatin remodeling has generally been considered to play a permissive role in development. However, recent evidence is suggesting a far more complex and programmatic function in the development of the nervous system of both invertebrates and vertebrates. The combinatorial assembly of the complexes makes genetic analysis complicated, yet current evidence indicates that combinatorial assembly underlies refinement and specificity of their functions.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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