MicroRNA-mediated switching of chromatin-remodelling complexes in neural development

By Andrew S. Yoo, Brett T. Staahl, Lei Chen, G. Crabtree. Nature, 2009

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One of the most distinctive steps in the development of the vertebrate nervous system occurs at mitotic exit when cells lose multipotency and begin to develop stable connections that will persist for a lifetime. This transition is accompanied by a switch in ATP-dependent chromatin-remodelling mechanisms that appears to coincide with the final mitotic division of neurons. This switch involves the exchange of the BAF53a (also known as ACTL6a) and BAF45a (PHF10) subunits within Swi/Snf-like neural-progenitor-specific BAF (npBAF) complexes for the homologous BAF53b (ACTL6b) and BAF45b (DPF1) subunits within neuron-specific BAF (nBAF) complexes in post-mitotic neurons. The subunits of the npBAF complex are essential for neural-progenitor proliferation, and mice with reduced dosage for the genes encoding its subunits have defects in neural-tube closure similar to those in human spina bifida, one of the most serious congenital birth defects. In contrast, BAF53b and the nBAF complex are essential for an evolutionarily conserved program of post-mitotic neural development and dendritic morphogenesis. Here we show that this essential transition is mediated by repression of BAF53a by miR-9* and miR-124. We find that BAF53a repression is mediated by sequences in the 3′ untranslated region corresponding to the recognition sites for miR-9* and miR-124, which are selectively expressed in post-mitotic neurons. Mutation of these sites led to persistent expression of BAF53a and defective activity-dependent dendritic outgrowth in neurons. In addition, overexpression of miR-9* and miR-124 in neural progenitors caused reduced proliferation. Previous studies have indicated that miR-9* and miR-124 are repressed by the repressor-element-1-silencing transcription factor (REST, also known as NRSF). Indeed, expression of REST in post-mitotic neurons led to derepression of BAF53a, indicating that REST-mediated repression of microRNAs directs the essential switch of chromatin regulatory complexes.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/50fcac5f569dee1ef7498d23b4871bb5a4466264

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Citations in the corpus

ATP-dependent chromatin remodeling during mammalian development (2016, background): “5 Post-natal BAF45A, BAF53A, SS18 9.5 10 10.5 11 11.5 12 12.5 13 13.5 ≥ P20 BAF45B, BAF45C, BAF53B and CREST Neural tube closure BAF subunit switch BRG1, BAF170 Gliogenesis BAF53 Dendrite development BAF170 SNF2H, CECR2 Neural maturation BRG1, BAF155 CECR2 CHD4 Parallel fiber/Purkinje cell synapsis ”
Epigenetic regulation of neurogenesis in the adult mammalian brain (2011, background): “1A; Yoo et al., 2009; Juliandi et al., 2010).”
Genome Regulation by Polycomb and Trithorax: 70 Years and Counting. (2017, positive): “Interestingly, beyond regulating Hox genes, the mammalian SWI/SNF complex is critically important in cell-fate decisions, such as neuronal differentiation andmitotic exit (Victor et al., 2014; Yoo et al., 2009, 2011).”
Epigenetic modifications and human disease (2010, background): “or interact with chromatin remodeling complexes mediating the exchange of specific subunit”
The Transcription Repressor REST in Adult Neurons: Physiology, Pathology, and Diseases,, (2015, background): “A small dsRNA acts by competing with REST for target gene function (Kuwabara et al., 2005; Yoo et al., 2009).”