Topic
NBAF complex
About: NBAF complex is a research topic. Over the lifetime, 5 publications have been published within this topic receiving 972 citations.
Papers
TL;DR: It is found 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.
Abstract: A key step in the development of the vertebrate nervous system occurs when cells exit the multipotent neural stem cell state and enter a phase of post-mitotic neural development. This involves a switch in subunit composition of the SWI/SNF-like BAF chromatin remodelling complexes. Here, Yoo et al. show that the switch in BAF subunits is mediated by two microRNAs that are selectively expressed in post-mitotic neurons. During development of the vertebrate nervous system, a switch in the subunit composition of the BAF chromatin-remodelling complex occurs when cells lose multipotency and begin to develop stable connections that will persist for a lifetime. Here, the switch in BAF subunits is shown to be mediated by two microRNAs that are selectively expressed in post-mitotic neurons. 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 lifetime1,2. 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 bifida3, 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 morphogenesis4,5. 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)6. 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.
625 citations
TL;DR: These studies suggest that the genes encoding the individual subunits of BAF complexes function like letters in a ten-letter word to produce biologically specific meanings (in this case dendritic outgrowth) by combinatorial assembly of their products.
406 citations
TL;DR: Surprisingly, mutation of Actl6b relieved repression of early response genes including AP1 transcription factors, increased chromatin accessibility at AP1 binding sites, and transcriptional changes in late response genes associated with early response transcription factor activity.
Abstract: Synaptic activity in neurons leads to the rapid activation of genes involved in mammalian behavior. ATP-dependent chromatin remodelers such as the BAF complex contribute to these responses and are generally thought to activate transcription. However, the mechanisms keeping such "early activation" genes silent have been a mystery. In the course of investigating Mendelian recessive autism, we identified six families with segregating loss-of-function mutations in the neuronal BAF (nBAF) subunit ACTL6B (originally named BAF53b). Accordingly, ACTL6B was the most significantly mutated gene in the Simons Recessive Autism Cohort. At least 14 subunits of the nBAF complex are mutated in autism, collectively making it a major contributor to autism spectrum disorder (ASD). Patient mutations destabilized ACTL6B protein in neurons and rerouted dendrites to the wrong glomerulus in the fly olfactory system. Humans and mice lacking ACTL6B showed corpus callosum hypoplasia, indicating a conserved role for ACTL6B in facilitating neural connectivity. Actl6b knockout mice on two genetic backgrounds exhibited ASD-related behaviors, including social and memory impairments, repetitive behaviors, and hyperactivity. Surprisingly, mutation of Actl6b relieved repression of early response genes including AP1 transcription factors (Fos, Fosl2, Fosb, and Junb), increased chromatin accessibility at AP1 binding sites, and transcriptional changes in late response genes associated with early response transcription factor activity. ACTL6B loss is thus an important cause of recessive ASD, with impaired neuron-specific chromatin repression indicated as a potential mechanism.
55 citations
TL;DR: In this article, the authors discuss the characteristics of CRPC tumors that lack AR activity and the temporal and spatial considerations for the conversion of an ARdependent to an AR-independent tumor type.
Abstract: The use of androgen deprivation therapy and second line anti-androgens in prostate cancer has led to the emergence of tumors employing multiple androgen receptor (AR)-dependent and AR-independent mechanisms to resist AR targeted therapies in castration-resistant prostate cancer (CRPC). While the AR signaling axis remains the cornerstone for therapeutic development in CRPC, a clearer understanding of the heterogeneous biology of CRPC tumors is needed for inno-vative treatment strategies. In this review, we discuss the characteristics of CRPC tumors that lack AR activity and the temporal and spatial considerations for the conversion of an AR-dependent to an AR-independent tumor type. We describe the more prevalent treatment-emergent phenotypes aris-ing in the CRPC disease continuum, including amphicrine, AR-low, double-negative, neuroendo-crine and small cell phenotypes. We discuss the association between the loss of AR activity and tumor plasticity with a focus on the roles of transcription factors like SOX2, DNA methylation, alterna-tive splicing, and the activity of epigenetic modifiers like EZH2, BRD4, LSD1, and the nBAF complex in conversion to a neuroendocrine or small cell phenotype in CRPC. We hypothesize that only a subset of CRPC tumors have the propensity for tumor plasticity and conversion to the neuroendo-crine phenotype and outline how we might target these plastic and emergent phenotypes in CRPC. In conclusion, we assess the current and future avenues for treatment and determine that the heter-ogeneity of CRPCs lacking AR activity will require diverse treatment approaches.
TL;DR: It is proposed that the nBAf complex is a novel epigenetic mechanism for regulating transcription required for long-lasting forms of synaptic plasticity and memory processes and that impaired nBAF function may result in human cognitive disorders.
Related Topics (5)
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| Year | Papers |
|---|---|
| 2021 | 1 |
| 2020 | 1 |
| 2014 | 1 |
| 2009 | 1 |
| 2007 | 1 |