Enhancer SINEs Link Pol III to Pol II Transcription in Neurons

Spatiotemporal regulation of gene expression depends on the cooperation of multiple mechanisms, including the functional interaction of promoters with distally located enhancers. Here, we show that, in cortical neurons, a subset of short interspersed nuclear elements (SINEs) located in the proximity of activity-regulated genes bears features of enhancers. Enhancer SINEs (eSINEs) recruit the Pol III cofactor complex TFIIIC in a stimulus-dependent manner and are transcribed by Pol III in response to neuronal depolarization. Characterization of an eSINE located in proximity to the Fos gene (FosRSINE1) indicated that the FosRSINE1-encoded transcript interacts with Pol II at the Fos promoter and mediates Fos relocation to Pol II factories, providing an unprecedented molecular link between Pol III and Pol II transcription. Strikingly, knockdown of the FosRSINE1 transcript induces defects of both cortical radial migration in vivo and activity-dependent dendritogenesis in vitro, demonstrating that FosRSINE1 acts as a strong enhancer of Fos expression in diverse physiological contexts

RanBP1 Couples Nuclear Export and Golgi Regulation through LKB1 to Promote Cortical Neuron Polarity

Neuronal polarity in the developing cortex begins during the early stages of neural progenitor migration toward the cortical plate and culminates with the specification of the axon and dendrites. Here, we demonstrate that the Ran-dependent nucleocytoplasmic transport machinery is essential for the establishment of cortical neuron polarity. We found that Ran-binding protein 1 (RanBP1) regulates axon specification and dendritic arborization in cultured neurons in vitro and radial neural migration in vivo. During axonogenesis, RanBP1 regulates the cytoplasmic levels of the polarity protein LKB1/Par4, and this is dependent on the nuclear export machinery. Our results show that downstream of RanBP1, LKB1 function is mediated by the STK25-GM130 pathway, which promotes axonogenesis through Golgi regulation. Our results indicate that the nucleocytoplasmic transport machinery is a main regulator of neuron polarity, including radial migration, and that the regulated export of LKB1 through RanBP1 is a limiting step of axonogenesis

H3.3(K27M) Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas

Gain-of-function mutations in histone 3 (H3) variants are found in a substantial proportion of pediatric high-grade gliomas (pHGG), often in association with TP53 loss and platelet-derived growth factor receptor alpha (PDGFRA) amplification. Here, we describe a somatic mouse model wherein H3.3K27M and Trp53 loss alone are sufficient for neoplastic transformation if introduced in utero. H3.3K27M-driven lesions are clonal, H3K27me3 depleted, Olig2 positive, highly proliferative, and diffusely spreading, thus recapitulating hallmark molecular and histopathological features of pHGG. Addition of wild-type PDGFRA decreases latency and increases tumor invasion, while ATRX knockdown is associated with more circumscribed tumors. H3.3K27M-tumor cells serially engraft in recipient mice, and preliminary drug screening reveals mutation-specific vulnerabilities. Overall, we provide a faithful H3.3K27M-pHGG model which enables insights into oncohistone pathogenesis and investigation of future therapies

The role of ATP-dependent chromatin remodelling factors in cortical development.

Epigenetic modifications of DNA and histones play a key role in governing the expression of genes essential during neural development. Histone deacetylase (HDAC) enzymes exert their functions by directly promoting changes in neuronal gene expression through the interaction with chromatin remodelling proteins and specific transcription factors. In cortical neurons, S-nitrosylation of HDAC2 results in transcriptional activation of genes that support neuronal survival and dendritogenesis (Nott et al., 2008). Bead array analysis identified brahma (Brm), a subunit of the ATP-dependent chromatin remodelling complex Brm/Brg-associated factor (BAF), as one of the genes regulated by HDAC2 S-nitrosylation. Expression of mutant form of HDAC2 that cannot be S-nitrosylated decreased Brm protein levels, leading to defects of radial neuronal migration and cortical laminar pattern. Thus, HDAC2 S-nitrosylation is necessary for the correct neuron radial migration during cortical development. HDACs are recruited to chromatin and exert their transcriptional regulatory functions via interaction with other nuclear factors, as part of multiprotein complexes. To identify the binding partners of HDAC2 in cortical neurons, whole sample mass spectrometry analysis was performed. Our analysis revealed a direct interaction of HDAC2 with nucleosome remodelling and histone deacetylase (NuRD) repressor complex. The core ATPase subunit of the NuRD complex includes a family of mutually exclusive chromodomain helicase DNA binding (CHD) proteins, named CHD3, CHD4 and CHD5. In embryonic cortex CHD4 is expressed in proliferating neuronal progenitors and maintained in postmitotic neurons, whereas homologous CHD3 and CHD5 are confined to postmitotic neurons. CHD3, CHD4 and CHD5 are associated with the promoters of neuronal genes indicating that they directly regulate transcriptional programs during neural development. Importantly, down-regulation of CHD3 subunit specifically expressed in postmitotic neurons, results in cortical radial migration defects, confirming the role of NuRD in cortical development. These studies highlight the importance of HDAC2 S-nitrosylation and ATP-dependent chromatin remodelling complexes in cortical development and cortical radial migration

S-nitrosylation of HDAC2 regulates the expression of the chromatin-remodeling factor Brm during radial neuron migration

<p>Dynamic epigenetic modifications play a key role in mediating the expression of genes required for neuronal development. We previously identified nitric oxide (NO) as a signaling molecule that mediates S-nitrosylation of histone deacetylase 2 (HDAC2) and epigenetic changes in neurons. Here, we show that HDAC2 nitrosylation regulates neuronal radial migration during cortical development. Bead-array analysis performed in the developing cortex revealed that brahma (Brm), a subunit of the ATP-dependent chromatin-remodeling complex BRG/brahma-associated factor, is one of the genes regulated by S-nitrosylation of HDAC2. In the cortex, expression of a mutant form of HDAC2 that cannot be nitrosylated dramatically inhibits Brm expression. Our study identifies NO and HDAC2 nitrosylation as part of a signaling pathway that regulates cortical development and the expression of Brm in neurons.</p>