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Nuclear Arc Interacts with the Histone Acetyltransferase Tip60 to Modify H4K12 Acetylation(1,2,3).

Wee CL, Teo S, Oey NE, Wright GD, VanDongen HM, VanDongen AM - eNeuro (2014)

Bottom Line: Although Arc protein is found at synapses, it also localizes to the neuronal nucleus, where its function is less understood.Neuronal activity-induced expression of Arc (1) increases endogenous nuclear Tip60 puncta, (2) recruits Tip60 to PML bodies, and (3) increases histone acetylation of Tip60 substrate H4K12, a learning-induced chromatin modification.These mechanisms point to an epigenetic role for Arc in regulating memory consolidation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School , Singapore 169857.

ABSTRACT
Arc is an immediate-early gene whose genetic ablation selectively abrogates long-term memory, indicating a critical role in memory consolidation. Although Arc protein is found at synapses, it also localizes to the neuronal nucleus, where its function is less understood. Nuclear Arc forms a complex with the β-spectrin isoform βSpIVΣ5 and associates with PML bodies, sites of epigenetic regulation of gene expression. We report here a novel interaction between Arc and Tip60, a histone-acetyltransferase and subunit of a chromatin-remodelling complex, using biochemistry and super-resolution microscopy in primary rat hippocampal neurons. Arc and βSpIVΣ5 are recruited to nuclear Tip60 speckles, and the three proteins form a tight complex that localizes to nuclear perichromatin regions, sites of transcriptional activity. Neuronal activity-induced expression of Arc (1) increases endogenous nuclear Tip60 puncta, (2) recruits Tip60 to PML bodies, and (3) increases histone acetylation of Tip60 substrate H4K12, a learning-induced chromatin modification. These mechanisms point to an epigenetic role for Arc in regulating memory consolidation.

No MeSH data available.


Related in: MedlinePlus

Arc, β-Spectrin IV (βSpec), and Tip60 colocalize in the nuclei of hippocampal neurons. Fluorescently tagged versions of each protein were (co-)expressed in cultured hippocampal neurons. See text for details. DNA was labeled using DAPI (blue). Wide-field z-stacks were deconvolved using AutoQuant 3D deconvolution and a representative optical section through the center of the nucleus is shown. Scale bars, 2 μm. Four insets on the right show the structures at higher resolution. Inset scale bars, 0.5 μm.
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f2: Arc, β-Spectrin IV (βSpec), and Tip60 colocalize in the nuclei of hippocampal neurons. Fluorescently tagged versions of each protein were (co-)expressed in cultured hippocampal neurons. See text for details. DNA was labeled using DAPI (blue). Wide-field z-stacks were deconvolved using AutoQuant 3D deconvolution and a representative optical section through the center of the nucleus is shown. Scale bars, 2 μm. Four insets on the right show the structures at higher resolution. Inset scale bars, 0.5 μm.

Mentions: Arc-YFP was expressed in cultured hippocampal neurons by transient transfection. Basal expression of Arc protein in cultured neurons is severely retarded due to a translation impediment, which can be rescued by activation of the cAMP-dependent protein kinase A pathway (Bloomer et al., 2008). Neurons transfected with Arc-YFP were allowed to express overnight, after which they were treated with forskolin for 4 h before fixation. As previously reported (Bloomer et al., 2007), a significant portion of Arc protein localizes to the nucleus, where it is enriched in puncta (Fig. 2A). These nuclear Arc puncta vary in size and number and are found in close proximity to nuclear domains densely labeled by the DNA stain DAPI (Fig. 2A, insets). At the light microscopy level, Arc and DAPI do not clearly overlap.


Nuclear Arc Interacts with the Histone Acetyltransferase Tip60 to Modify H4K12 Acetylation(1,2,3).

Wee CL, Teo S, Oey NE, Wright GD, VanDongen HM, VanDongen AM - eNeuro (2014)

Arc, β-Spectrin IV (βSpec), and Tip60 colocalize in the nuclei of hippocampal neurons. Fluorescently tagged versions of each protein were (co-)expressed in cultured hippocampal neurons. See text for details. DNA was labeled using DAPI (blue). Wide-field z-stacks were deconvolved using AutoQuant 3D deconvolution and a representative optical section through the center of the nucleus is shown. Scale bars, 2 μm. Four insets on the right show the structures at higher resolution. Inset scale bars, 0.5 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596143&req=5

f2: Arc, β-Spectrin IV (βSpec), and Tip60 colocalize in the nuclei of hippocampal neurons. Fluorescently tagged versions of each protein were (co-)expressed in cultured hippocampal neurons. See text for details. DNA was labeled using DAPI (blue). Wide-field z-stacks were deconvolved using AutoQuant 3D deconvolution and a representative optical section through the center of the nucleus is shown. Scale bars, 2 μm. Four insets on the right show the structures at higher resolution. Inset scale bars, 0.5 μm.
Mentions: Arc-YFP was expressed in cultured hippocampal neurons by transient transfection. Basal expression of Arc protein in cultured neurons is severely retarded due to a translation impediment, which can be rescued by activation of the cAMP-dependent protein kinase A pathway (Bloomer et al., 2008). Neurons transfected with Arc-YFP were allowed to express overnight, after which they were treated with forskolin for 4 h before fixation. As previously reported (Bloomer et al., 2007), a significant portion of Arc protein localizes to the nucleus, where it is enriched in puncta (Fig. 2A). These nuclear Arc puncta vary in size and number and are found in close proximity to nuclear domains densely labeled by the DNA stain DAPI (Fig. 2A, insets). At the light microscopy level, Arc and DAPI do not clearly overlap.

Bottom Line: Although Arc protein is found at synapses, it also localizes to the neuronal nucleus, where its function is less understood.Neuronal activity-induced expression of Arc (1) increases endogenous nuclear Tip60 puncta, (2) recruits Tip60 to PML bodies, and (3) increases histone acetylation of Tip60 substrate H4K12, a learning-induced chromatin modification.These mechanisms point to an epigenetic role for Arc in regulating memory consolidation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School , Singapore 169857.

ABSTRACT
Arc is an immediate-early gene whose genetic ablation selectively abrogates long-term memory, indicating a critical role in memory consolidation. Although Arc protein is found at synapses, it also localizes to the neuronal nucleus, where its function is less understood. Nuclear Arc forms a complex with the β-spectrin isoform βSpIVΣ5 and associates with PML bodies, sites of epigenetic regulation of gene expression. We report here a novel interaction between Arc and Tip60, a histone-acetyltransferase and subunit of a chromatin-remodelling complex, using biochemistry and super-resolution microscopy in primary rat hippocampal neurons. Arc and βSpIVΣ5 are recruited to nuclear Tip60 speckles, and the three proteins form a tight complex that localizes to nuclear perichromatin regions, sites of transcriptional activity. Neuronal activity-induced expression of Arc (1) increases endogenous nuclear Tip60 puncta, (2) recruits Tip60 to PML bodies, and (3) increases histone acetylation of Tip60 substrate H4K12, a learning-induced chromatin modification. These mechanisms point to an epigenetic role for Arc in regulating memory consolidation.

No MeSH data available.


Related in: MedlinePlus