HDAC4 Governs a Transcriptional Program Essential for Synaptic Plasticity and Memory

Sando, Richard; Gounko, Natalia V.; Pieraut, Simon; Liao, Lujian; Yates, John R.; Maximov, Anton

doi:10.1016/j.cell.2012.09.037

Cited by 225 publications

(262 citation statements)

References 118 publications

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“…1D). In contrast, in agreement with previous reports (18), dendritic spine density was not affected by the nuclear HDAC4 mutant (Fig. 1E, F).…”

Section: Resultscontrasting

confidence: 51%

“…In neuronal cells, HDAC4 is primarily localized in the cytoplasm (10,17,18) but it can accumulate in the nucleus in conditions of deprived synaptic activity (10,18) and in neuronal pathologies (20)(21)(22)(23)(24). In particular, extrasynaptic N-methyl-D-aspartate receptors (eNMDARs) that trigger excitotoxicity (25) have been associated with many neurodegenerative diseases (25)(26)(27)(28).…”

Section: Resultsmentioning

confidence: 99%

“…Blockade of synaptic activity and/or nuclear calcium signaling causes an accumulation of HDAC4 in the nucleus (10), which, in turn, leads to changes in the rate of transcription of many genes (10,18). HDAC4 activity can regulate the expression of synaptic proteins, alter the shape of synapses, and modulate neuronal survival (18).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Histone deacetylase 4 shapes neuronal morphology via a mechanism involving regulation of expression of vascular endothelial growth factor D

Litke¹,

Bading²,

Mauceri³

2018

Journal of Biological Chemistry

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Nucleo-cytoplasmic shuttling of class IIa histone deacetylases (HDAC4, -5, -7, and -9) is a synaptic activity-and nuclear calciumdependent mechanism important for epigenetic regulation of signal-regulated gene expression in hippocampal neurons. HDAC4 in particular has been linked to the regulation of genes important for both synaptic structure and plasticity. Here, using a constitutively nuclear-localized, dominant-active variant of HDAC4 (HDAC4 3SA), we demonstrate that HDAC4 accumulation in the nucleus severely reduces both the length and complexity of dendrites of cultured mature hippocampal neurons, but does not affect the number of dendritic spines. This phenomenon appeared to be specific to HDAC4, as increasing the expression of HDAC3 or HDAC11, belonging to class I and class IV HDACs, respectively, did not alter dendritic architecture. We also show that HDAC4 3SA decreases the expression of Vascular Endothelial Growth Factor D (VEGFD), a key protein required for the maintenance of dendritic arbors. The expression of other members of the VEGF family and of their receptors was not affected by the nuclear accumulation of HDAC4. VEGFD overexpression or administration of recombinant VEGFD, but not of VEGFC, the closest VEGFD homologue, rescued the impaired dendritic architecture caused by the nuclear-localized HDAC4 variant. These results identify HDAC4 as an epigenetic regulator of neuronal morphology that controls dendritic arborization via the expression of VEGFD.

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“…1D). In contrast, in agreement with previous reports (18), dendritic spine density was not affected by the nuclear HDAC4 mutant (Fig. 1E, F).…”

Section: Resultscontrasting

confidence: 51%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Histone deacetylase 4 shapes neuronal morphology via a mechanism involving regulation of expression of vascular endothelial growth factor D

Litke¹,

Bading²,

Mauceri³

2018

Journal of Biological Chemistry

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“…In contrast, HDAC4 promotes synaptic plasticity and memory formation (20,21). These findings suggest that specific inhibitors of subtypes of HDACs may be useful to modulate learning and memory, but in spite of a concerted effort, there remains limited progress in identifying CNS-penetrant, HDAC subtype-specific inhibitors capable of ameliorating learning deficits (22,23).…”

Section: Introductionmentioning

confidence: 87%

Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice

Pardo¹,

Cheng²,

Velmeshev³

et al. 2017

JCI Insight

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“…Indeed, an ever increasing number of studies is uncovering how these mechanisms underpin brain patterning [24], neural stem cell maintenance and differentiation, neuronal and glial subtype specification and maturation [25,26], neuronal migration [27,28], the establishment of neural network connectivity patterns [28], the development of sexually dimorphic neuronal circuitry [29], homeostasis [30], plasticity responses (e.g. learning and memory) [31][32][33] and brain aging [34].…”

Section: Histone Modifications and Higher Order Chromatin Remodellingmentioning

confidence: 99%

An evolving view of epigenetic complexity in the brain

Qureshi

Mehler

2014

Phil. Trans. R. Soc. B

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Recent scientific advances have revolutionized our understanding of classical epigenetic mechanisms and the broader landscape of molecular interactions and cellular functions that are inextricably linked to these processes. Our current view of epigenetics includes an increasing appreciation for the dynamic nature of DNA methylation, active mechanisms for DNA demethylation, differential functions of 5-methylcytosine and its oxidized derivatives, the intricate regulatory logic of histone post-translational modifications, the incorporation of histone variants into chromatin, nucleosome occupancy and dynamics, and direct links between cellular signalling pathways and the actions of chromatin 'reader', 'writer' and 'eraser' molecules. We also have an increasing awareness of the seemingly ubiquitous roles played by diverse classes of selectively expressed non-coding RNAs in transcriptional, post-transcriptional, post-translational and local and higher order chromatin modulatory processes. These perspectives are still evolving with novel insights continuing to emerge rapidly (e.g. those related to epigenetic regulation of mobile genetic elements, epigenetic mechanisms in mitochondria, roles in nuclear architecture and 'RNA epigenetics'). The precise functions of these epigenetic factors/phenomena are largely unknown. However, it is unequivocal that they serve as key mediators of brain complexity and flexibility, including neural development and aging, cellular differentiation, homeostasis, stress responses, and synaptic and neural network connectivity and plasticity.

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HDAC4 Governs a Transcriptional Program Essential for Synaptic Plasticity and Memory

Cited by 225 publications

References 118 publications

Histone deacetylase 4 shapes neuronal morphology via a mechanism involving regulation of expression of vascular endothelial growth factor D

Histone deacetylase 4 shapes neuronal morphology via a mechanism involving regulation of expression of vascular endothelial growth factor D

Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice

An evolving view of epigenetic complexity in the brain

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