Critical Role of Histone Turnover in Neuronal Transcription and Plasticity

Maze, Ian; Wenderski, Wendy; Noh, Kyung‐Min; Bagot, Rosemary C.; Tzavaras, Nikos; Purushothaman, Immanuel; Elsässer, Simon J.; Yin, Guisheng; Ionete, Carolina; Hurd, Yasmin L.; Tamminga, Carol A.; Halene, Tobias B.; Farrelly, Lorna A.; Soshnev, Alexey A.; Wen, Desheng; Rafii, Shahin; Birtwistle, Marc R.; Akbarian, Schahram; Buchholz, Bruce A.; Blitzer, Robert D.; Nestler, Eric J.; Yuan, Zuo Fei; Garcia, Benjamin A.; Shen, Li; Molina, Henrik; Allis, C. David

doi:10.1016/j.neuron.2015.06.014

Cited by 264 publications

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“…Furthermore, the genomic distribution of these events was found to be similar between the two stress groups, with the majority of differential sites occurring in gene bodies (Fig. 3A), a observation that is consistent with our current understanding of H3.3 turnover in neurons (10).…”

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confidence: 88%

“…Tables S1 and S2 for demographic information). H3F3A exists as the more abundant of the two transcripts; however, H3F3B is activity-dependent, and increases in its transcript levels have been tightly linked to potentiated rates of histone turnover in brain (10). Following quantitative PCR (qPCR), we observed a significant increase in H3F3B, but not in H3F3A, mRNA levels in nonmedicated depressed subjects compared with controls, an effect that is reversed in individuals with MDD on ADs (Fig.…”

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confidence: 85%

“…Recently, we demonstrated a mechanistic role for histone variant turnover/dynamics in the central nervous system, a process that is dissociated from histone PTMs in adult brain, in the regulation of activity-dependent gene transcription, synaptic connectivity, and behavioral plasticity (10). Moreover, the histone variant H3.3, which can be actively incorporated into neural chromatin, was found to accumulate to near saturating levels in neurons by midadolescence, but remains constitutively dynamic (i.e., it is continuously turned over and replaced by newly transcribed/translated H3.3) throughout life.…”

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confidence: 99%

“…To investigate causal roles for H3.3 dynamics in mediating depressive-like behaviors, we next used a recently described H3f3a/b viral knockdown strategy in NAc to stall histone turnover in neuronal chromatin by way of depletion of soluble nuclear "reserve" pools of H3.3 (10). Briefly, adeno-associated virus (AAV) vectors expressing synthetic microRNAs (miRs) targeting either both H3.3 gene copies [AAV-miR (H3f3a/b)] or a sequence not present in the vertebrate genome as a control [AAV-miR (-)] were injected bilaterally into NAc of wild-type mice.…”

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Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior

Lepack

Bagot

Peña

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Human major depressive disorder (MDD), along with related mood disorders, is among the world's greatest public health concerns; however, its pathophysiology remains poorly understood. Persistent changes in gene expression are known to promote physiological aberrations implicated in MDD. More recently, histone mechanisms affecting cell type-and regional-specific chromatin structures have also been shown to contribute to transcriptional programs related to depressive behaviors, as well as responses to antidepressants. Although much emphasis has been placed in recent years on roles for histone posttranslational modifications and chromatin-remodeling events in the etiology of MDD, it has become increasingly clear that replication-independent histone variants (e.g., H3.3), which differ in primary amino acid sequence from their canonical counterparts, similarly play critical roles in the regulation of activity-dependent neuronal transcription, synaptic connectivity, and behavioral plasticity. Here, we demonstrate a role for increased H3.3 dynamics in the nucleus accumbens (NAc)-a key limbic brain reward regionin the regulation of aberrant social stress-mediated gene expression and the precipitation of depressive-like behaviors in mice. We find that molecular blockade of these dynamics promotes resilience to chronic social stress and results in a partial renormalization of stressassociated transcriptional patterns in the NAc. In sum, our findings establish H3.3 dynamics as a critical, and previously undocumented, regulator of mood and suggest that future therapies aimed at modulating striatal histone dynamics may potentiate beneficial behavioral adaptations to negative emotional stimuli.H3.3 | nucleus accumbens | depression | chronic social defeat stress | histone dynamics M ajor depressive disorder (MDD) affects ∼17% of the population, making it the most prominent and debilitating psychiatric disease worldwide (1). Current antidepressants (ADs) can take weeks to months to produce an effective therapeutic response, with about one-third of patients remaining nonresponsive to existing treatment strategies. Although the prevalence of MDD and a lack of sufficient treatment options highlight the importance of identifying new drug targets, progress has been hindered by a general lack of understanding of the precise molecular mechanisms underlying this disorder.The nucleus accumbens (NAc), a critical component of the brain's limbic reward circuitry, has become increasingly implicated in depression, as well as in mechanisms of antidepressant action (2, 3). In recent years, numerous studies in both human MDD and in animal models of depression have identified changes in gene expression, along with related alterations in chromatin structure and function, that contribute to aberrant forms of transcriptional and behavioral plasticity associated with depressive-like phenotypes (4-9). Although multiple studies have successfully linked alterations in histone posttranslational modifications (PTMs) or chromatinremodeling events to chron...

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Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior

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Bagot

Peña

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent work has shown that H3.3 accumulates in mouse neurons with age, as well as in the human brain, whereas the other major histone 3 variants H3.1 and H3.2 decline. 6 The authors also showed that appropriately high expression of H3.3 is required for proper neuronal function, such as synapse formation. 6 We propose that H3.3 repression in GBM CSCs is consistent with achieving a brainspecific primordial state that allows self-renewal and tumor propagation.…”

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confidence: 99%