G9a influences neuronal subtype specification in striatum

Maze, Ian; Chaudhury, Dipesh; Dietz, David M.; Schimmelmann, Melanie von; Kennedy, Pamela J.; Lobo, Mary Kay; Sillivan, Stephanie E.; Miller, Michael L.; Bagot, Rosemary C.; Sun, HaoSheng; Turecki, Gustavo; Neve, Rachael L.; Hurd, Yasmin L.; Shen, Li; Han, Ming; Schaefer, Anne; Nestler, Eric J.

doi:10.1038/nn.3670

Cited by 79 publications

(86 citation statements)

References 35 publications

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“…We extended our genetic analysis of m109 to other common AD susceptibility variants 4 which, in earlier studies, displayed very little or no association with neuropathologic features of AD 32,33 . The 21 common AD variants did not associate with m109 (i.e., trans-eQTL analysis), consistent with the observed sparsity of trans-associations (trans-eQTLs) reported in studies with larger sample sizes 34 .…”

Section: Relation Of Rna Derived Modules To the Genetic Architecture supporting

confidence: 84%

A molecular network of the aging brain implicatesINPPL1andPLXNB1in Alzheimer’s disease

Mostafavi

Gaiteri

Sullivan

et al. 2017

Preprint

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One sentence summary: Molecular network analysis of RNA sequencing data from the aging human cortex identifies new Alzheimer's and cognitive decline genes.material for any purpose without crediting the original authors.was not peer-reviewed) in the Public Domain. It is no longer restricted by copyright. Anyone can legally share, reuse, remix, or adapt thisThe copyright holder has placed this preprint (which . http://dx.doi.org/10.1101/205807 doi: bioRxiv preprint first posted online 2 AbstractThe fact that only symptomatic therapies of small effect are available for Alzheimer's disease (AD) today highlights the need for new therapeutic targets with which to prevent a major contributor to aging-related cognitive decline. Here, we report the construction and validation of a molecular network of the aging human frontal cortex. Using RNA sequence data from 478 individuals, we first identify the role of modules of coexpressed genes, and then confirm them in independent AD datasets. Then, we prioritize influential genes in AD-related modules and test our predictions in human model systems. We functionally validate two putative regulator genes in human astrocytes: INPPL1 and PLXNB1, whose activity in AD may be related to semaphorin signalling and type II diabetes, which have both been implicated in AD. This arc of network identification followed by statistical and experimental validation provides specific new targets for therapeutic development and illustrates a network approach to a complex disease.

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Section: Relation Of Rna Derived Modules To the Genetic Architecture supporting

confidence: 84%

A molecular network of the aging brain implicatesINPPL1andPLXNB1in Alzheimer’s disease

Mostafavi

Gaiteri

Sullivan

et al. 2017

Preprint

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“…Although we found that the number of Foxp1 target genes is roughly equally distributed between genes enriched in both D 1 + and D 2 + MSNs (Fig. 2D), the number of Foxp2 target genes enriched in D 1 + MSNs is almost twice the number of Foxp2 target genes enriched in D 2 + MSNs (Heiman et al 2008;Vernes et al 2011;Maze et al 2014). These results are in line with published data showing that Foxp2 is more enriched in D 1 + MSNs.…”

Section: Foxp1 Regulates Shared Targets With Foxp2 In the Striatummentioning

confidence: 77%

“…in the coordination of motor activity (Gerfen and Surmeier 2011 (Maze et al 2014). We found a significant enrichment of both Foxp1 and Foxp2 target genes within D 1 + MSNs specifically (Fig.…”

Section: Foxp1 Regulates Shared Targets With Foxp2 In the Striatummentioning

confidence: 99%

FoxP1 orchestration of ASD-relevant signaling pathways in the striatum

et al. 2015

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Mutations in the transcription factor Forkhead box p1 (FOXP1) are causative for neurodevelopmental disorders such as autism. However, the function of FOXP1 within the brain remains largely uncharacterized. Here, we identify the gene expression program regulated by FoxP1 in both human neural cells and patient-relevant heterozygous Foxp1 mouse brains. We demonstrate a role for FoxP1 in the transcriptional regulation of autism-related pathways as well as genes involved in neuronal activity. We show that Foxp1 regulates the excitability of striatal medium spiny neurons and that reduction of Foxp1 correlates with defects in ultrasonic vocalizations. Finally, we demonstrate that FoxP1 has an evolutionarily conserved role in regulating pathways involved in striatal neuron identity through gene expression studies in human neural progenitors with altered FOXP1 levels. These data support an integral role for FoxP1 in regulating signaling pathways vulnerable in autism and the specific regulation of striatal pathways important for vocal communication.

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“…Although well beyond the scope of the current study, it will be necessary in the future to investigate the contributions of these numerous cell types to transcriptional, synaptic, and behavioral abnormalities observed following CSDS. Indeed, previous work has already provided a wealth of data demonstrating that distinct cell types and circuits in striatum are segregated, both molecularly and electrophysiologically, in their responses to chronic stress, thereby contributing differentially to distinct phenotypes observed across numerous psychiatric disease models (22,23).…”

mentioning

confidence: 99%

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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G9a influences neuronal subtype specification in striatum

Cited by 79 publications

References 35 publications

A molecular network of the aging brain implicatesINPPL1andPLXNB1in Alzheimer’s disease

A molecular network of the aging brain implicatesINPPL1andPLXNB1in Alzheimer’s disease

FoxP1 orchestration of ASD-relevant signaling pathways in the striatum

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

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