Histone post-translational modifications (PTMs) have emerged as exciting mechanisms of biological regulation, impacting pathways related to cancer, immunity, brain function, and more. Over the past ...decade alone, several histone PTMs have been discovered, including acylation, lipidation, monoaminylation, and glycation, many of which appear to have crucial roles in nucleosome stability and transcriptional regulation. In this review, we discuss novel histone PTMs identified within the past 10 years, with an extended focus on enzymatic versus nonenzymatic mechanisms underlying modification and adduction. Furthermore, we consider how these novel histone PTMs might fit within the framework of a so-called ‘histone code’, emphasizing the physiological relevance of these PTMs in metabolism, development, and disease states.
Histone post‐translational modifications (PTMs) regulate several biological processes, including transcription and nucleosome assembly, that can contribute to functional consequences in disease, physiology, and behavior.Over the past decade, new histone PTMs (monoaminylation, lipidation, hydroxylation, etc.) have been identified using technological advances that allow the detection of low-abundance PTMs; yet, our understanding of these PTMs alone or in combination, such as in the context of a ‘histone code’, remains poor.New studies reveal a class of nonenzymatic histone PTMs derived from covalent binding of highly reactive species, refuting the common notion that histone PTMs require writers, readers, and erasers for biological significance.Despite numerous studies highlighting the importance of histone PTMs in various biological pathways, their causal roles remain undefined and will require innovative techniques to manipulate them in a cell type-, locus-, and site-specific manner.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The epigenetic landscape of addiction Maze, Ian; Nestler, Eric J.
Annals of the New York Academy of Sciences,
01/2011, Volume:
1216, Issue:
1
Journal Article
Peer reviewed
Open access
Drug‐induced alterations in gene expression throughout the reward circuitry of the brain are likely components of the persistence of the drug‐addicted state. Recent studies examining the molecular ...mechanisms controlling drug‐induced transcriptional, behavioral, and synaptic plasticity have indicated a direct role for chromatin remodeling in the regulation and stability of drug‐mediated neuronal gene programs, and the subsequent promulgation of addictive behaviors. In this review, we discuss recent advances in our understanding of chromatin phenomena—or epigenetics, by one definition—that contribute to drug addiction, with the hope that such mechanistic insights may aid in the development of novel therapeutics for future treatments of addiction.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Despite a conserved role for histones as general DNA packaging agents, it is now clear that another key function of these proteins is to confer variations in chromatin structure to ensure dynamic ...patterns of transcriptional regulation in eukaryotes. The incorporation of histone variants is particularly important to this process. Recent knockdown and knockout studies in various cellular systems, as well as direct mutational evidence from human cancers, now suggest a crucial role for histone variant regulation in processes as diverse as differentiation and proliferation, meiosis and nuclear reprogramming. In this Review, we provide an overview of histone variants in the context of their unique functions during mammalian germ cell and embryonic development, and examine the consequences of aberrant histone variant regulation in human disease.
Full text
Available for:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
ChIP-seq is increasingly being used for genome-wide profiling of histone modification marks. It is of particular importance to compare ChIP-seq data of two different conditions, such as disease vs. ...control, and identify regions that show differences in ChIP enrichment. We have developed a powerful and easy to use program, called diffReps, to detect those differential sites from ChIP-seq data, with or without biological replicates. In addition, we have developed two useful tools for ChIP-seq analysis in the diffReps package: one for the annotation of the differential sites and the other for finding chromatin modification "hotspots". diffReps is developed in PERL programming language and runs on all platforms as a command line script. We tested diffReps on two different datasets. One is the comparison of H3K4me3 between two human cell lines from the ENCODE project. The other is the comparison of H3K9me3 in a discrete region of mouse brain between cocaine- and saline-treated conditions. The results indicated that diffReps is a highly sensitive program in detecting differential sites from ChIP-seq data.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In postmitotic neurons, nucleosomal turnover was long considered to be a static process that is inconsequential to transcription. However, our recent studies in human and rodent brain indicate that ...replication‐independent (RI) nucleosomal turnover, which requires the histone variant H3.3, is dynamic throughout life and is necessary for activity‐dependent gene expression, synaptic connectivity, and cognition. H3.3 turnover also facilitates cellular lineage specification and plays a role in suppressing the expression of heterochromatic repetitive elements, including mutagenic transposable sequences, in mouse embryonic stem cells. In this essay, we review mechanisms and functions for RI nucleosomal turnover in brain and present the hypothesis that defects in histone dynamics may represent a common mechanism underlying neurological aging and disease.
Wenderski and Maze discuss an emerging role for replication‐independent (RI) nucleosomal dynamics/chromatin accessibility in orchestrating cell type‐specific transcriptional responses in brain, synaptic plasticity, and cognition. The authors review and hypothesize on the mechanisms involved in this process and provide evidence for a relationship between defects in RI histone turnover and neurological disease.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Enhanced glutamatergic transmission in the nucleus accumbens (NAc), a region critical for reward and motivation, has been implicated in the pathophysiology of depression; however, the afferent source ...of this increased glutamate tone is not known. The NAc receives glutamatergic inputs from the medial prefrontal cortex (mPFC), ventral hippocampus (vHIP) and basolateral amygdala (AMY). Here, we demonstrate that glutamatergic vHIP afferents to NAc regulate susceptibility to chronic social defeat stress (CSDS). We observe reduced activity in vHIP in mice resilient to CSDS. Furthermore, attenuation of vHIP-NAc transmission by optogenetic induction of long-term depression is pro-resilient, whereas acute enhancement of this input is pro-susceptible. This effect is specific to vHIP afferents to the NAc, as optogenetic stimulation of either mPFC or AMY afferents to the NAc is pro-resilient. These data indicate that vHIP afferents to NAc uniquely regulate susceptibility to CSDS, highlighting an important, novel circuit-specific mechanism in depression.
Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from the rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) ...dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in the midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the VTA. By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in the VTA.
Brain stimulation and imaging studies in humans have highlighted a key role for the prefrontal cortex in clinical depression; however, it remains unknown whether excitation or inhibition of ...prefrontal cortical neuronal activity is associated with antidepressant responses. Here, we examined cellular indicators of functional activity, including the immediate early genes (IEGs) zif268 (egr1), c-fos, and arc, in the prefrontal cortex of clinically depressed humans obtained postmortem. We also examined these genes in the ventral portion of the medial prefrontal cortex (mPFC) of mice after chronic social defeat stress, a mouse model of depression. In addition, we used viral vectors to overexpress channel rhodopsin 2 (a light-activated cation channel) in mouse mPFC to optogenetically drive "burst" patterns of cortical firing in vivo and examine the behavioral consequences. Prefrontal cortical tissue derived from clinically depressed humans displayed significant reductions in IEG expression, consistent with a deficit in neuronal activity within this brain region. Mice subjected to chronic social defeat stress exhibited similar reductions in levels of IEG expression in mPFC. Interestingly, some of these changes were not observed in defeated mice that escape the deleterious consequences of the stress, i.e., resilient animals. In those mice that expressed a strong depressive-like phenotype, i.e., susceptible animals, optogenetic stimulation of mPFC exerted potent antidepressant-like effects, without affecting general locomotor activity, anxiety-like behaviors, or social memory. These results indicate that the activity of the mPFC is a key determinant of depression-like behavior, as well as antidepressant responses.
Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to ...depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery.
•A large-scale multi-brain region transcriptomic cohort to probe stress susceptibility•Reveals susceptible and resilient transcriptional networks across brain regions•Identifies many novel hub genes that emerge in susceptible mice•In vivo validation of key regulators at molecular, synaptic, and behavioral levels
Molecular mechanisms of dysregulated circuit function in depression are poorly understood. Employing integrative network analysis of large-scale RNA sequencing data, Bagot et al. identify distinct inter-regional transcriptional networks regulating depression susceptibility versus resilience. In vivo validation of networks suggests novel antidepressant targets.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Repeated cocaine exposure induces persistent alterations in genome-wide transcriptional regulatory networks, chromatin remodeling activity and, ultimately, gene expression profiles in the brain's ...reward circuitry. Virtually all previous investigations have centered on drug-mediated effects occurring throughout active euchromatic regions of the genome, with very little known concerning the impact of cocaine exposure on the regulation and maintenance of heterochromatin in adult brain. Here, we report that cocaine dramatically and dynamically alters heterochromatic histone H3 lysine 9 trimethylation (H3K9me3) in the nucleus accumbens (NAc), a key brain reward region. Furthermore, we demonstrate that repeated cocaine exposure causes persistent decreases in heterochromatization in this brain region, suggesting a potential role for heterochromatic regulation in the long-term actions of cocaine. To identify precise genomic loci affected by these alterations, chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-Seq) was performed on NAc. ChIP-Seq analyses confirmed the existence of the H3K9me3 mark mainly within intergenic regions of the genome and identified specific patterns of cocaine-induced H3K9me3 regulation at repetitive genomic sequences. Cocaine-mediated decreases in H3K9me3 enrichment at specific genomic repeats e.g., long interspersed nuclear element (LINE)-1 repeats were further confirmed by the increased expression of LINE-1 retrotransposon-associated repetitive elements in NAc. Such increases likely reflect global patterns of genomic destabilization in this brain region after repeated cocaine administration and open the door for future investigations into the epigenetic and genetic basis of drug addiction.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
PDF
