Activity-dependent induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation

Sardar, Debosmita; Cheng, Yi-Ting; Woo, Junsung; Choi, Dong‐Joo; Lee, Zhung-Fu; Kwon, Wookbong; Chen, Hsiao‐Chi; Lozzi, Brittney; Cervantes, Alexis; Rajendran, Kavitha; Huang, Teng-Wei; Jain, Antrix; Arenkiel, Benjamin R.; Maze, Ian; Deneen, Benjamin

doi:10.1101/2023.02.24.529904

Cited by 3 publications

(3 citation statements)

References 57 publications

(75 reference statements)

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“…In addition to its role as a neuromodulator, 5-HT was previously shown to be capable of forming covalent bonds with certain substrate proteins via transamidation by the tissue Transglutaminase 2 enzyme, a process referred to as serotonylation (17). In more recent studies, our group identified a new class of histone posttranslational modification (PTM) termed monoaminylation, whereby monoamine neurotransmitters, such as 5-HT, dopamine and histamine, can be transamidated onto histone glutamine residues (18)(19)(20)(21)(22)(23). We showed that histone H3 glutamine (Q) 5 is a primary site for these PTMs and demonstrated that H3 monoaminylation states play important roles in the regulation of neuronal transcriptional programs, both during early development/cellular differentiation and in adult brain.…”

Section: Introductionmentioning

confidence: 99%

Histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to stress- and antidepressant-mediated gene expression and behavior

Al-Kachak

Fulton

Farrelly

et al. 2023

Preprint

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Background: Major depressive disorder (MDD) is a debilitating illness that affects millions of individuals worldwide. While chronic stress increases incidence levels of MDD, stress-mediated disruptions in brain function that precipitate the disorder remain elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with MDD, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding precise roles for serotonin in the precipitation of MDD. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this phenomenon has not yet been explored following stress and/or AD exposures. Methods: Here, we employed a combination of genome-wide (ChIP-seq, RNA-seq) and western blotting analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress to examine the impact of stress exposures on H3K4me3Q5ser dynamics in DRN, as well as associations between the mark and stress-induced gene expression. Stress-induced regulation of H3K4me3Q5ser levels were also assessed in the context of AD exposures, and viral-mediated gene therapy was employed to manipulate H3K4me3Q5ser levels to examine the impact of reducing the mark in DRN on stress-associated gene expression and behavior. Results: We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity in DRN. Mice exposed to chronic stress displayed dysregulated dynamics of H3K4me3Q5ser in DRN, and viral-mediated attenuation of these dynamics rescued stress-mediated gene expression programs and behavior. Conclusions: These findings establish a neurotransmission-independent role for serotonin in stress-associated transcriptional and behavioral plasticity in DRN.

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Section: Introductionmentioning

confidence: 99%

Histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to stress- and antidepressant-mediated gene expression and behavior

Al-Kachak

Fulton

Farrelly

et al. 2023

Preprint

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“…The findings of unique transcriptomic profiles of astrocytes highlight several intriguing possibilities, including functional specializations within known astrocyte function 75,80,81 . Furthermore, the number of unique genes between ASTs outnumbered the shared ones, which indicates potentially uniquely specialized astrocyte cell types 76,82,83 . For example, AST4 possesses a unique transcriptome with a small overlap with other ASTs, and GO terms suggest that this subtype could be linked to functions in the neuro-vascular unit 80 .…”

Section: Discussionmentioning

confidence: 99%

Functional diversities within neurons and astrocytes in the adult rat auditory cortex revealed by single-nucleus RNA sequencing

Aydin,

Lemenze,

Bieszczad

2024

Preprint

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The mammalian cerebral cortex is composed of a rich diversity of cell types. Cortical cells are organized into networks that rely on their functional diversity to ultimately carry out a variety of sophisticated cognitive functions. To investigate the breadth of transcriptionally diverse cell types in the cortex, we used single-nucleus RNA sequencing (snRNA-seq) in the auditory cortex of the adult rat. A variety of unique excitatory and inhibitory neuron types were identified. In addition, we report for the first time a diversity of astrocytes in the auditory cortex that may represent functionally unique subtypes. Together, these results pave the way for building models of how neurons in the sensory cortex work in concert with astrocytes at synapses to fulfill high-cognitive functions like learning and memory.

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“…At this site, H3 serotonylation epigenetically regulates transcription either alone or in combination with the neighboring lysine 4 tri-methylation (K4me3) PTM to enhance permissive gene expression through interactions with reader proteins 33 . The combinatorial H3K4me3Q5ser PTM has been detected in regions throughout the adult brain, where it coordinates relevant gene expression programs upstream of neural differentiation and contributes to sensory processing and stress-induced behavioral plasticity in adult brain, demonstrating diverse roles for this PTM across various functional domains 34,35 . Moreover, the presence of histone serotonylation in heart, testes and other mouse organs suggest additional actions in peripheral tissues 24 .…”

Section: Introductionmentioning

confidence: 99%

Serotonin transporter-dependent histone serotonylation in placenta contributes to the neurodevelopmental transcriptome

Chan,

Alenina,

Cunningham

et al. 2023

Preprint

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Brain development requires appropriate regulation of serotonin (5-HT) signaling from distinct tissue sources across embryogenesis. At the maternal-fetal interface, the placenta is thought to be an important contributor of offspring brain 5-HT and is critical to overall fetal health. Yet, how placental 5-HT is acquired, and the mechanisms through which 5-HT influences placental functions, are not well understood. Recently, our group identified a novel epigenetic role for 5-HT, in which 5-HT can be added to histone proteins to regulate transcription, a process called H3 serotonylation. Here, we show that H3 serotonylation undergoes dynamic regulation during placental development, corresponding to gene expression changes that are known to influence key metabolic processes. Using transgenic mice, we demonstrate that placental H3 serotonylation largely depends on 5-HT uptake by the serotonin transporter (SERT/SLC6A4). SERT deletion robustly reduces enrichment of H3 serotonylation across the placental genome, and disrupts neurodevelopmental gene networks in early embryonic brain tissues. Thus, these findings suggest a novel role for H3 serotonylation in coordinating placental transcription at the intersection of maternal physiology and offspring brain development.

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Activity-dependent induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation

Cited by 3 publications

References 57 publications

Histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to stress- and antidepressant-mediated gene expression and behavior

Histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to stress- and antidepressant-mediated gene expression and behavior

Functional diversities within neurons and astrocytes in the adult rat auditory cortex revealed by single-nucleus RNA sequencing

Serotonin transporter-dependent histone serotonylation in placenta contributes to the neurodevelopmental transcriptome

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