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Yin Yang 1 and guanine quadruplexes protect dopaminergic neurons from cellular stress via transmissive dormancy [YY1 CUT&RUN]

ABSTRACT: Neurons deploy diverse adaptive strategies to ensure survival and neurotransmission amid cellular stress. Yet, when these adaptive pathways are overwhelmed, functional impairment or neurodegeneration follow. Herein we report a scenario where stressed neurons actively adopt a state of transmissive dormancy, despite rapid activation of stress response pathways, as a terminal protective measure. Examination of dopaminergic neurons surviving severe cellular stress, revealed decreased spontaneous activity accompanied by dynamic control of dopamine metabolism through the Yin Yang 1 (YY1) transcriptional regulator. Under conditions of ionic imbalance or oxidative stress, YY1 promotes expression of the SLC18A2 transporter with the capacity to enhance sequestration of dopamine into transport vesicles. Subsequent DNA damage represses the rate-limiting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), through YY1 mediated stabilization of an intronic guanine quadruplex. This cascade has the potential to drive circuit inactivation and safeguard neurons by minimizing the toxic accumulation of cytosolic dopamine and reducing the energetic expenditure associated with cellular depolarization. In essence, neurons appear to actively prioritize viability over functionality.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254192 | GEO | 2024/10/28

REPOSITORIES: GEO

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Yin Yang 1 and guanine quadruplexes protect dopaminergic neurons from cellular stress via transmissive dormancy [TG timeline RNA-seq]

Project description:Neurons deploy diverse adaptive strategies to ensure survival and neurotransmission amid cellular stress. Yet, when these adaptive pathways are overwhelmed, functional impairment or neurodegeneration follow. Herein we report a scenario where stressed neurons actively adopt a state of transmissive dormancy, despite rapid activation of stress response pathways, as a terminal protective measure. Examination of dopaminergic neurons surviving severe cellular stress, revealed decreased spontaneous activity accompanied by dynamic control of dopamine metabolism through the Yin Yang 1 (YY1) transcriptional regulator. Under conditions of ionic imbalance or oxidative stress, YY1 promotes expression of the SLC18A2 transporter with the capacity to enhance sequestration of dopamine into transport vesicles. Subsequent DNA damage represses the rate-limiting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), through YY1 mediated stabilization of an intronic guanine quadruplex. This cascade has the potential to drive circuit inactivation and safeguard neurons by minimizing the toxic accumulation of cytosolic dopamine and reducing the energetic expenditure associated with cellular depolarization. In essence, neurons appear to actively prioritize viability over functionality.

2024-10-28 | GSE254139 | GEO

Yin Yang 1 and guanine quadruplexes protect dopaminergic neurons from cellular stress via transmissive dormancy [BG4 CUT&RUN]

Project description:Neurons deploy diverse adaptive strategies to ensure survival and neurotransmission amid cellular stress. When these adaptive pathways are overwhelmed, functional impairment or neurodegeneration follows. Here, we report a scenario where stressed neurons actively induce a state of transmissive dormancy as a protective measure. Examination of dopaminergic neurons surviving severe cellular challenges revealed decreased spontaneous activity accompanied by dynamic control of dopamine metabolism through the transcriptional regulator Yin Yang 1 (YY1). Under these conditions, YY1 increases expression of the vesicular monoamine transporter 2, promoting sequestration of dopamine into synaptic vesicles. Following oxidative stress and subsequent DNA damage, YY1 inhibits dopamine synthesis through stabilization of a guanine quadruplex in intron 10 of tyrosine hydroxylase. This cytoprotective response has the potential to drive circuit inactivation and safeguard neurons by minimizing the toxic accumulation of cytosolic dopamine and inducing a state of neuronal dormancy. In essence, neurons appear to actively prioritize viability over functionality.

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Yin Yang 1 and guanine quadruplexes protect dopaminergic neurons from cellular stress via transmissive dormancy [YY1 CUT&RUN]

Project description:Yin Yang 1 and guanine quadruplexes protect dopaminergic neurons from cellular stress via transmissive dormancy [YY1 CUT&RUN]

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Yin Yang 1 and guanine quadruplexes protect dopaminergic neurons from cellular stress via transmissive dormancy

Project description:Yin Yang 1 and guanine quadruplexes protect dopaminergic neurons from cellular stress via transmissive dormancy

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Yin Yang 1 and guanine quadruplexes protect dopaminergic neurons from cellular stress via transmissive dormancy [BG4 CUT&RUN]

Project description:Yin Yang 1 and guanine quadruplexes protect dopaminergic neurons from cellular stress via transmissive dormancy [BG4 CUT&RUN]

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Yin Yang 1 and guanine quadruplexes protect dopaminergic neurons from cellular stress via transmissive dormancy [TG timeline RNA-seq]

Project description:Yin Yang 1 and guanine quadruplexes protect dopaminergic neurons from cellular stress via transmissive dormancy [TG timeline RNA-seq]

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Yin Yang 1 sets up the stage for cerebellar astrocyte maturation

Project description:Diverse subpopulations of astrocytes tile different brain regions to accommodate local requirements of neurons and associated neuronal circuits. Nevertheless, molecular mechanisms governing astrocyte diversity remain mostly unknown. We explored the role of a zinc finger transcription factor Yin Yang 1 (YY1) that is expressed in astrocytes. We found that specific deletion of YY1 from astrocytes causes severe motor deficits in mice, induces Bergmann gliosis, and results in simultaneous loss of GFAP expression in velate and fibrous cerebellar astrocytes. Single cell RNA-seq analysis showed that YY1 exerts specific effects on gene expression in subpopulations of cerebellar astrocytes. We found that although YY1 is dispensable for the initial stages of astrocyte development, it regulates subtype-specific gene expression during astrocyte maturation. Moreover, YY1 is continuously needed to maintain astrocyte identity in the adult cerebellum. Our findings suggest that YY1 plays critical roles regulating cerebellar astrocyte maturation during development and maintaining a mature phenotype of astrocytes in the adult cerebellum.

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Single cell sequencing of iPSC-dopamine neurons reconstructs disease progression and identifies HDAC4 as a regulator of Parkinson cell phenotypes

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A neuronal transcription factor is required in the prefrontal cortex for transcriptional and behavioral adaptation to chronic stress

Project description:Stressful life events increase risk for depression, yet the molecular mechanisms by which stress is encoded in the brain to induce maladaptive behaviors are not well understood. Emerging evidence has shown that stress dysregulates gene expression in the brain, yet the cellular origin of these gene expression alterations has yet to be determined. To address this question, we used a chronic unpredictable stress (CUS) paradigm that drives depressive- and anxiety-like behaviors in male and female mice and single-nucleus transcriptomics to identify cell type-specific gene expression changes in the cortex. We find that neocortical excitatory neurons are particularly vulnerable to chronic stress exposure, and that CUS reprograms these cells to decrease transcription of synaptic genes involved in glutamatergic neurotransmission. We identify the ubiquitously expressed factor, Yin Yang 1 (YY1), as a key driver of the transcriptional reprogramming observed in excitatory neurons isolated from CUS mice. Selective depletion of YY1 in excitatory neurons of the prefrontal cortex (PFC) increases the stress sensitivity of mice, inducing depressive- and anxiety-related behaviors following an abbreviated stress exposure and deregulating expression of key stress-related genes in the PFC. Importantly, we find that YY1 functions in both males and females to facilitate stress coping. This work establishes a novel mechanism underlying chronic stress-induced behavior, in which epigenetic responses to stress in PFC excitatory neurons are mediated by stress-dependent YY1 activity. Our findings demonstrate how post-mitotic neurons adapt to stress experience and identify a novel molecular target that is generalizable to males and females for therapeutic treatment of stress-related neuropsychiatric disorders.

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Yin Yang 1 regulates cohesin complex protein SMC3 in mouse hematopoietic stem cells

Project description:Yin Yang 1 (YY1) and Structural Maintenance of Chromosomes 3 (SMC3) are two critical chromatin structural factors that mediate long-distance enhancer-promoter interactions and promote developmentally regulated changes in chromatin architecture in hematopoietic stem/progenitor cells (HSPCs). While YY1 plays critical functions in maintaining hematopoietic stem cell (HSC) quiescence, SMC3 is required for proper lineage differentiation. However, many questions remain unanswered regarding how YY1 and SMC3 interact with each other and impact hematopoiesis. We found that YY1 physically interacts with SMC3 and co-occupies with SMC3 at a large cohort of promoters genome-wide, and YY1 deficiency deregulates the genetic network governing cell metabolism. YY1 occupies the Smc3 promoter and represses SMC3 expression in HSPCs. While deletion of one Smc3 allele partially restores HSC numbers and quiescence in YY1 knockout mice, HSC self-renewal remains defective. YY1 regulates HSC metabolic pathways and maintains proper intracellular reactive oxygen species (ROS) levels in HSCs, and this regulation is independent of YY1- SMC3 axis. Our results establish a distinct YY1-SMC3 axis and its impact on HSC quiescence, self-renewal and metabolism

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