Neuronal <i>Lhx1</i> expression is regulated by DNMT1-dependent modulation of histone marks

Symmank, Judit; Bayer, Cathrin; Reichard, Julia; Pensold, Daniel; Zimmer-Bensch, Geraldine

doi:10.1080/15592294.2020.1767372

Cited by 17 publications

(15 citation statements)

References 76 publications

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“…Hence Dnmt1 deficiency substantially improves long-term survival of PV-expressing cortical interneurons, indicating that DNMT1 function either directly or indirectly impairs cortical PV-interneuron survival in aged mice. This is in striking contrast to DNMT1 function during brain development, where it promotes POA-derived interneuron survival through non-canonical actions ( Pensold et al, 2017 ; Symmank et al, 2018 , 2020 ).…”

Section: Resultsmentioning

confidence: 68%

DNA Methyltransferase 1 (DNMT1) Function Is Implicated in the Age-Related Loss of Cortical Interneurons

Hahn

Pensold

Bayer

et al. 2020

Front. Cell Dev. Biol.

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Increased life expectancy in modern society comes at the cost of age-associated disabilities and diseases. Aged brains not only show reduced excitability and plasticity, but also a decline in inhibition. Age-associated defects in inhibitory circuits likely contribute to cognitive decline and age-related disorders. Molecular mechanisms that exert epigenetic control of gene expression contribute to age-associated neuronal impairments. Both DNA methylation, mediated by DNA methyltransferases (DNMTs), and histone modifications maintain neuronal function throughout lifespan. Here we provide evidence that DNMT1 function is implicated in the age-related loss of cortical inhibitory interneurons. Dnmt1 deletion in parvalbumin-positive interneurons attenuates their age-related decline in the cerebral cortex. Moreover, conditional Dnmt1-deficient mice show improved somatomotor performance and reduced agingassociated transcriptional changes. A decline in the proteostasis network, responsible for the proper degradation and removal of defective proteins, is implicated in ageand disease-related neurodegeneration. Our data suggest that DNMT1 acts indirectly on interneuron survival in aged mice by modulating the proteostasis network during lifetime .

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Section: Resultsmentioning

confidence: 68%

DNA Methyltransferase 1 (DNMT1) Function Is Implicated in the Age-Related Loss of Cortical Interneurons

Hahn

Pensold

Bayer

et al. 2020

Front. Cell Dev. Biol.

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“…Although direct interaction of HTT and DNMT1 have to our best knowledge not been described thus far, mutant HTT could also indirectly interfere with DNMT1 function, as DNMT1 has been proposed to interact with PRC2 [ 70 , 71 , 72 , 73 ]. Moreover, certain histone modifications can prevent or promote DNA methylation [ 74 ], whereby DNMT1 function could be secondarily affected by mutant HTT-induced changes of the histone code.…”

Section: Discussionmentioning

confidence: 99%

DNA Methyltransferase 1 (DNMT1) Acts on Neurodegeneration by Modulating Proteostasis-Relevant Intracellular Processes

Bayer

Pitschelatow

Hannemann

et al. 2020

IJMS

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The limited regenerative capacity of neurons requires a tightly orchestrated cell death and survival regulation in the context of longevity, as well as age-associated and neurodegenerative diseases. Subordinate to genetic networks, epigenetic mechanisms, such as DNA methylation and histone modifications, are involved in the regulation of neuronal functionality and emerge as key contributors to the pathophysiology of neurodegenerative diseases. DNA methylation, a dynamic and reversible process, is executed by DNA methyltransferases (DNMTs). DNMT1 was previously shown to act on neuronal survival in the aged brain, whereby a DNMT1-dependent modulation of processes relevant for protein degradation was proposed as an underlying mechanism. Properly operating proteostasis networks are a mandatory prerequisite for the functionality and long-term survival of neurons. Malfunctioning proteostasis is found, inter alia, in neurodegenerative contexts. Here, we investigated whether DNMT1 affects critical aspects of the proteostasis network by a combination of expression studies, live cell imaging, and protein biochemical analyses. We found that DNMT1 negatively impacts retrograde trafficking and autophagy, with both being involved in the clearance of aggregation-prone proteins by the aggresome–autophagy pathway. In line with this, we found that the transport of GFP-labeled mutant huntingtin (HTT) to perinuclear regions, proposed to be cytoprotective, also depends on DNMT1. Depletion of Dnmt1 accelerated perinuclear HTT aggregation and improved the survival of cells transfected with mutant HTT. This suggests that mutant HTT-induced cytotoxicity is at least in part mediated by DNMT1-dependent modulation of degradative pathways.

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Section: Dnmt Function In Interneuron Developmentmentioning

confidence: 99%

“…At post-mitotic level, DNMT1 was described to regulate cortical interneuron migration by promoting the migratory morphology and survival ( Pensold et al, 2017 ) in part through modulating Pak6 and Lhx1 expression as downstream targets ( Symmank et al, 2018 , 2019 , 2020 ). Interestingly, these genes are DNA methylation-independently regulated by DNMT1 via a crosstalk with histone modifications ( Symmank et al, 2019 , 2020 ). In line with this, DNMTs and DNA methylation were further shown to be essential for the maturation of diverse other neuronal subtypes ( Fan et al, 2001 ; Hutnick et al, 2009 ; Chestnut et al, 2011 ; Rhee et al, 2012 ), including cortical excitatory neurons ( Hutnick et al, 2009 ; Feng et al, 2010 ), and dentate gyrus neurons ( Noguchi et al, 2016 ).…”

Section: Dnmt Function In Interneuron Developmentmentioning

confidence: 99%

“…Of note, alterations in DNA methylation signatures of GABA-related genes and/or changed expression of DNMTs in GABAergic interneurons were reported for diverse neuropsychiatric diseases ( Veldic et al, 2004 ; Guidotti et al, 2011 ). Given that DNMTs and DNA methylation not only regulate cortical interneuron functionality ( Pensold et al, 2020 ) but also their development ( Pensold et al, 2017 ; Symmank et al, 2018 , 2020 ), an implication of altered DNA methylation in inhibitory interneurons for disease manifestation seems plausible. On the other hand, a dysregulated epigenetic machinery could also constitute a secondary effect of disease progression.…”

Section: Introductionmentioning

confidence: 99%

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DNA Methylation-Dependent Dysregulation of GABAergic Interneuron Functionality in Neuropsychiatric Diseases

Linde

Zimmer-Bensch

2020

Front. Neurosci.

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Neuropsychiatric diseases, such as mood disorders, schizophrenia, and autism, represent multifactorial disorders, differing in causes, disease onset, severity, and symptoms. A common feature of numerous neuropsychiatric conditions are defects in the cortical inhibitory GABAergic system. The balance of excitation and inhibition is fundamental for proper and efficient information processing in the cerebral cortex. Thus, altered inhibition is suggested to account for pathological symptoms like cognitive impairments and dysfunctional multisensory integration. While it became apparent that most of these diseases have a clear genetic component, environmental influences emerged as an impact of disease manifestation, onset, and severity. Epigenetic mechanisms of transcriptional control, such as DNA methylation, are known to be responsive to external stimuli, and are suspected to be implicated in the functional impairments of GABAergic interneurons, and hence, the pathophysiology of neuropsychiatric diseases. Here, we provide an overview about the multifaceted functional implications of DNA methylation and DNA methyltransferases in cortical interneuron development and function in health and disease. Apart from the regulation of gamma-aminobutyric acid-related genes and genes relevant for interneuron development, we discuss the role of DNA methylation-dependent regulation of synaptic transmission by the modulation of endocytosis-related genes as potential pathophysiological mechanisms underlying neuropsychiatric conditions. Deciphering the hierarchy and mechanisms of changes in epigenetic signatures is crucial to develop effective strategies for treatment and prevention.

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Neuronal Lhx1 expression is regulated by DNMT1-dependent modulation of histone marks

Cited by 17 publications

References 76 publications

DNA Methyltransferase 1 (DNMT1) Function Is Implicated in the Age-Related Loss of Cortical Interneurons

DNA Methyltransferase 1 (DNMT1) Function Is Implicated in the Age-Related Loss of Cortical Interneurons

DNA Methyltransferase 1 (DNMT1) Acts on Neurodegeneration by Modulating Proteostasis-Relevant Intracellular Processes

DNA Methylation-Dependent Dysregulation of GABAergic Interneuron Functionality in Neuropsychiatric Diseases

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