Tet1 overexpression leads to anxiety‐like behavior and enhanced fear memories<i>via</i>the activation of calcium‐dependent cascade through Egr1 expression in mice

Kwon, Wookbong; Kim, Hyeng-Soo; Jeong, Jin Woo; Sung, Yonghun; Choi, Minjee; Park, Song; Lee, Jin‐Hee; Jang, Soyoung; Kim, Sung Hyun; Lee, Sanggyu; Kim, Myoung Ok; Ryoo, Zae Young

doi:10.1096/fj.201601340rr

Cited by 22 publications

(24 citation statements)

References 62 publications

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“…In contrast, acute Tet1 FL repression resulted in memory deficits. In line with our results, a recent study showed that transgenic overexpression of the Tet1 FL gene causes enhanced memory formation and increased anxiety in mice (Kwon et al, 2018), suggesting that overexpression of the fulllength enzyme acts oppositely to our SID4X-mediated suppression. It is important to note that while our isoform-specific behavioral findings generally agree with previous reports, several groups have found that pan-Tet1 deficient mice either have normal memory or exhibit an impairment (Zhang et al, 2013;Towers et al, 2018).…”

Section: Discussionsupporting

confidence: 92%

“…For instance, depending on the study, loss of the gene in KO mice has been reported to either impair, enhance, or have no effect, on memory (Rudenko et al, 2013;Zhang et al, 2013;Kumar et al, 2015;Towers et al, 2018). Likewise, overexpression of Tet1 enhances memory, while expression of its catalytic domain does the opposite (Kaas et al, 2013;Kwon et al, 2018). A potential explanation for some of these inconsistences comes from a recent report that the Tet1 gene undergoes an isoform switch from the full-length, canonical transcript (hereafter Tet1 FL ) in embryonic stem cells to a shorter, truncated variant (hereafter Tet1 S ) exclusive to somatic tissues (Zhang et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Tet1isoforms differentially regulate gene expression, synaptic transmission and memory in the mammalian brain

Greer

Wright

Weiss

et al. 2020

Preprint

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The dynamic regulation of DNA methylation in post-mitotic neurons is necessary for memory formation and other adaptive behaviors. Ten-eleven translocation 1 (TET1) plays a part in these processes by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby initiating active DNA demethylation. However, attempts to pinpoint its exact role in the nervous system have been hindered by contradictory findings, perhaps due in part, to a recent discovery that two isoforms of the Tet1 gene are differentially expressed from early development into adulthood. Here, we demonstrate that both the shorter transcript (Tet1S) encoding an N-terminally truncated TET1 protein and a full-length Tet1 (Tet1FL) transcript encoding canonical TET1 are co-expressed in the adult brain. We show that Tet1S is the predominantly expressed isoform, and is highly enriched in neurons, whereas Tet1FL is generally expressed at lower levels and more abundant in glia, suggesting their roles are at least partially cell-type specific. Using viral-mediated, isoform- and neuron-specific molecular tools, we find that Tet1S repression enhances, while Tet1FL impairs, hippocampal-dependent memory. In addition, the individual disruption of the two isoforms leads to contrasting changes in basal synaptic transmission and the dysregulation of unique gene ensembles in hippocampal neurons. Together, our findings demonstrate that each Tet1 isoform serves a distinct role in the mammalian brain.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Tet1isoforms differentially regulate gene expression, synaptic transmission and memory in the mammalian brain

Greer

Wright

Weiss

et al. 2020

Preprint

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“…4c). The activation of 16 EGR1 is involved in peripheral myelin development and adult neurogenesis through oligodendrocyte differentiation via neuron-glia signaling (Kwon et al, 2018;Stevens & Fields, 2000). Therefore, the activation of EGR1 may mediate LCN2-regulated remyelination by inhibiting OPC differentiation.…”

Section: Lcn2 Activates Egr1 In Opcsmentioning

confidence: 99%

Inactivation of LCN2/EGR1 Promotes Oligodendrocyte Progenitor Cell Differentiation and Remyelination after White Matter Injury

Yang

et al. 2020

Preprint

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The insufficient remyelination due to the impaired oligodendrocyte precursor cell differentiation and maturation is highly associated with irreversible white matter injury and neurological deficits. Consequently, inhibitory components and microenvironment for remyelination might serve as potential therapeutic targets for treating white matter injury after acute central nervous system injury and neurodegeneration diseases. Lipocalin-2 was recently reported to corelate with white matter in both atypical, acute white matter injured disease subarachnoid hemorrhage and typical, chronic white matter injured disease multiple sclerosis. To elucidate the role and underlying mechanism of Lipocalin-2 in oligodendrocyte precursor cell differentiation and remyelination, we used genetic inhibition and a constitutive conditional knockout model with subarachnoid hemorrhage or multiple sclerosis. We found that the genetic inhibition of the increase in Lipocalin-2 promoted oligodendrocyte precursor cell differentiation, remyelination, and functional recovery after subarachnoid hemorrhage or multiple sclerosis. Unexpectedly, the inhibition of Lipocalin-2 did not reduce glial activation and inflammation. Lipocalin-2 was shown to activate Early Growth Response Protein 1 in oligodendrocyte precursor cells, which is partly regulated by its receptor SLC22A17. In the conditional knockout of Early Growth Response Protein 1 in oligodendrocyte precursor cells, we discovered enhanced oligodendrocyte precursor cell differentiation in developing and 4 injured white matter; consistently, the specific inactivation of Early Growth Response Protein 1 promoted remyelination and neurological recovery after subarachnoid hemorrhage or multiple sclerosis. Thus, we propose that following white matter injury in humans, the increase in Lipocalin-2 activates Early Growth Response Protein 1 and consequently impair oligodendrocyte precursor cell differentiation and myelin repair. Our results suggest that therapies specifically inactivating Lipocalin-2/ Early Growth Response Protein 1 signal in oligodendroglial lineage cells could represent a novel strategy to enhance differentiation and remyelination in white matter injury patients.

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“…Intriguingly, converging evidence suggests that psychotic AD (AD + P) [96] is associated with an acceleration of frontal degeneration, with tau pathology playing a primary role [97]. Within this context, a new study by Kwon et al [98] shows that Tet1 over-expression leads to anxiety-like behavior and enhanced fear memories via the activation of calcium-dependent cascade through Egr1 expression in mice.…”

Section: Mirna Regulation Of Taumentioning

confidence: 99%

Neuroepigenetics and Alzheimer’s Disease: An Update

Zusso

Barbierato

Facci

et al. 2018

JAD

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Epigenetics is the study of changes in gene expression which may be triggered by both genetic and environmental factors, and independent from changes to the underlying DNA sequence-a change in phenotype without a change in genotype-which in turn affects how cells read genes. Epigenetic changes represent a regular and natural occurrence but can be influenced also by factors such as age, environment, and disease state. Epigenetic modifications can manifest themselves not only as the manner in which cells terminally differentiate, but can have also deleterious effects, resulting in diseases such as cancer. At least three systems including DNA methylation, histone modification, and non-coding RNA (ncRNA)-associated gene silencing are thought to initiate and sustain epigenetic change. For example, in Alzheimer's disease (AD), both genetic and non-genetic factors contribute to disease etiopathology. While over 250 gene mutations have been related to familial AD, less than 5% of AD cases are explained by known disease genes. More than likely, non-genetic factors, probably triggered by environmental factors, are causative factors of late-onset AD. AD is associated with dysregulation of DNA methylation, histone modifications, and ncRNAs. Among the classes of ncRNA, microRNAs (miRNAs) have a well-established regulatory relevance. MicroRNAs are highly expressed in CNS neurons, where they play a major role in neuron differentiation, synaptogenesis, and plasticity. MicroRNAs impact higher cognitive functions, as their functional impairment is involved in the etiology of neurological diseases, including AD. Alterations in the miRNA network contribute to AD disease processes, e.g., in the regulation of amyloid peptides, tau, lipid metabolism, and neuroinflammation. MicroRNAs, both as biomarkers for AD and therapeutic targets, are in the early stages of exploration. In addition, emerging data suggest that altered transcription of long ncRNAs, endogenous, ncRNAs longer than 200 nucleotides, may be involved in an elevated risk for AD.

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Tet1 overexpression leads to anxiety‐like behavior and enhanced fear memoriesviathe activation of calcium‐dependent cascade through Egr1 expression in mice

Cited by 22 publications

References 62 publications

Tet1isoforms differentially regulate gene expression, synaptic transmission and memory in the mammalian brain

Tet1isoforms differentially regulate gene expression, synaptic transmission and memory in the mammalian brain

Inactivation of LCN2/EGR1 Promotes Oligodendrocyte Progenitor Cell Differentiation and Remyelination after White Matter Injury

Neuroepigenetics and Alzheimer’s Disease: An Update

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