Knockdown of Butyrylcholinesterase but Not Inhibition by Chlorpyrifos Alters Early Differentiation Mechanisms in Human Neural Stem Cells

Tiethof, Angela K; Richardson, Jason R.; Hart, Ronald P.

doi:10.3390/toxics6030052

Cited by 6 publications

(8 citation statements)

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“…TFAP2A is known to regulate neural crest induction and cranial placode specification (64,65). BCHE is expressed early in nervous system development and plays a role in neural stem cell development (51). Only co-localization with one PRC2 subunit was detected for MBD1 and PHOX2B in MB hypermethylated and hypomethylated regions, respectively ( Figure 2D, Supplementary Figure 7 ).…”

Section: Resultsmentioning

confidence: 99%

“…TFAP2A is known to regulate neural crest induction and cranial placode specification 85,86 ; thus, it might mark regions relevant for developmental branches being silenced in AT/RT, MB, and even in the brain in general. BCHE is expressed early in nervous system development and plays a role in neural stem cell development 49 . This could possibly contribute to the observed differentiation blockage.…”

Section: Discussionmentioning

confidence: 99%

“…However, five of these (REST, SIN3A, ZEB1, TBX1, and ZHX2) inhibit neural differentiation [39][40][41][42] . In addition, six of the remaining 11 TFs were active in the later phases of neural differentiation, whereas seven TFs hypermethylated in AT/RTs were active in earlier stages [43][44][45][46][47][48][49][50][51][52][53][54][55] . Furthermore, among the TFs uniquely enriched in MB hypermethylated regions, 9 TFs (11%) were related to the pluripotent stem cell state and early differentiation (Supplementary Table 2) 39,[56][57][58] .…”

Section: At/rt Hypermethylated Sites Are Enriched With Neural Differe...mentioning

confidence: 99%

“…However, five of these (REST, SIN3A, ZEB1, TBX1, and ZHX2) inhibit neural differentiation (42)(43)(44)(45). In addition, four of the remaining 11 TFs were active in the later phases of neural differentiation namely during differentiation from neural precursors, whereas seven TFs hypermethylated in AT/RTs were active in earlier stages, namely during differentiation from pluripotent stem cells and during differentiation from neural stem cells (46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56). Finally, among the TFs uniquely enriched in MB hypermethylated regions, 9 TFs (11%) were related to the pluripotent stem cell state and early differentiation (Figure 2B, Supplementary Table 2) (42,(57)(58)(59).…”

Section: Distinct Neural Differentiation Related Tfs Are Enriched To ...mentioning

confidence: 99%

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Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors

Pekkarinen

Nordfors

Uusi-Mäkelä

et al. 2022

Preprint

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Understanding oncogenic epigenetic mechanisms in brain tumors is crucial for improved diagnosis and treatment. To evaluate tumor type-specific features, we compared atypical teratoid/rhabdoid tumors (AT/RTs), medulloblastomas, and choroid plexus tumors with each other by integrating DNA methylation (507 samples), gene expression (120 samples), and transcription factor (TF) -binding data. Our results suggest that aberrant DNA methylation plays a vital role in the oncogenesis of AT/RTs, which are known for their aggressiveness and exceptionally low mutation rates. In AT/RT, elevated DNA methylation masks the binding sites of TFs driving neural development and is associated with reduced gene expression for specific neural regulators, whereas DNA methylation patterns predict a more advanced differentiation state for MB. By analyzing the data together with pluripotent stem cells, we found two regulatory programs in AT/RT: pluripotent stem cell -like DNA methylation patterns and AT/RT-specific DNA methylation uniquely associated with polycomb repressive complex 2 (PRC2) members. Both methylation patterns cover neural TF binding sites in a TF-specific manner, suggesting their relevance for oncogenic regulation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: At/rt Hypermethylated Sites Are Enriched With Neural Differe...mentioning

confidence: 99%

Section: Distinct Neural Differentiation Related Tfs Are Enriched To ...mentioning

confidence: 99%

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Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors

Pekkarinen

Nordfors

Uusi-Mäkelä

et al. 2022

Preprint

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“…Although the enzyme BChE and its coding gene were discovered years ago, still little is known about the regulation of the expression and its biological role, particularly in the central nervous system (CNS) [ 133 , 134 ]. BChE is expressed during mitosis in early embryonic development and promotes proliferation prior to differentiation [ 135 ].…”

Section: Butyrylcholinesterase In Admentioning

confidence: 99%

The Role of Butyrylcholinesterase and Iron in the Regulation of Cholinergic Network and Cognitive Dysfunction in Alzheimer’s Disease Pathogenesis

Jasiecki

Targońska

Wasąg

2021

IJMS

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Alzheimer’s disease (AD), the most common form of dementia in elderly individuals, is marked by progressive neuron loss. Despite more than 100 years of research on AD, there is still no treatment to cure or prevent the disease. High levels of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain are neuropathological hallmarks of AD. However, based on postmortem analyses, up to 44% of individuals have been shown to have high Aβ deposits with no clinical signs, due to having a “cognitive reserve”. The biochemical mechanism explaining the prevention of cognitive impairment in the presence of Aβ plaques is still unknown. It seems that in addition to protein aggregation, neuroinflammatory changes associated with aging are present in AD brains that are correlated with a higher level of brain iron and oxidative stress. It has been shown that iron accumulates around amyloid plaques in AD mouse models and postmortem brain tissues of AD patients. Iron is required for essential brain functions, including oxidative metabolism, myelination, and neurotransmitter synthesis. However, an imbalance in brain iron homeostasis caused by aging underlies many neurodegenerative diseases. It has been proposed that high iron levels trigger an avalanche of events that push the progress of the disease, accelerating cognitive decline. Patients with increased amyloid plaques and iron are highly likely to develop dementia. Our observations indicate that the butyrylcholinesterase (BChE) level seems to be iron-dependent, and reports show that BChE produced by reactive astrocytes can make cognitive functions worse by accelerating the decay of acetylcholine in aging brains. Why, even when there is a genetic risk, do symptoms of the disease appear after many years? Here, we discuss the relationship between genetic factors, age-dependent iron tissue accumulation, and inflammation, focusing on AD.

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Impact of environmental neurotoxic: current methods and usefulness of human stem cells

Rosca

Coronel

Moreno

et al. 2020

Heliyon

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The development of central nervous system is a highly coordinated and complex process. Any alteration of this process can lead to disturbances in the structure and function of the brain, which can cause deficits in neurological development, resulting in neurodevelopmental disorders, including, for example, autism or attention-deficit hyperactivity disorder. Exposure to certain chemicals during the fetal period and childhood is known to cause developmental neurotoxicity and has serious consequences that persist into adult life. For regulatory purposes, determination of the potential for developmental neurotoxicity is performed according the OECD Guideline 426, in which the test substance is administered to animals during gestation and lactation. However, these animal models are expensive, long-time consuming and may not reflect the physiology in humans; that makes it an unsustainable model to test the large amount of existing chemical products, hence alternative models to the use of animals are needed. One of the most promising methods is based on the use of stem cell technology. Stem cells are undifferentiated cells with the ability to self-renew and differentiate into more specialized cell types. Because of these properties, these cells have gained increased attention as possible therapeutic agents or as disease models. Here, we provide an overview of the current models both animal and cellular, available to study developmental neurotoxicity and review in more detail the usefulness of human stem cells, their properties and how they are becoming an alternative to evaluate and study the mechanisms of action of different environmental toxicants.

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Knockdown of Butyrylcholinesterase but Not Inhibition by Chlorpyrifos Alters Early Differentiation Mechanisms in Human Neural Stem Cells

Cited by 6 publications

References 56 publications

Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors

Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors

The Role of Butyrylcholinesterase and Iron in the Regulation of Cholinergic Network and Cognitive Dysfunction in Alzheimer’s Disease Pathogenesis

Impact of environmental neurotoxic: current methods and usefulness of human stem cells

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