Maintenance-Type DNA Methyltransferase Is Highly Expressed in Post-Mitotic Neurons and Localized in the Cytoplasmic Compartment

Inano, Koichi; Suetake, Isao; Ueda, Takayuki; Miyake, Yuka; Nakamura, Masahiko; Okada, Masahiko; Tsuji, Shoji

doi:10.1093/oxfordjournals.jbchem.a022755

Cited by 88 publications

(83 citation statements)

References 28 publications

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“…Sections were fixed with 3.7% formaldehyde in PBS for 10 min at room temperature. After fixation, the sections were blocked with 1% BSA, 0.1% (w/v) Triton X-100 in PBS for the anti-N-terminal Dnmt1 antibodies, or with 1% BSA, 0.4 % (w/ v) SDS, 2% (w/v) Triton X-100 in PBS for the anti-C-terminal Dnmt1 antibodies (Inano et al, 2000). For fluorescent staining, sections were incubated overnight at 4°C with the anti-N-terminal or the C-terminal Dnmt1 antibodies, and diluted 1/1,000 with corresponding blocking buffers.…”

Section: Immunocytochemistrymentioning

confidence: 99%

“…As a consequence, Dnmt1 abruptly decreases in spermatocytes at this stage (Jue et al, 1995). Recently, the transcript, of which 5' sequence is identical to that in pachytene spermatocyte, was also identified in neurons (Inano et al, 2000) and differentiated myotubes (Aguirre-Arteta et al, 2000). Interestingly, the translation product is also identified in skeletal muscle (AguirreArteta et al, 2000).…”

mentioning

confidence: 98%

“…All these results, however, are obtained from the data using cultured cells. In the vivo state, as an exception, differentiated neurons express high levels of Dnmt1, both mRNA (Goto et al, 1994) and protein (Inano et al, 2000), even if they are in post-mitotic state. In addition, surprisingly, the Dnmt1 protein is mainly localized in the cytoplasmic compartment in neurons (Inano et al, 2000).…”

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confidence: 99%

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Proliferation Stage-dependent Expression of DNA Methyltransferase (Dnmt1) in Mouse Small Intestine.

Suetake

Shi

Watanabe

et al. 2001

Cell Struct. Funct.

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ABSTRACT. In cultured cells, the maintenance-type DNA methyltransferase Dnmt1 is highly expressed during the proliferation stage. In the present study, we detected significant expression of Dnmt1 protein in the nuclear fraction of mouse small intestine. From its mobility in SDS polyacrylamide gel electrophoresis and the specific antibodies against the somatic cell-type Dnmt1, Dnmt1 was determined as a somatic cell type. Immunofluorescence study revealed that the Dnmt1 was highly expressed in the proliferating stem cells in crypts, and was localized in the nuclei. The present results indicate that the expression of Dnmt1 in vivo is also under the control of cell proliferation as in cultured cells.

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Section: Immunocytochemistrymentioning

confidence: 99%

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confidence: 98%

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confidence: 99%

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Proliferation Stage-dependent Expression of DNA Methyltransferase (Dnmt1) in Mouse Small Intestine.

Suetake

Shi

Watanabe

et al. 2001

Cell Struct. Funct.

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“…Mature neurons are enriched in Dnmts [66][67][68][69][70]. We have shown that Dnmt1 and Dnmt3a are expressed in adult mouse brain and spinal cord, and in adult human cerebral cortex and spinal cord, and that mouse and human spinal motor neurons are enriched in these proteins [70].…”

Section: Mammalian Dnmts In the Central Nervous Systemmentioning

confidence: 91%

“…Several studies have found high levels of Dnmt enzyme activity, mRNA, and protein in adult mammalian central nervous system (CNS) [66][67][68][69][70]. Mature neurons are enriched in Dnmts [66][67][68][69][70].…”

Section: Mammalian Dnmts In the Central Nervous Systemmentioning

confidence: 99%

Aberrant Regulation of DNA Methylation in Amyotrophic Lateral Sclerosis: A New Target of Disease Mechanisms

Martin

Wong

2013

Neurotherapeutics

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Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. A diagnosis is fatal owing to degeneration of motor neurons in brain and spinal cord that control swallowing, breathing, and movement. ALS can be inherited, but most cases are not associated with a family history of the disease. The mechanisms causing motor neuron death in ALS are still unknown. Given the suspected complex interplay between multiple genes, the environment, metabolism, and lifestyle in the pathogenesis of ALS, we have hypothesized that the mechanisms of disease in ALS involve epigenetic contributions that can drive motor neuron degeneration. DNA methylation is an epigenetic mechanism for gene regulation engaged by DNA methyltransferase (Dnmt)-catalyzed methyl group transfer to carbon-5 in cytosine residues in gene regulatory promoter and nonpromoter regions. Recent genome-wide analyses have found differential gene methylation in human ALS. Neuropathologic assessments have revealed that motor neurons in human ALS show significant abnormalities in Dnmt1, Dnmt3a, and 5-methylcytosine. Similar changes are seen in mice with motor neuron degeneration, and Dnmt3a was found abundantly at synapses and in mitochondria. During apoptosis of cultured motor neuron-like cells, Dnmt1 and Dnmt3a protein levels increase, and 5-methylcytosine accumulates. Enforced expression of Dnmt3a, but not Dnmt1, induces degeneration of cultured neurons. Truncation mutation of the Dnmt3a catalytic domain and Dnmt3a RNAi blocks apoptosis of cultured neurons. Inhibition of Dnmt catalytic activity with small molecules RG108 and procainamide protects motor neurons from excessive DNA methylation and apoptosis in cell culture and in a mouse model of ALS. Thus, motor neurons can engage epigenetic mechanisms to cause their degeneration, involving Dnmts and increased DNA methylation. Aberrant DNA methylation in vulnerable cells is a new direction for discovering mechanisms of ALS pathogenesis that could be relevant to new disease target identification and therapies for ALS.

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Distinct nuclear localization patterns of DNA methyltransferases in developing and mature mammalian retina

Nasonkin

Lazo

Hambright

et al. 2011

J of Comparative Neurology

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DNA methyltransferases--DNMT1, DNMT3a, and DNMT3b--produce methylation patterns that dynamically regulate chromatin remodeling and gene expression. The vertebrate retina provides an ideal model to elucidate molecular control of neurogenesis as all neuronal cell types and Müller glia are generated in a conserved order from common pools of progenitor cells. As a prelude to exploring epigenetic regulation of mammalian retinal development, we investigated the expression of Dnmt1, Dnmt3a, and Dnmt3b in the mouse retina from embryonic day (E) 10.5 to 10 months of age. High levels of transcripts for all three Dnmt genes were observed in early stages of retinal differentiation, with significantly reduced expression after birth. Although DNMT1 protein is abundant in retinal progenitors at E10.5, it becomes restricted to postmitotic cells by E15.5. Most cells in the postnatal retina show nuclear immunostaining of DNMT1; however, the photoreceptors exhibit distinctive patterns. In rods, weak expression of DNMT1 is detected in perinuclear region and in the nucleus, whereas a strong nuclear labeling is evident in cones. DNMT3a and DNMT3b show a discrete pattern in developing retina with high expression at E11.5, little or no immunostaining by E15.5, and then postnatal expression overlapping with DNMT1 in early born neurons (ganglion, amacrine and horizontal cells, and cones). Robust nuclear localization of DNMTs in cones compared to rods suggests a potential role of DNA methylation in differential remodeling of chromatin in these two specialized neurons. Our studies indicate that DNA methyltransferases contribute to the establishment and maturation of cell fates during retinal development.

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Maintenance-Type DNA Methyltransferase Is Highly Expressed in Post-Mitotic Neurons and Localized in the Cytoplasmic Compartment

Cited by 88 publications

References 28 publications

Proliferation Stage-dependent Expression of DNA Methyltransferase (Dnmt1) in Mouse Small Intestine.

Proliferation Stage-dependent Expression of DNA Methyltransferase (Dnmt1) in Mouse Small Intestine.

Aberrant Regulation of DNA Methylation in Amyotrophic Lateral Sclerosis: A New Target of Disease Mechanisms

Distinct nuclear localization patterns of DNA methyltransferases in developing and mature mammalian retina

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