Methyl-CpG binding proteins in the nervous system

Fan, Guoping; Hutnick, Leah

doi:10.1038/sj.cr.7290294

Cited by 94 publications

(61 citation statements)

References 67 publications

(112 reference statements)

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“…However, we cannot rule out the possible involvement of other methyl binding proteins (e.g. MBD1-3) in the nervous system for their potential role in glial gene silencing during early CNS development (Heinrich and Bird, 1998) (reviewed by Fan and Hutnick, 2005).…”

Section: Discussionmentioning

confidence: 99%

DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling

et al. 2005

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DNA methylation is a major epigenetic factor that has been postulated to regulate cell lineage differentiation. We report here that conditional gene deletion of the maintenance DNA methyltransferase I (Dnmt1) in neural progenitor cells (NPCs) results in DNA hypomethylation and precocious astroglial differentiation. The developmentally regulated demethylation of astrocyte marker genes as well as genes encoding the crucial components of the gliogenic JAK-STAT pathway is accelerated in Dnmt1–/– NPCs. Through a chromatin remodeling process, demethylation of genes in the JAK-STAT pathway leads to an enhanced activation of STATs, which in turn triggers astrocyte differentiation. Our study suggests that during the neurogenic period, DNA methylation inhibits not only astroglial marker genes but also genes that are essential for JAK-STAT signaling. Thus, demethylation of these two groups of genes and subsequent elevation of STAT activity are key mechanisms that control the timing and magnitude of astroglial differentiation.

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Section: Discussionmentioning

confidence: 99%

DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling

et al. 2005

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“…This raises the interesting possibility that a reduction in Freud-1-mediated repression of the DRD2 gene may contribute to the mental retardation phenotype or to other developmental disorders in which dysregulation of the dopamine system is implicated, such as attention deficit hyperactivity disorder, autism, or schizophrenia (25). In some cases mental retardation has been linked to global regulators of gene transcription, such as the ATPase/helicase ATRX (alpha thalassemia/mental retardation syndrome X-linked) (43,44) or the methyl binding repressor methyl CpG-binding protein 2 (45,46). Likewise, Freud-1 may regulate other genes in addition to 5-HT1A or dopamine-D2 receptor genes to regulate cognitive development.…”

Section: Freud-1 Mediated Repression Of the Dopamine-d2mentioning

confidence: 99%

Differential Repression by Freud-1/CC2D1A at a Polymorphic Site in the Dopamine-D2 Receptor Gene

Rogaeva

Jafar‐Nejad

et al. 2007

Journal of Biological Chemistry

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Freud-1/CC2D1A is a transcriptional repressor of the serotonin-1A receptor gene and was recently genetically linked to non-syndromic mental retardation. To identify new Freud-1 gene targets, data base mining for Freud-1 recognition sequences was done. A highly homologous intronic element (D2-DRE) was identified in the human dopamine-D2 receptor (DRD2) gene, and the role of Freud-1 in regulating the gene at this site was assessed. Recombinant Freud-1 bound specifically to the D2-DRE, and a major protein-D2-DRE complex was identified in nuclear extracts that was supershifted using Freud-1-specific antibodies. Endogenous Freud-1 binding to the D2-DRE in cells was detected using chromatin immunoprecipitation. The D2-DRE conferred strong repressor activity in transcriptional reporter assays that was dependent on the Freud-1 recognition sequence. In three different human cell lines, the level of Freud-1 protein was inversely related to DRD2 expression. Knockdown of endogenous Freud-1 using small interfering RNA resulted in an up-regulation of DRD2 RNA and binding sites, demonstrating a crucial role for Freud-1 in DRD2 regulation. A previously uncharacterized single nucleotide A/G polymorphism (rs2734836) was located adjacent to the D2-DRE and conferred allele-specific Freud-1 binding and repression, with the major G-allele having reduced activity. These studies demonstrate a key role for Freud-1 to regulate DRD2 expression and provide the first mechanistic insights into its transcriptional regulation. Allele-specific regulation of DRD2 expression by Freud-1 may possibly associate with psychiatric disorders or mental retardation.Dopamine-D2 receptors function as both pre-synaptic autoreceptors and post-synaptic receptors, and play key roles in regulating dopaminergic neurotransmission. Increased levels of dopamine-D2 receptors or dopaminergic hyperactivity have been implicated in schizophrenia (1-3), and most antipsychotic drugs inhibit dopamine-D2 receptors (4 -6). Although transcriptional regulation of the rat dopamine D2 receptor (DRD2) 5 gene has been examined, very little is known regarding the regulation of the human DRD2 gene. A polymorphism in the putative DRD2 promoter confers decreased transcriptional activity and has been negatively associated with schizophrenia (7). However, the transcriptional mechanisms for regulation of the human DRD2 gene have yet to be elucidated.To identify new transcriptional regulators in the nervous system, we previously characterized the serotonin-1A (5-HT1A) receptor promoter region and identified a novel dual repressor element (DRE) that negatively regulates its expression (8, 9). The DRE consists of adjacent and partially overlapping repressor elements: 5Ј-repressor element (FRE; major regulator in neuronal cells) and 3Ј-repressor element (9). Analysis of DREbinding proteins revealed that a novel protein, Freud-1 (Five prime repressor under dual repression-binding protein-1)/ CC2D1A (Coiled-coil and C2 Domain containing 1A) binds to and represses the 5-HT1A receptor gene throug...

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“…Recently, studies have suggested a relationship between RTT and MECP2 in the regulation of UBE3A (Ubiquitin-Protein ligase E3A), GABRB3 (the beta3 subunit of the GABAA receptor) and CDKL5 (Cyclin-dependent kinase-like5) expression (Fan G and Hutnick L, 2005;Milani et al, 2005;Samaco et al, 2005;Segawa and Nomura, 2005). In this study, we did not detect any mutations of MECP2 in seventeen of the patients.…”

Section: Discussionmentioning

confidence: 58%

Diagnostic mutational analysis of MECP2 in Korean patients with Rett syndrome

Kim

Kim²,

Son³

et al. 2006

Exp Mol Med

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Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder affecting 1 per 10,000-15,000 female births worldwide. The disease-causing gene has been identified as MECP2 (methylCpG-binding protein 2). In this study, we performed diagnostic mutational analysis of the MECP2 gene in RTT patients. Four exons and a putative promoter of the MECP2 gene were analyzed from the peripheral blood of 43 Korean patients with Rett syndrome by PCR-RFLP and direct sequencing. Mutations were detected in the MECP2 gene in approximately 60.5% of patients (26 cases/43 cases). The mutations consisted of 14 different types, including 9 missense mutations, 4 nonsense mutations and 1 frameshift mutation. Of these, three mutations (G161E, T311M, p385fsX409) were newly identified and were determined to be disease-causing mutations by PCR-RFLP and direct sequencing analysis. Most of the mutations were located within MBD (42.3%) and TRD (50%). T158M, R270X, and R306C mutations were identified at a high frequency. Additionally, an intronic SNP (IVS3 + 23C＞G) was newly identified in three of the patients. IVS3 + 23C＞G may be a disease-related and Korea-specific SNP for RTT. L100V and A201V are apparently disease-causing mutations in Korean RTT, contrary to previous studies. Disease-causing mutations and polymorphisms are important tools for diagnosing RTT in Koreans. The experimental procedures used in this study should be considered for clinical molecular biologic diagnosis.

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Methyl-CpG binding proteins in the nervous system

Cited by 94 publications

References 67 publications

DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling

DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling

Differential Repression by Freud-1/CC2D1A at a Polymorphic Site in the Dopamine-D2 Receptor Gene

Diagnostic mutational analysis of MECP2 in Korean patients with Rett syndrome

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