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The methyl binding domain containing protein MBD5 is a transcriptional regulator responsible for 2q23.1 deletion syndrome.

ABSTRACT: 2Iq23.1 microdeletion syndrome is a recently described rare disease that includes intellectual disability, motor delay, autistic-like behaviors, and craniofacial abnormalities. Dosage insufficiency of the methyl-CpG-binding domain protein 5 (MBD5) gene was suggested as the genetic cause, since all the described patients carry a partial or total heterozygous deletion of MBD5. We reported the generation and characterization of a mouse model with haploinsufficiency for Mbd5 that confirmed this hypothesis. As in human 2q23.1 microdeletion syndrome, the MBD5 (+/GT) mouse model exhibited abnormal social behavior, cognitive impairment, and motor and craniofacial abnormalities, supporting a causal role for MBD5 in 2q23.1 microdeletion syndrome. The use of mouse neuronal cultures uncovered a deficiency in neurite outgrowth, suggesting the participation of MBD5 in neuronal processes. The study of the MBD5 (+/GT) mouse advanced our understanding of the abnormal brain development associated with behavioral and cognitive symptoms.

SUBMITTER: Walz K

PROVIDER: S-EPMC4755234 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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An epigenetic regulator: methyl-CpG-binding domain protein 1 (MBD1).

Project description:DNA methylation is an important form of epigenetic regulation in both normal development and cancer. Methyl-CpG-binding domain protein 1 (MBD1) is highly related to DNA methylation. Its MBD domain recognizes and binds to methylated CpGs. This binding allows it to trigger methylation of H3K9 and results in transcriptional repression. The CXXC3 domain of MBD1 makes it a unique member of the MBD family due to its affinity to unmethylated DNA. MBD1 acts as an epigenetic regulator via different mechanisms, such as the formation of the MCAF1/MBD1/SETDB1 complex or the MBD1-HDAC3 complex. As methylation status always changes along with carcinogenesis or neurogenesis, MBD1 with its interacting partners, including proteins and non-coding RNAs, participates in normal or pathological processes and functions in different regulatory systems. Because of the important role of MBD1 in epigenetic regulation, it is a good candidate as a therapeutic target for diseases.

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Protein-protein interactions between jasmonate-related master regulator MYC and transcriptional mediator MED25 depend on a short binding domain.

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The GAF-like-domain-containing transcriptional regulator DfdR is a sensor protein for dibenzofuran and several hydrophobic aromatic compounds.

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Binding Analysis of Methyl-CpG Binding Domain of MeCP2 and Rett Syndrome Mutations.

Project description:Methyl-CpG binding protein 2 (MeCP2) binds to methylated cytosine in CpG island through its methyl-CpG binding domain (MBD). Here, the effects of the Rett syndrome-causing missense mutations on binding affinity of MBD to cytosine (C), methylcytosine (mC), hydroxymethylcytosine (hmC), formylcytosine (fC), and carboxylcytosine (caC) in CpG dinucleotide are investigated. MeCP2-MBD binds to mC-containing variants of double stranded CpG stronger than any other cytosine modified CpG with the strongest affinity to mC/mC. Thirteen MBD missense mutations show reduced binding affinity for mC/mC ranging with a 2-fold decrease for T158M to 88-fold for R111G. The binding affinities of these mutants to C/C are also reduced to various degrees except for T158M. Consistent with free energy perturbation analysis, correlation of binding affinity with protein unfolding allows for grouping mutations into three clusters. Correlation of the first cluster includes mutations that have a higher tendency to unfold and have lesser affinity to mC/mC and C/C. Mutations in the second cluster have similar structural stability but various affinities to mC/mC and C/C. R111G and A140V belong to the third cluster in which the loss of protein flexibility may underlie their reduction in binding affinity to mC/mC and C/C. Most notably, R111 emerges as the key structural element that modulates the specific contacts with mCpG. Implications of the results for the mCpG binding mechanism of MeCP2-MBD are discussed. These analyses provide new insights on the structure and function relationships in MeCP2-MBD and offer new clues to their roles in the pathology of Rett syndrome.

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Project description:Jumonji domain-containing protein 6 (JMJD6) is a nuclear protein involved in histone modification, transcription and RNA processing. Although JMJD6 is crucial for tissue development, the link between its molecular functions and its roles in any given differentiation process is unknown. We report that JMJD6 is required for adipogenic gene expression and differentiation in a manner independent of Jumonji C domain catalytic activity. JMJD6 knockdown led to a reduction of C/EBP? and C/EBP? protein expression without affecting mRNA levels in the early phase of differentiation. However, ectopic expression of C/EBP? and C/EBP? did not rescue differentiation. Further analysis demonstrated that JMJD6 was associated with the Ppar?2 and Cebp? loci and putative enhancers. JMJD6 was previously found associated with bromodomain and extra-terminal domain (BET) proteins, which can be targeted by the bromodomain inhibitor JQ1. JQ1 treatment prevented chromatin binding of JMJD6, Ppar?2 and Cebp? expression, and adipogenic differentiation, yet had no effect on C/EBP? and C/EBP? expression or chromatin binding. These results indicate dual roles for JMJD6 in promoting adipogenic gene expression program by post-transcriptional regulation of C/EBP? and C/EBP? and direct transcriptional activation of Ppar?2 and Cebp? during adipocyte differentiation.

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Ssk1p response regulator binding surface on histidine-containing phosphotransfer protein Ypd1p.

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Project description:The methyl-CpG binding domain (MBD) protein MBD4 participates in DNA repair as a glycosylase that excises mismatched thymine bases in CpG sites and also functions in transcriptional repression. Unlike other MBD proteins, MBD4 recognizes not only methylated CpG dinucleotides ((5m)CG/(5m)CG) but also T/G mismatched sites generated by spontaneous deamination of 5-methylcytosine ((5m)CG/TG). The glycosylase activity of MBD4 is also implicated in active DNA demethylation initiated by the deaminase-catalyzed conversion of 5-methylcytosine to thymine. Here, we report the crystal structures of the MBD of MBD4 (MBDMBD4) complexed with (5m)CG/(5m)CG and (5m)CG/TG. The crystal structures show that the DNA interface of MBD4 has flexible structural features and harbors an extensive water network that supports its dual base specificities. Combined with the results of biochemical analyses, the crystal structure of MBD4 bound to 5-hydroxymethylcytosine further demonstrates that MBDMBD4 is able to recognize a wide range of 5-methylcytosine modifications through the unique water network. The versatile base recognition ability of MBDMBD4 implies multifunctional roles for MBD4 in the regulation of dynamic DNA methylation patterns coupled with deamination and/or oxidation of 5-methylcytosine.

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Project description:Estrogen receptor (ER) alpha is an essential component in human physiology and is a key factor involved in the development of breast and endometrial cancers. ERalpha protein levels and transcriptional activity are tightly controlled by the ubiquitin proteasome system. Deubiquitinating enzymes, a class of proteases capable of removing ubiquitin from proteins, are increasingly being seen as key modulators of the ubiquitin proteasome system, regulating protein stability and other functions by countering the actions of ubiquitin ligases. Using mass spectrometry analysis of an ERalpha protein complex, we identified OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) as a novel ERalpha-interacting protein capable of deubiquitinating ERalpha in cells and in vitro. We show that OTUB1 negatively regulates transcription mediated by ERalpha in transient reporter gene assays and transcription mediated by endogenous ERalpha in Ishikawa endometrial cancer cells. We also show that OTUB1 regulates the availability and functional activity of ERalpha in Ishikawa cells by affecting the transcription of the ERalpha gene and by stabilizing the ERalpha protein in the chromatin.

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Histone deacetylase-independent transcriptional repression by methyl-CpG-binding protein 2.

Project description:Methyl-CpG-binding protein 2 (MeCP2) contains a transcriptional repression domain (TRD), which can act by recruitment of a large transcriptional co-repressor complex containing histone deacetylases HDAC1 and 2. We demonstrate here that transient transcription from the SV40 enhancer/promoter or the SV40 promoter is strongly repressed in a histone deacetylase-independent manner, since repression is not alleviated by Trichostatin A (TSA). In a mutational analysis, repression depends on a conserved 30 residue sequence containing two clusters of basic amino acids. Mutation of the first of these clusters inhibits in vitro interaction between TRD and mSin3A. Furthermore, a subdomain of the TRD containing the conserved 30-residue sequence and 16 flanking amino acids was sufficient to compromise VP16-activated transcription. In summary, our results indicate an alternative, histone deacetylase-independent pathway of transcriptional repression by MeCP2.

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