scholarly journals Methyl-CpG2-binding protein 2 mediates overlapping mechanisms across brain disorders

2019 ◽  
Author(s):  
Snow Bach ◽  
Niamh M. Ryan ◽  
Paolo Guasoni ◽  
Aiden Corvin ◽  
Daniela Tropea
Keyword(s):  
Target Genes ◽  
Binding Protein ◽  
Brain Disorders ◽  
Chromatin Binding ◽  
Binding Properties ◽  
Hyperactivity Disorder ◽  
Potential Applications ◽  
Neuronal Transmission ◽  
Neuropsychiatric Conditions ◽  
Common Molecular Basis

AbstractMethyl-CpG binding protein 2 (MeCP2) is a chromatin-binding protein and a modulator of gene expression. Initially identified as an oncogene, MECP2 is now mostly associated to Rett Syndrome, a neurodevelopmental condition, though there is evidence of its influence in other brain disorders.We design a procedure that considers several binding properties of MeCP2 and we screen for potential targets across neurological and neuropsychiatric conditions.We find MeCP2 target genes associated to a range of disorders, including - among others-Alzheimer Disease, Autism, Attention Deficit Hyperactivity Disorder and Multiple Sclerosis. The analysis of biological mechanisms and pathways modulated by MeCP2’s target genes shows that such mechanisms are involved in three main processes: neuronal transmission, immuno-reactivity and development.These results suggest that similar symptoms present in different pathologies have a common molecular basis, and that treatments for one condition have potential applications to related disorders.

scholarly journals Methyl-CpG-binding protein 2 mediates overlapping mechanisms across brain disorders

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Snow Bach ◽  
Niamh M. Ryan ◽  
Paolo Guasoni ◽  
Aiden P. Corvin ◽  
Rania A. El-Nemr ◽  
...  
Keyword(s):  
Nervous System ◽  
Rett Syndrome ◽  
Transcriptome Analysis ◽  
Target Genes ◽  
Binding Protein ◽  
Neurodevelopmental Disorder ◽  
Brain Disorders ◽  
Binding Properties ◽  
Neurological Conditions ◽  
Neuronal Transmission

AbstractMECP2 and its product, Methyl-CpG binding protein 2 (MeCP2), are mostly known for their association to Rett Syndrome (RTT), a rare neurodevelopmental disorder. Additional evidence suggests that MECP2 may underlie other neuropsychiatric and neurological conditions, and perhaps modulate common presentations and pathophysiology across disorders. To clarify the mechanisms of these interactions, we develop a method that uses the binding properties of MeCP2 to identify its targets, and in particular, the genes recognized by MeCP2 and associated to several neurological and neuropsychiatric disorders. Analysing mechanisms and pathways modulated by these genes, we find that they are involved in three main processes: neuronal transmission, immuno-reactivity, and development. Also, while the nervous system is the most relevant in the pathophysiology of the disorders, additional systems may contribute to MeCP2 action through its target genes. We tested our results with transcriptome analysis on Mecp2-null models and cells derived from a patient with RTT, confirming that the genes identified by our procedure are directly modulated by MeCP2. Thus, MeCP2 may modulate similar mechanisms in different pathologies, suggesting that treatments for one condition may be effective for related disorders.

scholarly journals Chromatin Opening and Stable Perturbation of Core Histone:DNA Contacts by FoxO1

2007 ◽  
Vol 282 (49) ◽  
pp. 35583-35593 ◽  
Author(s):  
Mitsutoki Hatta ◽  
Lisa Ann Cirillo
Keyword(s):  
Growth Factor ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Binding Protein ◽  
Insulin Like Growth Factor ◽  
Chromatin Binding ◽  
Factor Binding ◽  
Forkhead Box ◽  
Stable Perturbation ◽  
Chromatin Opening

FoxO1, a member of the forkhead rabdomyosarcoma (FoxO) subfamily of transcription factors, binds DNA via a highly conserved winged-helix “forkhead box” motif used by other regulatory proteins to mediate their effects through chromatin binding and remodeling. To examine how FoxO1 regulates target genes in chromatin, we studied the binding of purified recombinant FoxO1 protein to nucleosome particles and chromatin arrays containing the insulin-like growth factor-binding protein 1 promoter. We found that FoxO1 is able to bind to its cognate sites within the insulin-like growth factor-binding protein 1 promoter on a nucleosome. This binding stably perturbs core histone:DNA contacts extending up- and downstream from sites of FoxO1 binding without disrupting the underlying core particle. FoxO1 is able to harness these capabilities to bind to and de-condense linker histone-compacted chromatin arrays. Chromatin opening by FoxO1 requires both the N and C termini of the protein, which are also required for high affinity core histone binding and, in the case of the N terminus, nucleosome perturbation. We suggest that the chromatin binding and remodeling functions revealed here for FoxO1 endow all FoxO factors with the ability to initiate and dynamically modulate active chromatin states, enabling their diverse roles as gene regulatory factors in metabolism, cell survival, apoptosis, cell cycle progression, DNA repair, and protection against oxidative stress.

Analysis of Sterol-Regulatory Element-Binding Protein 1c Target Genes in Mouse Liver during Aging and High-Fat Diet

2013 ◽  
Vol 6 (2) ◽  
pp. 107-122 ◽  
Author(s):  
Frédéric Capel ◽  
Gaëlle Rolland-Valognes ◽  
Catherine Dacquet ◽  
Manuel Brun ◽  
Michel Lonchampt ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Mouse Liver ◽  
Target Genes ◽  
Binding Protein ◽  
Regulatory Element ◽  
High Fat ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Abstract P347: Retinol-binding Protein 7 (RBP7) is Required for PPARG-mediated Endothelial Protection via Adiponectin

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Chunyan Hu ◽  
Henry L Keen ◽  
Ko-Ting Lu ◽  
Deborah R Davis ◽  
Xuebo Liu ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Rna Sequencing ◽  
Basilar Artery ◽  
Vascular Function ◽  
Carotid Arteries ◽  
Target Genes ◽  
Binding Protein ◽  
Retinol Binding Protein ◽  
Specific Expression ◽  
Fatty Acid Binding

PPARγ protects against endothelial dysfunction by regulation of unknown target genes. One such target, RBP7, an intracellular fatty acid-binding protein, exhibits endothelium-specific expression, but its effect on vascular function remain unknown. We hypothesize that RBP7 is endothelial protective. We examined vascular responses in basilar artery (pressurized myograph) of RBP7-knockout (KO) and wild type (WT) mice fed normal chow (ND) or high fat diet (HFD) for 8 wks. Endothelium-dependent acetylcholine (ACh)-induced relaxation was significantly impaired in HFD-fed KO mice (ACh, 100μM: 33±7% KO vs 83±10% WT, p<0.05), but not in ND-fed groups. This response was ameliorated by pre-incubation with superoxide scavenger tempol (1mM) or PEG-superoxide dismutase (100 U/ml). Mean arterial pressure (measured by radiotelemetry), body weight, hepatic steatosis, fasting glucose, glucose tolerance, and insulin sensitivity were similar in HFD-fed KO and WT mice. To identify targets downstream of RBP7, RNA-Sequencing was performed on carotid arteries from 8-week HFD-fed WT and KO mice as well as ND-fed age-matched littermates. Adiponectin (AdipoQ), a PPARγ target, was increased ~6-fold in HFD-fed WT mice, a response that was markedly blunted in KO mice. RNA sequencing was confirmed by qPCR. There was no difference in plasma AdipoQ. AdipoQ protein is expressed in endothelial cells of carotid arteries and its level of expression was increased in HFD-fed WT but not KO mice (AdipoQ/CD31: 1.14±0.1 WT-HFD vs 0.82±0.1 WT-ND, p<0.05; 0.79±0.1 KO-HFD vs 0.81±0.04 KO-ND). This led us to hypothesize that AdipoQ is involved in RBP7-mediated endothelial protection. Incubation of basilar artery with mouse full-length AdipoQ protein (5 μg/mL, 4 hours) significantly ameliorated endothelial dysfunction (ACh, 100 μM: 56±6% AdipoQ+KO vs 26±3% KO, p<0.05) and blunted carotid artery superoxide production in HFD-fed KO mice. AdipoQ also protects against endothelial dysfunction caused by subpressor Ang-II in KO mice. We conclude that RBP7 protects the endothelium from oxidative stress-induced dysfunction through an AdipoQ-dependent mechanism. Our evidence suggests RBP7 is an essential cofactor for activation of some PPARγ target genes in the endothelium.

scholarly journals Binding abilities of polyaminocyclodextrins: polarimetric investigations and biological assays

2017 ◽  
Vol 13 ◽  
pp. 2751-2763 ◽  
Author(s):  
Marco Russo ◽  
Daniele La Corte ◽  
Annalisa Pisciotta ◽  
Serena Riela ◽  
Rosa Alduina ◽  
...  
Keyword(s):  
Sodium Alginate ◽  
Cellular Uptake ◽  
Biological Systems ◽  
Direct Reaction ◽  
Coulomb Interactions ◽  
Binding Properties ◽  
Biological Assays ◽  
Potential Applications

Three polyaminocyclodextrin materials, obtained by direct reaction between heptakis(6-deoxy-6-iodo)-β-cyclodextrin and the proper linear polyamines, were investigated for their binding properties, in order to assess their potential applications in biological systems, such as vectors for simultaneous drug and gene cellular uptake or alternatively for the protection of macromolecules. In particular, we exploited polarimetry to test their interaction with some model p-nitroaniline derivatives, chosen as probe guests. The data obtained indicate that binding inside the host cavity is mainly affected by interplay between Coulomb interactions and conformational restraints. Moreover, simultaneous interaction of the cationic polyamine pendant bush at the primary rim was positively assessed. Insights on quantitative aspects of the interaction between our materials and polyanions were investigated by studying the binding with sodium alginate. Finally, the complexation abilities of the same materials towards polynucleotides were assessed by studying their interaction with the model plasmid pUC19. Our results positively highlight the ability of our materials to exploit both the cavity and the polycationic branches, thus functioning as bimodal ligands.

scholarly journals Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein

2005 ◽  
Vol 203 (1) ◽  
pp. 63-72 ◽  
Author(s):  
Chang Hoon Lee ◽  
Mark Melchers ◽  
Hongsheng Wang ◽  
Ted A. Torrey ◽  
Rebecca Slota ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Transcriptional Activation ◽  
Germinal Center ◽  
Target Genes ◽  
Fluorescent Protein ◽  
Binding Protein ◽  
Consensus Sequence ◽  
B Cell Lymphoma ◽  
Regulatory Factor

Interferon (IFN) consensus sequence-binding protein/IFN regulatory factor 8 (IRF8) is a transcription factor that regulates the differentiation and function of macrophages, granulocytes, and dendritic cells through activation or repression of target genes. Although IRF8 is also expressed in lymphocytes, its roles in B cell and T cell maturation or function are ill defined, and few transcriptional targets are known. Gene expression profiling of human tonsillar B cells and mouse B cell lymphomas showed that IRF8 transcripts were expressed at highest levels in centroblasts, either from secondary lymphoid tissue or transformed cells. In addition, staining for IRF8 was most intense in tonsillar germinal center (GC) dark-zone centroblasts. To discover B cell genes regulated by IRF8, we transfected purified primary tonsillar B cells with enhanced green fluorescent protein–tagged IRF8, generated small interfering RNA knockdowns of IRF8 expression in a mouse B cell lymphoma cell line, and examined the effects of a null mutation of IRF8 on B cells. Each approach identified activation-induced cytidine deaminase (AICDA) and BCL6 as targets of transcriptional activation. Chromatin immunoprecipitation studies demonstrated in vivo occupancy of 5′ sequences of both genes by IRF8 protein. These results suggest previously unappreciated roles for IRF8 in the transcriptional regulation of B cell GC reactions that include direct regulation of AICDA and BCL6.

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