scholarly journals BETting on a Transcriptional Deficit as the Main Cause for Cornelia de Lange Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Pablo García-Gutiérrez ◽  
Mario García-Domínguez
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Complex Function ◽  
Clinical Manifestations ◽  
Cornelia De Lange Syndrome ◽  
Cohesin Complex ◽  
Developmental Defects ◽  
Cornelia De Lange

Cornelia de Lange Syndrome (CdLS) is a human developmental syndrome with complex multisystem phenotypic features. It has been traditionally considered a cohesinopathy together with other phenotypically related diseases because of their association with mutations in subunits of the cohesin complex. Despite some overlap, the clinical manifestations of cohesinopathies vary considerably and, although their precise molecular mechanisms are not well defined yet, the potential pathomechanisms underlying these diverse developmental defects have been theoretically linked to alterations of the cohesin complex function. The cohesin complex plays a critical role in sister chromatid cohesion, but this function is not affected in CdLS. In the last decades, a non-cohesion-related function of this complex on transcriptional regulation has been well established and CdLS pathoetiology has been recently associated to gene expression deregulation. Up to 70% of CdLS cases are linked to mutations in the cohesin-loading factor NIPBL, which has been shown to play a prominent function on chromatin architecture and transcriptional regulation. Therefore, it has been suggested that CdLS can be considered a transcriptomopathy. Actually, CdLS-like phenotypes have been associated to mutations in chromatin-associated proteins, as KMT2A, AFF4, EP300, TAF6, SETD5, SMARCB1, MAU2, ZMYND11, MED13L, PHIP, ARID1B, NAA10, BRD4 or ANKRD11, most of which have no known direct association with cohesin. In the case of BRD4, a critical highly investigated transcriptional coregulator, an interaction with NIPBL has been recently revealed, providing evidence on their cooperation in transcriptional regulation of developmentally important genes. This new finding reinforces the notion of an altered gene expression program during development as the major etiological basis for CdLS. In this review, we intend to integrate the recent available evidence on the molecular mechanisms underlying the clinical manifestations of CdLS, highlighting data that favors a transcription-centered framework, which support the idea that CdLS could be conceptualized as a transcriptomopathy.

scholarly journals Cornelia de Lange Syndrome as Paradigm of Chromatinopathies

2021 ◽  
Vol 15 ◽  
Author(s):  
Ilaria Parenti ◽  
Frank J. Kaiser
Keyword(s):  
Transcriptional Regulation ◽  
Chromatin Remodeling ◽  
Neurodevelopmental Disorders ◽  
Molecular Mechanisms ◽  
Cornelia De Lange Syndrome ◽  
Facial Dysmorphism ◽  
Behavioral Disturbances ◽  
Chromatid Cohesion ◽  
Topologically Associated Domains ◽  
Cornelia De Lange

Chromatinopathies can be defined as a class of neurodevelopmental disorders caused by mutations affecting proteins responsible for chromatin remodeling and transcriptional regulation. The resulting dysregulation of gene expression favors the onset of a series of clinical features such as developmental delay, intellectual disability, facial dysmorphism, and behavioral disturbances. Cornelia de Lange syndrome (CdLS) is a prime example of a chromatinopathy. It is caused by mutations affecting subunits or regulators of the cohesin complex, a multisubunit protein complex involved in various molecular mechanisms such as sister chromatid cohesion, transcriptional regulation and formation of topologically associated domains. However, disease-causing variants in non-cohesin genes with overlapping functions have also been described in association with CdLS. Notably, the majority of these genes had been previously found responsible for distinct neurodevelopmental disorders that also fall within the category of chromatinopathies and are frequently considered as differential diagnosis for CdLS. In this review, we provide a systematic overview of the current literature to summarize all mutations in non-cohesin genes identified in association with CdLS phenotypes and discuss about the interconnection of proteins belonging to the chromatinopathies network.

scholarly journals Endurance Training Regulates Expression of Some Angiogenesis-Related Genes in Cardiac Tissue of Experimentally Induced Diabetic Rats

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 498
Author(s):  
Mojdeh Khajehlandi ◽  
Lotfali Bolboli ◽  
Marefat Siahkuhian ◽  
Mohammad Rami ◽  
Mohammadreza Tabandeh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endurance Training ◽  
Molecular Mechanisms ◽  
Cardiac Tissue ◽  
Critical Role ◽  
Diabetic Rats ◽  
Moderate Intensity ◽  
Pcr Analysis ◽  
Cardiac Tissues ◽  
The Impact

Exercise can ameliorate cardiovascular dysfunctions in the diabetes condition, but its precise molecular mechanisms have not been entirely understood. The aim of the present study was to determine the impact of endurance training on expression of angiogenesis-related genes in cardiac tissue of diabetic rats. Thirty adults male Wistar rats were randomly divided into three groups (N = 10) including diabetic training (DT), sedentary diabetes (SD), and sedentary healthy (SH), in which diabetes was induced by a single dose of streptozotocin (50 mg/kg). Endurance training (ET) with moderate-intensity was performed on a motorized treadmill for six weeks. Training duration and treadmill speed were increased during five weeks, but they were kept constant at the final week, and slope was zero at all stages. Real-time polymerase chain reaction (RT-PCR) analysis was used to measure the expression of myocyte enhancer factor-2C (MEF2C), histone deacetylase-4 (HDAC4) and Calmodulin-dependent protein kinase II (CaMKII) in cardiac tissues of the rats. Our results demonstrated that six weeks of ET increased gene expression of MEF2C significantly (p < 0.05), and caused a significant reduction in HDAC4 and CaMKII gene expression in the DT rats compared to the SD rats (p < 0.05). We concluded that moderate-intensity ET could play a critical role in ameliorating cardiovascular dysfunction in a diabetes condition by regulating the expression of some angiogenesis-related genes in cardiac tissues.

scholarly journals Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Yuen Gao ◽  
Natalia Duque-Wilckens ◽  
Mohammad B. Aljazi ◽  
Yan Wu ◽  
Adam J. Moeser ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Brain ◽  
Molecular Mechanisms ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Normal Brain ◽  
Critical Function ◽  
Developmental Defects ◽  
Neurodevelopmental Disease ◽  
Developing Mouse Brain

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causality and underlying molecular mechanisms linking ASH1L mutations to genesis of ASD/ID remain undetermined. Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes an ASD/ID mouse model revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.

scholarly journals The ETS-Domain Transcription Factor Elk-1 Regulates COX-2 Gene Expression and Inhibits Glucose-Stimulated Insulin Secretion in the Pancreaticβ-Cell Line INS-1

2013 ◽  
Vol 2013 ◽  
pp. 1-8
Author(s):  
Xiong-Fei Zhang ◽  
Yi Zhu ◽  
Wen-Biao Liang ◽  
Jing-Jing Zhang
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Insulin Secretion ◽  
Cell Line ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Cell Dysfunction ◽  
Cox 2 ◽  
Glucose Stimulated Insulin Secretion

Cyclooxygenase-2 (COX-2) expression is associated with many aspects of physiological and pathological conditions, including pancreaticβ-cell dysfunction. Prostaglandin E2 (PGE2) production, as a consequence of COX-2 gene induction, has been reported to impairβ-cell function. The molecular mechanisms involved in the regulation of COX-2 gene expression are not fully understood. We previously demonstrated that transcription factor Elk-1 significantly upregulated COX-2 gene promoter activity. In this report, we used pancreaticβ-cell line (INS-1) to explore the relationships between Elk-1 and COX-2. We first investigated the effects of Elk-1 on COX-2 transcriptional regulation and expression in INS-1 cells. We thus undertook to study the binding of Elk-1 to its putative binding sites in the COX-2 promoter. We also analysed glucose-stimulated insulin secretion (GSIS) in INS-1 cells that overexpressed Elk-1. Our results demonstrate that Elk-1 efficiently upregulates COX-2 expression at least partly through directly binding to the −82/−69 region of COX-2 promoter. Overexpression of Elk-1 inhibits GSIS in INS-1 cells. These findings will be helpful for better understanding the transcriptional regulation of COX-2 in pancreaticβ-cell. Moreover, Elk-1, the transcriptional regulator of COX-2 expression, will be a potential target for the prevention ofβ-cell dysfunction mediated by PGE2.

Stat6 Inhibits Human Interleukin-4 Promoter Activity in T Cells

Blood ◽  
1998 ◽  
Vol 92 (12) ◽  
pp. 4529-4538 ◽  
Author(s):  
Steve N. Georas ◽  
John E. Cumberland ◽  
Thomas F. Burke ◽  
Rongbing Chen ◽  
Ulrike Schindler ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Regulatory Elements ◽  
Jurkat Cells ◽  
Proximal Promoter ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Th Cells

Abstract The differentiation of naive T-helper (Th) cells into cytokine-secreting effector Th cells requires exposure to multiple signals, including exogenous cytokines. Interleukin-4 (IL-4) plays a major role in this process by promoting the differentiation of IL-4–secreting Th2 cells. In Th2 cells, IL-4 gene expression is tightly controlled at the level of transcription by the coordinated binding of multiple transcription factors to regulatory elements in the proximal promoter region. Nuclear factor of activated T cell (NFAT) family members play a critical role in regulating IL-4 transcription and interact with up to five sequences (termed P0 through P4) in the IL-4 promoter. The molecular mechanisms by which IL-4 induces expression of the IL-4 gene are not known, although the IL-4–activated transcription factor signal transducer and activator of transcription 6 (Stat6) is required for this effect. We report here that Stat6 interacts with three binding sites in the human IL-4 promoter by electrophoretic mobility shift assays. These sites overlap the P1, P2, and P4 NFAT elements. To investigate the role of Stat6 in regulating IL-4 transcription, we used Stat6-deficient Jurkat T cells with different intact IL-4 promoter constructs in cotransfection assays. We show that, whereas a multimerized response element from the germline IgE promoter was highly induced by IL-4 in Stat6-expressing Jurkat cells, the intact human IL-4 promoter was repressed under similar conditions. We conclude that the function of Stat6 is highly dependent on promoter context and that this factor promotes IL-4 gene expression in an indirect manner.

Cornelia de Lange syndrome, related disorders, and the Cohesin complex: Abstracts from the 8th biennial scientific and educational symposium 2018

2019 ◽  
Vol 179 (6) ◽  
pp. 1080-1090
Author(s):  
Antonie D. Kline ◽  
Ian D. Krantz ◽  
Masashige Bando ◽  
Katsuhiko Shirahige ◽  
Stephenson Chea ◽  
...  
Keyword(s):  
Cornelia De Lange Syndrome ◽  
Cohesin Complex ◽  
Educational Symposium ◽  
Cornelia De Lange

scholarly journals Cornelia de Lange syndrome and molecular implications of the cohesin complex: Abstracts from the 7th biennial scientific and educational symposium 2016

2017 ◽  
Vol 173 (5) ◽  
pp. 1172-1185 ◽  
Author(s):  
Antonie D. Kline ◽  
Ian D. Krantz ◽  
Matthew A. Deardorff ◽  
Katsuhiko Shirahige ◽  
Dale Dorsett ◽  
...  
Keyword(s):  
Cornelia De Lange Syndrome ◽  
Cohesin Complex ◽  
Educational Symposium ◽  
Cornelia De Lange

scholarly journals Cornelia de Lange Syndrome-associated mutations in Smc1 cause both sister chromatid cohesion and cohesion-independent defects

2018 ◽  
Author(s):  
Jingrong Chen ◽  
Frank Wu ◽  
Dean Dawson ◽  
Susannah Rankin
Keyword(s):  
Chromosome Segregation ◽  
Developmental Disorders ◽  
Cell Cycle Progression ◽  
Budding Yeast ◽  
Critical Role ◽  
Cornelia De Lange Syndrome ◽  
Chromosome Loss ◽  
Genes Encoding ◽  
Cornelia De Lange ◽  
The Impact

AbstractCornelia de Lange Syndrome is a pervasive developmental disorder characterized by limb truncations, craniofacial abnormalities, and cognitive delays. This syndrome is a member of a class of developmental disorders referred to as cohesinopathies, which result from mutations in the genes encoding subunits or regulators of the cohesin complex. The phenotypic consequences of these mutations may reflect the critical role that cohesin plays in chromosome structure, its ability to tether sister chromatids together during cell cycle progression, or some combination of both. Here we show that a sensitized assay for chromosome loss in budding yeast can be used to assess the impact of Cornelia de Lange syndrome (CdLS)-associated mutations in the core cohesin subunit Smc1 on cohesin function. We find that the CdLS-associated mutations can be grouped into two classes based on their impact on chromosome segregation. One class of mutations includes those that are defective in promoting accurate chromosome segregation, some no better than the null allele. Another class promotes both accurate chromosome cohesion and segregation. Strikingly, the mutations that have no impact chromosome dynamics in this assay are clustered near each other in the context of the folded SMC1 protein suggesting a previously uncharacterized region of functional importance in higher eukaryotes. This analysis illustrates how budding yeast can be used to elucidate mechanisms important in human health and development.

scholarly journals Pulmonary Hypertension Associated With Scleroderma and Connective Tissue Disease: Potential Molecular and Cellular Targets

2017 ◽  
Vol 16 (2) ◽  
pp. 61-67
Author(s):  
Maria Trojanowska
Keyword(s):  
Pulmonary Hypertension ◽  
Connective Tissue ◽  
Connective Tissue Disease ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Connective Tissue Diseases ◽  
Clinical Manifestations ◽  
Response To Treatment ◽  
Organ Systems

Systemic sclerosis (SSc) is characterized by autoimmunity, small-vessel vasculopathy, and fibrosis causing damage in multiple organ systems. Pulmonary arterial hypertension (PAH) is a serious and often fatal complication of SSc, occurring in patients with the limited (lcSSc) and diffuse (dcSSc) forms of the disease and affecting 8% to 15% of patients.12 While pulmonary hypertension associated with connective tissue disease (CTD-PAH) has similar clinical features as idiopathic PAH, 1-year survival and freedom from hospitalization are lower in CTD-PAH.3 SSc-PAH has the worst 1-year survival rate at 82% compared with other connective tissue diseases, including systemic lupus erythematosus, mixed connective tissue disease, and rheumatoid arthritis.34 Despite the recent progress in the development of disease-targeted therapies, patients with SSc-PAH have a poorer response to treatment and a worse prognosis than other subgroups of PAH.1 Autoimmunity and prolonged vasculopathy preceding the development of clinical manifestations of SSc-PAH may play a critical role in the poorer outcome of SSc-PAH patients.1 This article will provide an overview of the recent findings related to cellular and molecular mechanisms associated with the development of PAH, with an emphasis on SSc-PAH.

scholarly journals Identification of Key Genes and MicroRNAs in Gastric Cancer via miRNA-mRNA Regulatory Network

2020 ◽  
Author(s):  
Chao Huang ◽  
Xiaojian Zhu ◽  
Jiefeng Zhao ◽  
Fanqin Bu ◽  
Jun Huang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Molecular Markers ◽  
Expression Profiling ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Differentially Expressed ◽  
Expression Levels ◽  
Receptor Interactions

Abstract Background Gastric cancer (GC) is a malignant tumor with high mortality. MicroRNAs (miRNAs) participate in various biological processes and disease pathogenesis by targeting messenger RNA (mRNA). The purpose of this study was to identify potential prognostic molecular markers of GC and to characterize the molecular mechanisms of GC. Methods A gene expression profiling dataset (GSE54129) and miRNA expression profiling dataset (GSE113486) were downloaded from the Gene Expression Omnibus (GEO) database. A miRNA-mRNA interaction network was established. Functional and pathway enrichment analyses were performed for differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) using FunRich, the clusterProfiler package, and DIANA-mirPath. Survival analysis of key molecular markers was performed using the online tool Kaplan-Meier Plotter and the database OncomiR. Finally, experiments were carried out to verify the expression levels and biological functions of a key gene. Results A total of 390 DEMs and 341 DEGs were identified. Ultimately, 45 genes and 31 miRNAs were selected to establish a miRNA-mRNA regulatory network. Four hub genes (ZFPM2, FUT9, NEUROD1 and LIPH) and six miRNAs (hsa-let-7d-5p, hsa-miR-23b-3p, hsa-miR-23a-3p, hsa-miR-133b, hsa-miR-130a-3p and hsa-miR-124-3p) were identified in the network. DEGs and DEMs were associated with ECM-receptor interactions and metabolic pathways. Two genes (ZFPM2 and LIPH) and two miRNAs (hsa-miR-23a-3p and hsa-miR-130a-3p) were observed to be related to the prognosis of GC. ZFPM2 was highly expressed in GC tissues and various GC cell lines and could promote the proliferation, invasion and migration of GC cells. Conclusion The expression levels of ZFPM2, LIPH, hsa-miR-23a-3p and hsa-miR-130a-3p were closely related to the prognosis of GC. ZFPM2 may serve as a potential molecular marker and therapeutic target for GC. ECM receptor interactions and metabolic abnormalities play a critical role in the GC progression.

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