scholarly journals Mutations in EBF3 disturb transcriptional profiles and underlie a novel syndrome of intellectual disability, ataxia and facial dysmorphism

2016 ◽  
Author(s):  
Frederike Leonie Harms ◽  
Katta Mohan Girisha ◽  
Andrew A. Hardigan ◽  
Fanny Kortüm ◽  
Anju Shukla ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Intellectual Disability ◽  
Neuronal Differentiation ◽  
Neuronal Development ◽  
Facial Dysmorphism ◽  
Rna Seq ◽  
Speech Delay

AbstractFrom a GeneMatcher-enabled international collaboration, we identified ten individuals with intellectual disability, speech delay, ataxia and facial dysmorphism and a mutation in EBF3, encoding a transcription factor required for neuronal differentiation. Structural assessments, transactivation assays, in situ fractionation, RNA-seq and ChlP-seq experiments collectively show that the mutations are deleterious and impair EBF3 transcriptional regulation. These findings demonstrate that EBF3-mediated dysregulation of gene expression has profound effects on neuronal development in humans.

scholarly journals Transcription Factor VAX1 Regulates the Regional Specification of the Subpallium through Repressing Gsx2

2020 ◽  
Author(s):  
Yan Wen ◽  
Zihao Su ◽  
Ziwu Wang ◽  
Lin Yang ◽  
Guoping Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
Cerebral Cortex ◽  
Basal Ganglia ◽  
Neuronal Differentiation ◽  
Molecular Mechanisms ◽  
Regional Identity ◽  
Immunofluorescence Staining ◽  
Rna Seq

Abstract Specification of the progenitors’ regional identity is a pivotal step during development of the cerebral cortex and basal ganglia. The molecular mechanisms underlying progenitor regionalization, however, are poorly understood. Here we showed that the transcription factors Vax1 was highly expressed in the developing subpallium. In its absence, the RNA-Seq analysis, in situ RNA hybridization, and immunofluorescence staining results showed that the cell proliferation was increased in the subpallium, but the neuronal differentiation was blocked. Moreover, the dLGE region severely expanded ventrally at the expense of the vLGE, MGE, and septum. Finally, overexpressed VAX1 in the LGE progenitors strongly inhibits Gsx2 expression. Taken together, our findings show that Vax1 is crucial for subpallium regionalization by repressing Gsx2.

scholarly journals Transcription Factor VAX1 Regulates the Regional Specification of the Subpallium through Repressing Gsx2

2020 ◽  
Author(s):  
Yan Wen ◽  
Zihao Su ◽  
Ziwu Wang ◽  
Lin Yang ◽  
Guoping Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
Cerebral Cortex ◽  
Basal Ganglia ◽  
Neuronal Differentiation ◽  
Molecular Mechanisms ◽  
Regional Identity ◽  
Immunofluorescence Staining ◽  
Rna Seq

Abstract Specification of the progenitors’ regional identity is a pivotal step during development of the cerebral cortex and basal ganglia. The molecular mechanisms underlying progenitor regionalization, however, are poorly understood. Here we showed that the transcription factors Vax1 was highly expressed in the developing subpallium. In its absence, the RNA-Seq analysis, in situ RNA hybridization, and immunofluorescence staining results showed that the cell proliferation was increased in the subpallium, but the neuronal differentiation was blocked. Moreover, the dLGE region severely expanded ventrally at the expense of the vLGE, MGE, and septum. Finally, overexpressed VAX1 in the LGE progenitors strongly inhibits Gsx2 expression. Taken together, our findings show that Vax1 is crucial for subpallium regionalization by repressing Gsx2.

scholarly journals Modeling transcriptional regulation using gene regulatory networks based on multi-omics data sources

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Neel Patel ◽  
William S. Bush
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Prediction Models ◽  
Long Distance ◽  
Chromatin Looping ◽  
Gene Regulatory ◽  
The Impact

Abstract Background Transcriptional regulation is complex, requiring multiple cis (local) and trans acting mechanisms working in concert to drive gene expression, with disruption of these processes linked to multiple diseases. Previous computational attempts to understand the influence of regulatory mechanisms on gene expression have used prediction models containing input features derived from cis regulatory factors. However, local chromatin looping and trans-acting mechanisms are known to also influence transcriptional regulation, and their inclusion may improve model accuracy and interpretation. In this study, we create a general model of transcription factor influence on gene expression by incorporating both cis and trans gene regulatory features. Results We describe a computational framework to model gene expression for GM12878 and K562 cell lines. This framework weights the impact of transcription factor-based regulatory data using multi-omics gene regulatory networks to account for both cis and trans acting mechanisms, and measures of the local chromatin context. These prediction models perform significantly better compared to models containing cis-regulatory features alone. Models that additionally integrate long distance chromatin interactions (or chromatin looping) between distal transcription factor binding regions and gene promoters also show improved accuracy. As a demonstration of their utility, effect estimates from these models were used to weight cis-regulatory rare variants for sequence kernel association test analyses of gene expression. Conclusions Our models generate refined effect estimates for the influence of individual transcription factors on gene expression, allowing characterization of their roles across the genome. This work also provides a framework for integrating multiple data types into a single model of transcriptional regulation.

scholarly journals Pitt–Hopkins syndrome with electrical stat us epileptic us in slo w-wave sleep: a case report

2019 ◽  
Vol 14 (2) ◽  
pp. 42-48
Author(s):  
N. G. Lyukshina
Keyword(s):  
Case Report ◽  
Intellectual Disability ◽  
Status Epilepticus ◽  
Neuronal Differentiation ◽  
Clinical Case ◽  
Genetic Disorder ◽  
Facial Dysmorphism ◽  
Autistic Behavior ◽  
Rare Genetic Disorder ◽  
Molecular Variant

Pitt–Hoppkins syndrome is rare genetic disorder caused by a molecular variant of TCF4 which is involved in embryologic neuronal differentiation. The syndrome is characterized by specific facial dysmorphism, phychomotor delay, autistic behavior and intellectual disability. Other associated features include ealy-onset myopia, seizures, constipation and hyperventilation-apneic spells. We introduced a clinical case of the patient with molecularly confirmed TCF4 variant and previously undescribed combination with syndrome of the electrical status epilepticus during sleep.

scholarly journals MED13L-related intellectual disability due to paternal germinal mosaicism

2021 ◽  
pp. mcs.a006124
Author(s):  
Beata Bessenyei ◽  
Istvan Balogh ◽  
Attila Mokanszki ◽  
Aniko Ujfalusi ◽  
Rolph Pfundt ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Mediator Complex ◽  
Facial Dysmorphism ◽  
Facial Features ◽  
Speech Delay ◽  
Motor Delay ◽  
First Case ◽  
Intragenic Deletion ◽  
Germinal Mosaicism

The MED13L-related intellectual disability or MRFACD syndrome (Mental retardation and distinctive facial features with or without cardiac defects; MIM # 616789) is one of the most common form of syndromic intellectual disability with about a hundred cases reported so far. Affected individuals share overlapping features comprising intellectual disability, hypotonia, motor delay, remarkable speech delay, and a recognizable facial gestalt. De novo disruption of the MED13L gene by deletions, duplications or sequence variants has been identified deleterious. Siblings affected by intragenic deletion transmitted from a mosaic parent have been reported once in the literature. We now present the first case of paternal germinal mosaicism for a missense MED13L variant causing MRFACD syndrome in one of the father's children and be the likely cause of intellectual disability and facial dysmorphism in the other. As part of the Mediator complex, the MED proteins have an essential role in regulating transcription. 32 subunits of the Mediator complex genes have been linked to congenital malformations that are now acknowledged as transcriptomopathies. The MRFACD syndrome has been suggested to represent a recognizable phenotype.

scholarly journals BgeeDB, an R package for retrieval of curated expression datasets and for gene list expression localization enrichment tests

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2748 ◽  
Author(s):  
Andrea Komljenovic ◽  
Julien Roux ◽  
Marc Robinson-Rechavi ◽  
Frederic B. Bastian
Keyword(s):  
Gene Expression ◽  
Gene List ◽  
R Package ◽  
Rna Seq ◽  
Anatomical Structures ◽  
Enrichment Test ◽  
Expression Of Genes ◽  
Affymetrix Microarrays ◽  
New Gene

BgeeDB is a collection of functions to import into R re-annotated, quality-controlled and reprocessed expression data available in the Bgee database. This includes data from thousands of wild-type healthy samples of multiple animal species, generated with different gene expression technologies (RNA-seq, Affymetrix microarrays, expressed sequence tags, and in situ hybridizations). BgeeDB facilitates downstream analyses, such as gene expression analyses with other Bioconductor packages. Moreover, BgeeDB includes a new gene set enrichment test for preferred localization of expression of genes in anatomical structures (“TopAnat”). Along with the classical Gene Ontology enrichment test, this test provides a complementary way to interpret gene lists. Availability: http://www.bioconductor.org/packages/BgeeDB/

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.

scholarly journals A t(5;16) translocation is the likely driver of a syndrome with ambiguous genitalia, facial dysmorphism, intellectual disability, and speech delay

2015 ◽  
Vol 2 (2) ◽  
pp. a000703 ◽  
Author(s):  
Ayşegül Ozantürk ◽  
Erica E. Davis ◽  
Aniko Sabo ◽  
Marjan M. Weiss ◽  
Donna Muzny ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Ambiguous Genitalia ◽  
Facial Dysmorphism ◽  
Speech Delay
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