scholarly journals Global differential expression of genes located in the Down Syndrome Critical Region in normal human brain

2014 ◽  
pp. 154-161 ◽  
Author(s):  
Julio Cesar Montoya ◽  
Dianora Fajardo ◽  
Ángela Peña ◽  
Adalberto Sánchez ◽  
Martha C Domínguez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Down Syndrome ◽  
Human Brain ◽  
Critical Region ◽  
Expression Profiles ◽  
Brain Atlas ◽  
Normal Human Brain ◽  
Normal Human ◽  
The Brain ◽  
Brain Homeostasis

Background: The information of gene expression obtained from databases, have made possible the extraction and analysis of data related with several molecular processes involving not only in brain homeostasis but its disruption in some neuropathologies; principally in Down syndrome and the Alzheimer disease. Objective: To correlate the levels of transcription of 19 genes located in the Down Syndrome Critical Region (DSCR) with their expression in several substructures of normal human brain. Methods: There were obtained expression profiles of 19 DSCR genes in 42 brain substructures, from gene expression values available at the database of the human brain of the Brain Atlas of the Allen Institute for Brain Sciences", (http://human.brain-map.org/). The co-expression patterns of DSCR genes in brain were calculated by using multivariate statistical methods. Results: Highest levels of gene expression were registered at caudate nucleus, nucleus accumbens and putamen among central areas of cerebral cortex. Increased expression levels of RCAN1 that encode by a protein involved in signal transduction process of the CNS were recorded for PCP4 that participates in the binding to calmodulin and TTC3; a protein that is associated with differentiation of neurons. That previously idenjpgied brain structures play a crucial role in the learning process, in different class of memory and in motor skills. Conclusion: The precise regulation of DSCR gene expression is crucial to maintain the brain homeostasis, especially in those areas with high levels of gene expression associated with a remarkable process of learning and cognition.

scholarly journals Complex networks of interaction of genes located in the critical region of Down syndrome expressed in the normal human brain

2018 ◽  
Vol 29 (18) ◽  
Author(s):  
Dianora Fajardo ◽  
Karla Vinasco ◽  
Julio C Montoya ◽  
Jose M Satizabal ◽  
Adalberto Sanchez ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Human Brain ◽  
Complex Networks ◽  
Critical Region ◽  
Normal Human Brain ◽  
Normal Human

scholarly journals Human brain harbors single nucleotide somatic variations in functionally relevant genes possibly mediated by oxidative stress

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2520 ◽  
Author(s):  
Anchal Sharma ◽  
Asgar Hussain Ansari ◽  
Renu Kumari ◽  
Rajesh Pandey ◽  
Rakhshinda Rehman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Corpus Callosum ◽  
Human Brain ◽  
Frontal Cortex ◽  
Oxidative Stress Marker ◽  
Somatic Variation ◽  
Single Nucleotide ◽  
Normal Human Brain ◽  
Normal Human ◽  
The Brain

Somatic variation in DNA can cause cells to deviate from the preordained genomic path in both disease and healthy conditions. Here, using exome sequencing of paired tissue samples, we show that the normal human brain harbors somatic single base variations measuring up to 0.48% of the total variations. Interestingly, about 64% of these somatic variations in the brain are expected to lead to non-synonymous changes, and as much as 87% of these represent G:C>T:A transversion events. Further, the transversion events in the brain were mostly found in the frontal cortex, whereas the corpus callosum from the same individuals harbors the reference genotype. We found a significantly higher amount of 8-OHdG (oxidative stress marker) in the frontal cortex compared to the corpus callosum of the same subjects (p<0.01), correlating with the higher G:C>T:A transversions in the cortex. We found significant enrichment for axon guidance and related pathways for genes harbouring somatic variations. This could represent either a directed selection of genetic variations in these pathways or increased susceptibility of some loci towards oxidative stress. This study highlights that oxidative stress possibly influence single nucleotide somatic variations in normal human brain.

scholarly journals Hydroxysteroid sulfotransferase 2B1b expression and localization in normal human brain

2011 ◽  
Vol 8 (1) ◽  
Author(s):  
Emily D. Salman ◽  
Ona Faye-Petersen ◽  
Charles N. Falany
Keyword(s):  
Protein Expression ◽  
Human Brain ◽  
Fetal Brain ◽  
Immunohistochemical Analysis ◽  
Adult Brain ◽  
Sterol Metabolism ◽  
Normal Human Brain ◽  
Mrna And Protein Expression ◽  
Normal Human ◽  
The Brain

AbstractSteroid sulfonation in the human brain has not been well characterized. The major sulfotransferase (SULT) isoforms that conjugate steroids in humans are SULT1E1, SULT2A1, and SULT2B1b. SULT2B1b catalyzes the sulfonation of 3β-hydroxysteroids, including neurosteroids dehydroepiandrosterone and pregnenolone, as well as cholesterol and several hydroxycholesterols. SULT2B1b mRNA and protein expression were detected in adult and fetal human brain sections, whereas neither mRNA, nor protein expression were identified for SULT1E1 or SULT2A1. Using immunohistochemical analysis, SULT2B1b expression was detected in neurons and oligodendrocytes in adult brain and in epithelial tissues in 28-week-old fetal brain. Sulfonation of cholesterol, oxysterols, and neurosteroids in the brain is apparently catalyzed by SULT2B1b since expression of neither SULT2A1 nor SULT1E1 was detected in human brain sections. SULT2B1b mRNA and protein were also detected in human U373-MG glioblastoma cells. Both mRNA and protein expression of liver X receptor (LXR)-β, but not LXR-α, were detected in U373-MG cells, and LXR-β activation resulted in a decrease in SULT2B1b protein expression. Since hydroxycholesterols are important physiological LXR activators, this suggests a role for regulation of sterol metabolism by LXR and SULT2B1b. Therefore, elucidating key enzymes in the metabolism of cholesterol and neuro­steroids could help define the properties of steroid conjugation in the human brain.

scholarly journals Imaging transcriptomics: Convergent cellular, transcriptomic, and molecular neuroimaging signatures in the healthy adult human brain

2021 ◽  
Author(s):  
Daniel Martins ◽  
Alessio Giacomel ◽  
Steven CR Williams ◽  
Federico E Turkheimer ◽  
Ottavia Dipasquale ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Brain ◽  
Regional Distribution ◽  
Partial Least Square ◽  
Least Square ◽  
Synaptic Proteins ◽  
Brain Atlas ◽  
Wide Range ◽  
Neuroimaging Data ◽  
The Brain

The expansion of neuroimaging techniques over the last decades has opened a wide range of new possibilities to characterize brain dysfunction in several neurological and psychiatric disorders. However, the lack of specificity of most of these techniques, such as magnetic resonance imaging (MRI)-derived measures, to the underlying molecular and cellular properties of the brain tissue poses limitations to the amount of information one can extract to inform precise models of brain disease. The integration of transcriptomic and neuroimaging data, known as 'imaging transcriptomics', has recently emerged as an indirect way forward to test and/or generate hypotheses about potential cellular and transcriptomic pathways that might underly specific changes in neuroimaging MRI biomarkers. However, the validity of this approach is yet to be examined in-depth. Here, we sought to bridge this gap by performing imaging transcriptomic analyses of the regional distribution of well-known molecular markers, assessed by positron emission tomography (PET), in the healthy human brain. We focused on tracers spanning different elements of the biology of the brain, including neuroreceptors, synaptic proteins, metabolism, and glia. Using transcriptome-wide data from the Allen Brain Atlas, we applied partial least square regression to rank genes according to their level of spatial alignment with the regional distribution of these neuroimaging markers in the brain. Then, we performed gene set enrichment analyses to explore the enrichment for specific biological and cell-type pathways among the genes most strongly associated with each neuroimaging marker. Overall, our findings show that imaging transcriptomics can recover plausible transcriptomic and cellular correlates of the regional distribution of benchmark molecular imaging markers, independently of the type of parcellation used to map gene expression and neuroimaging data. Our data support the plausibility and robustness of imaging transcriptomics as an indirect approach for bridging gene expression, cells and macroscopical neuroimaging and improving our understanding of the biological pathways underlying regional variability in neuroimaging features

scholarly journals TAMI-22. VARIATION AMONG INTACT TISSUE SAMPLES REVEALS THE CORE TRANSCRIPTIONAL IDENTITIES OF CELL TYPES IN THE GLIOMA MICROENVIRONMENT

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii218-ii218
Author(s):  
Patrick Schupp ◽  
Michael Oldham
Keyword(s):  
Gene Expression ◽  
Human Brain ◽  
Cell Types ◽  
Surface Proteins ◽  
Specific Gene ◽  
Specific Cell ◽  
Low Grade ◽  
Tissue Samples ◽  
Normal Human Brain ◽  
Normal Human

Abstract Adult low-grade gliomas generally progress to glioblastoma, a more aggressive CNS tumor with an extremely poor prognosis. Despite intensive efforts, numerous promising glioma therapies have failed to provide survival benefits. These failures reflect many factors, including intertumoral heterogeneity and immunosuppression by the tumor microenvironment (TME). We propose a novel approach to addresses these challenges through integrative deconvolution of bulk gene expression data generated from more than 5000 human gliomas and 7000 normal human brain samples. Inherent variation in the cellular composition and cellular activities of these samples allowed us to identify highly correlated modules of genes that represent specific cell types and cell states. By comparing gene coexpression modules in glioma vs. normal human brain, we have identified cell type-specific gene expression changes in the glioma TME that are highly reproducible. In contrast to single-cell methods, which sample only a fraction of the tumor tissue and fail to capture major nonmalignant cell-types, our results derive from billions of cells and thousands of individuals and are therefore highly robust. We find that a number of genes encoding cell-surface proteins are specifically up-regulated in immune and vascular cells of the glioma TME. Surprisingly, among those genes up-regulated in glioma vasculature are multiple members of the angiotensin pathway, suggesting non-canonical roles for these proteins in the glioma setting. We propose that these proteins may form a specific ‘zip code’ for glioma within the brain’s vasculature that can be targeted directly or by conjugation with existing drugs. More generally, our analytical approach has revealed reproducible gene expression changes in specific cell types of the glioma TME that provide more stable therapeutic targets than those that are expressed by genetically mutable malignant cells. We have also discovered novel, aberrantly coexpressed genes in microglia, oligodendrocytes, and astrocytes which we are testing in state-of-the-art human brain assembloid systems.

scholarly journals Human brain harbors single nucleotide somatic variations in functionally relevant genes possibly mediated by oxidative stress

F1000Research ◽  
2017 ◽  
Vol 5 ◽  
pp. 2520 ◽  
Author(s):  
Anchal Sharma ◽  
Asgar Hussain Ansari ◽  
Renu Kumari ◽  
Rajesh Pandey ◽  
Rakhshinda Rehman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Corpus Callosum ◽  
Human Brain ◽  
Frontal Cortex ◽  
Oxidative Stress Marker ◽  
Somatic Variation ◽  
Single Nucleotide ◽  
Normal Human Brain ◽  
Normal Human ◽  
The Brain

Somatic variation in DNA can cause cells to deviate from the preordained genomic path in both disease and healthy conditions. Here, using exome sequencing of paired tissue samples, we show that the normal human brain harbors somatic single base variations measuring up to 0.48% of the total variations. Interestingly, about 64% of these somatic variations in the brain are expected to lead to non-synonymous changes, and as much as 87% of these represent G:C>T:A transversion events. Further, the transversion events in the brain were mostly found in the frontal cortex, whereas the corpus callosum from the same individuals harbors the reference genotype. We found a significantly higher amount of 8-OHdG (oxidative stress marker) in the frontal cortex compared to the corpus callosum of the same subjects (p<0.01), correlating with the higher G:C>T:A transversions in the cortex. We found significant enrichment for axon guidance and related pathways for genes harbouring somatic variations. This could represent either a directed selection of genetic variations in these pathways or increased susceptibility of some loci towards oxidative stress. This study highlights that oxidative stress possibly influence single nucleotide somatic variations in normal human brain.

scholarly journals Human brain harbors single nucleotide somatic variations in functionally relevant genes possibly mediated by oxidative stress

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2520 ◽  
Author(s):  
Anchal Sharma ◽  
Asgar Hussain Ansari ◽  
Renu Kumari ◽  
Rajesh Pandey ◽  
Rakhshinda Rehman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Corpus Callosum ◽  
Human Brain ◽  
Frontal Cortex ◽  
Oxidative Stress Marker ◽  
Somatic Variation ◽  
Single Nucleotide ◽  
Normal Human Brain ◽  
Normal Human ◽  
The Brain

Somatic variation in DNA can cause cells to deviate from the preordained genomic path in both disease and healthy conditions. Here, using exome sequencing of paired tissue samples, we show that the normal human brain harbors somatic single base variations measuring up to 0.48% of the total variations. Interestingly, about 64% of these somatic variations in the brain are expected to lead to non-synonymous changes, and as much as 87% of these represent G:C>T:A transversion events. Further, the transversion events in the brain were mostly found in the frontal cortex, whereas the corpus callosum from the same individuals harbors the reference genotype. We found a significantly higher amount of 8-OHdG (oxidative stress marker) in the frontal cortex compared to the corpus callosum of the same subjects (p<0.01), correlating with the higher G:C>T:A transversions in the cortex. We found significant enrichment for axon guidance and related pathways for genes harbouring somatic variations. This could represent either a directed selection of genetic variations in these pathways or increased susceptibility of some loci towards oxidative stress. This study highlights that oxidative stress possibly influence single nucleotide somatic variations in normal human brain.

Mixed-Model Reanalysis of Primate Data Suggests Tissue and Species Biases in Oligonucleotide-Based Gene Expression Profiles

Genetics ◽  
2003 ◽  
Vol 165 (2) ◽  
pp. 747-757 ◽  
Author(s):  
Wen-Ping Hsieh ◽  
Tzu-Ming Chu ◽  
Russell D Wolfinger ◽  
Greg Gibson
Keyword(s):  
Gene Expression ◽  
Human Brain ◽  
Mixed Model ◽  
Expression Profiles ◽  
Evolutionary Genetics ◽  
Primate Species ◽  
Adaptive Divergence ◽  
Small Subset ◽  
Data Set ◽  
The Brain

Abstract An emerging issue in evolutionary genetics is whether it is possible to use gene expression profiling to identify genes that are associated with morphological, physiological, or behavioral divergence between species and whether these genes have undergone positive selection. Some of these questions were addressed in a recent study (Enard  et al. 2002) of the difference in gene expression among human, chimp, and orangutan, which suggested an accelerated rate of divergence in gene expression in the human brain relative to liver. Reanalysis of the Affymetrix data set using analysis of variance methods to quantify the contributions of individuals and species to variation in expression of 12,600 genes indicates that as much as one-quarter of the genome shows divergent expression between primate species at the 5% level. The magnitude of fold change ranges from 1.2-fold up to 8-fold. Similar conclusions apply to reanalysis of Enard  et al.'s (2002) parallel murine data set. However, biases inherent to short oligonucleotide microarray technology may account for some of the tissue and species effects. At high significance levels, more differences were observed in the liver than in the brain in each of the pairwise species comparisons, so it is not clear that expression divergence is accelerated in the human brain. Further, there is an apparent bias toward upregulation of gene expression in the brain in both primates and mice, whereas genes are equally likely to be up- or downregulated in the liver when these species diverge. A small subset of genes that are candidates for adaptive divergence may be identified on the basis of a high ratio of interspecific to intraspecific divergence.

The human survivin promoter: a novel transcriptional targeting strategy for treatment of glioma

2006 ◽  
Vol 104 (4) ◽  
pp. 583-592 ◽  
Author(s):  
Winan J. Van Houdt ◽  
Yosef S. Haviv ◽  
Baogen Lu ◽  
Minghui Wang ◽  
Angel A. Rivera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Tumors ◽  
Human Brain ◽  
Cell Lines ◽  
Reporter Gene ◽  
Transcriptional Targeting ◽  
Survivin Promoter ◽  
Normal Human Brain ◽  
Apoptosis Protein ◽  
Normal Human

Object Malignant brain tumors have been proved to be resistant to standard treatments and therefore require new therapeutic strategies. Survivin, a recently described member of the inhibitor of apoptosis protein family, is overexpressed in several human brain tumors, primarily gliomas, but is downregulated in normal tissues. The authors hypothesized that the expression of tumor-specific survivin could be exploited for treatment of gliomas by targeting the tumors with gene therapy vectors. Methods Following confirmation of survivin expression in glioma cell lines, an adenoviral vector containing the survivin promoter and the reporter gene luciferase was tested in established and primary glioma cells, normal astrocytic cells, and normal human brain tissues. High levels of reporter gene expression were observed in established tumor and primary tumor cell lines and low levels of expression in astrocytes and normal human brain tissue. To test oncolytic potency, the authors constructed survivin promoter–based conditionally replicative adenoviruses (CRAds), composed of survivin promoter–regulated E1 gene expression and an RGD-4C capsid modification. These CRAds could efficiently replicate within and kill a variety of established glioma tumor cells, but were inactive in a normal human liver organ culture. Finally, survivin promoter–based CRAds significantly inhibited the growth of glioma xenografts in vivo. Conclusions Together these data indicate that the survivin promoter is a promising tumor-specific promoter for transcriptional targeting of adenovirus-based vectors and CRAds for malignant gliomas. The strategy of using survivin–CRAds may thus translate into an experimental therapeutic approach that can be used in human clinical trials.

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