scholarly journals Spatial and Temporal Expression of High-Mobility-Group Nucleosome-Binding (HMGN) Genes in Brain Areas Associated with Cognition in Individuals with Down Syndrome

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 2000
Author(s):  
Alejandra Rodríguez-Ortiz ◽  
Julio César Montoya-Villegas ◽  
Felipe García-Vallejo ◽  
Yecid Mina-Paz
Keyword(s):  
Down Syndrome ◽  
Differential Expression ◽  
Protein Interactions ◽  
Strong Evidence ◽  
High Mobility ◽  
Brain Structures ◽  
Microarray Experiment ◽  
High Mobility Group ◽  
Postmortem Brain ◽  
Brain Areas

DNA methylation and histone posttranslational modifications are epigenetics processes that contribute to neurophenotype of Down Syndrome (DS). Previous reports present strong evidence that nonhistone high-mobility-group N proteins (HMGN) are epigenetic regulators. They play important functions in various process to maintain homeostasis in the brain. We aimed to analyze the differential expression of five human HMGN genes in some brain structures and age ranks from DS postmortem brain samples. Methodology: We performed a computational analysis of the expression of human HMGN from the data of a DNA microarray experiment (GEO database ID GSE59630). Using the transformed log2 data, we analyzed the differential expression of five HMGN genes in several brain areas associated with cognition in patients with DS. Moreover, using information from different genome databases, we explored the co-expression and protein interactions of HMNGs with the histones of nucleosome core particle and linker H1 histone. Results: We registered that HMGN1 and HMGN5 were significantly overexpressed in the hippocampus and areas of prefrontal cortex including DFC, OFC, and VFC of DS patients. Age-rank comparisons between euploid control and DS individuals showed that HMGN2 and HMGN4 were overexpressed in the DS brain at 16 to 22 gestation weeks. From the BioGRID database, we registered high interaction scores of HMGN2 and HMGN4 with Hist1H1A and Hist1H3A. Conclusions: Overall, our results give strong evidence to propose that DS would be an epigenetics-based aneuploidy. Remodeling brain chromatin by HMGN1 and HMGN5 would be an essential pathway in the modification of brain homeostasis in DS.

scholarly journals Spatial and Temporal Expression of High Mobility Group Nucleosome-Binding (HMGN) Genes in Brain Areas Associated With Cognition in Individuals With Down Syndrome

2021 ◽  
Author(s):  
Alejandra Rodriguez-Ortiz ◽  
Julio Cesar Montoya-Villegas ◽  
Felipe García-Vallejo ◽  
Yecid Mina-Paz
Keyword(s):  
Down Syndrome ◽  
Differential Expression ◽  
Protein Interactions ◽  
Strong Evidence ◽  
High Mobility ◽  
Microarray Experiment ◽  
High Mobility Group ◽  
Brain Areas ◽  
The Brain ◽  
Brain Homeostasis

Abstract Background: DNA methylation and histone posttranslational modifications are epigenetics processes which contribute to neurophenotype of Down Syndrome (DS). Previous reports present strong evidence that nonhistone High mobility group N proteins (HMGN) are epigenetic regulators. They play important functions in several process to maintain the brain homeostasis. We aimed to analyze the differential expression of five human HMGN genes along some brain structures and age ranks from DS postmorten brain samples.Methodology: We performed a computational analysis of human HMGN expression from a DNA microarray experiment data (GEO database ID GSE59630). Using the transformed log2 data, we analyzed the differential expression of five HMGN genes in several brain areas associated with cognition in patients with DS. Moreover, using information from several genome databases, we explore the coexpression and protein interactions with the histones of nucleosome core particle and linker H1 histone. Results: We registered that HMGN1 and HMGN5 were significantly overexpressed in hippocampus and areas of prefrontal cortex including DFC, OFC and VFC of DS patients. Age ranks comparisons between euploid control and DS individuals showed that HMGN2 and HMGN4 were overexpressed in the DS brain of 16 to 22 weeks of gestation. From BioGRID database we registered high interaction scores of HMGN2 and HMGN4 with Hist1H1A and Hist1H2BA, Hist2AG, and Hist1H3A respectively. Conclusions: Overall our results give strong evidence to propose that DS would be an epigenetics-based aneuploidy. Remodeling the brain chromatin by HMGN1 and HMGN5 would essential pathway in the modification of brain homeostasis in DS.

scholarly journals A New Approach to The Pathogenesis of Down Syndrome: An Integrated Quantitative Neuro-Transcriptome Analysis of Several Brain Areas in Human Trisomy 21.

2021 ◽  
Author(s):  
Alejandra Rodriguez-Ortiz ◽  
Julio Cesar Montoya Villegas ◽  
Adalberto Sánchez-Gomez ◽  
José María Satizábal Soto ◽  
Yecid Mina-Paz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Down Syndrome ◽  
Cerebellar Cortex ◽  
Gene Expression Pattern ◽  
Microarray Experiment ◽  
Chromosome 21 ◽  
Postmortem Brain ◽  
Brain Areas ◽  
New Approach ◽  
Ratio Correlation

Abstract Background: Although Down syndrome (DS) is a trisomy of chromosome 21 being the most frequent human chromosomal disorder mainly associated with variable levels of intellectual disability and other dysfunctions, the only dose disbalance effect would not enough to explain its genetic and functional complexity neurophenotype. In this context, we aimed to analyze and compare the disruption of transcriptome of several brain areas from individuals with DS and euploid controls as a new approach to consider a global systemic differential disruption of gene expression beyond of chromosome 21. Methodology: To perform the analysis carried out in the present study, we used data from a DNA microarray experiment with ID GSE59630 previously deposited in the GEO DataSet of NCBI database. The array contained log2 values of 17,537 human genes expressed in several aeras of human brain. The data was collected from 58 postmortem brain samples of individuals with DS and 58 samples from euploid controls. We calculated the differential gene expression (Z-ratio) of all genes from the microarray according to the several brain areas, gene distribution per chromosome and age ranks. Results: We found several differences in gene expression along the DS brain transcriptome, not only in the genes located at chromosome 21 but in other chromosomes. Moreover, we registered the lowest Z-ratio correlation between the age ranks of 16-22 weeks of gestation and 39-42 years (R2=0.06) and the highest Z-ratio correlation between the age ranks of 30-39 years and 40-42 years (R2=0.89). The analysis per brain areas showed that the hippocampus and the cerebellar cortex had the most different gene expression pattern when compared to the brain as a whole. Conclusions: Our results revealed the complexity of gene expression networks in the transcriptome profiles of hippocampus, dorsolateral prefrontal cortex (DFC) and cerebellar cortex (CBC). Moreover, our approach opens a new vision of the genomic complexity of DS as a pathology of multiple and complex variables that are playing altogether to modeling their pathogenesis.

scholarly journals Intra- and intermolecular cooperative binding of high-mobility-group protein I(Y) to the beta-interferon promoter.

1997 ◽  
Vol 17 (7) ◽  
pp. 3649-3662 ◽  
Author(s):  
J Yie ◽  
S Liang ◽  
M Merika ◽  
D Thanos
Keyword(s):  
Protein Interactions ◽  
Binding Sites ◽  
Specific Binding ◽  
High Mobility ◽  
High Mobility Group ◽  
High Mobility Group Protein ◽  
Beta Interferon ◽  
Eukaryotic Genes ◽  
Group Protein

The mammalian high-mobility-group protein I(Y) [HMG I(Y)], while not a typical transcriptional activator, is required for the expression of many eukaryotic genes. HMG I(Y) appears to recruit and stabilize complexes of transcriptional activators through protein-DNA and protein-protein interactions. The protein binds to the minor groove of DNA via three short basic repeats, preferring tracts of adenines and thymines arranged on the same face of the DNA helix. However, the mode by which these three basic repeats function together to recognize HMG I(Y) binding sites has remained unclear. Here, using deletion mutants of HMG I(Y), DNase I footprinting, methylation interference, and in vivo transcriptional assays, we have characterized the binding of HMG I(Y) to the model beta-interferon enhancer. We show that two molecules of HMG I(Y) bind to the enhancer in a highly cooperative fashion, each molecule using a distinct pair of basic repeats to recognize the tandem AT-rich regions of the binding sites. We have also characterized the function of each basic repeat, showing that only the central repeat accounts for specific DNA binding and that the presence of a second repeat bound to an adjacent AT-rich region results in intramolecular cooperativity in binding. Surprisingly, the carboxyl-terminal acidic tail of HMG I(Y) is also important for specific binding in the context of the full-length protein. Our results present a detailed examination of HMG I(Y) binding in an important biological context, which can be extended not only to HMG I(Y) binding in other systems but also to the binding mode of many other proteins containing homologous basic repeats, which have been conserved from bacteria to humans.

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