Abstract
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.
Highlights
The continuous chromatin modification and the binding of tissue-specific transcription factors to their specific targets in chromatin maintain the epigenetic landscape necessary to regulate the cell-type-specific transcription [1,2]
According to the information consigned in the GEO database, the selected microarray experiment included gene expression data of more than 17000 probes from 58 post-mortem brain samples of Down Syndrome (DS) individuals (25 from females and 33 from males) and 58 euploid samples as euploid controls (25 from females and 33 from males) that were classified by sex, age, and by some brain areas including the hippocampus (HIP), cerebellar cortex (CBC), dorsolateral prefrontal cortex (DFC), orbital prefrontal cortex (OFC), ventrolateral prefrontal cortex (VFC), medial prefrontal cortex (MFC), primary somatosensory cortex (S1C), inferior parietal cortex (IPC), primary visual cortex (V1C), superior temporal cortex (STC), and inferior temporal cortex (ITC)
The genes encoding for HMGN1 and HMGN5 were overexpressed in HIP, CBC, and V1C and in some areas of prefrontal cortex including DFC, OFC, and VFC; in contrast, HMGN2 and HMGN3 genes had not significant overexpression
Summary
The continuous chromatin modification and the binding of tissue-specific transcription factors to their specific targets in chromatin maintain the epigenetic landscape necessary to regulate the cell-type-specific transcription [1,2]. Additional chromatin modifiers, including the H1 linker histones [2] and the high mobility group N (HMGN) proteins, can remodel the chromatin organization and transcription regulation, playing important functions in several process to maintain the general homeostasis [3]. Down Syndrome (DS) is a chromosomal aneuploidy caused by a total or partial triplication of chromosome 21, but in rare cases it can be associated with a process of chromosome translocation [4]. In people with DS, the gene dose imbalance by triplication of genes on HSA21 is mostly associated with a wide spectrum of pathologies that include neurological and systemic diseases [4]. The incidence of trisomy 21 is influenced by maternal age and differs throughout the population [5,6]. The average life span for DS population is 55 years [7]. DS is the result of the increased copy number of a single 21 chromosome, the regulation of gene expression is affected at a genome-wide level [8–11]
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