scholarly journals Accelerated evolution of oligodendrocytes in the human brain

2019 ◽  
Vol 116 (48) ◽  
pp. 24334-24342 ◽  
Author(s):  
Stefano Berto ◽  
Isabel Mendizabal ◽  
Noriyoshi Usui ◽  
Kazuya Toriumi ◽  
Paramita Chatterjee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Brain ◽  
Molecular Mechanisms ◽  
Rhesus Macaques ◽  
Brain Evolution ◽  
Neuropsychiatric Disorders ◽  
Cell Types ◽  
Accelerated Evolution ◽  
Expression Evolution ◽  
Human Specific

Recent discussions of human brain evolution have largely focused on increased neuron numbers and changes in their connectivity and expression. However, it is increasingly appreciated that oligodendrocytes play important roles in cognitive function and disease. Whether both cell types follow similar or distinctive evolutionary trajectories is not known. We examined the transcriptomes of neurons and oligodendrocytes in the frontal cortex of humans, chimpanzees, and rhesus macaques. We identified human-specific trajectories of gene expression in neurons and oligodendrocytes and show that both cell types exhibit human-specific up-regulation. Moreover, oligodendrocytes have undergone more pronounced accelerated gene expression evolution in the human lineage compared to neurons. We highlighted human-specific coexpression networks with specific functions. Our data suggest that oligodendrocyte human-specific networks are enriched for alternative splicing and transcriptional regulation. Oligodendrocyte networks are also enriched for variants associated with schizophrenia and other neuropsychiatric disorders. Such enrichments were not found in neuronal networks. These results offer a glimpse into the molecular mechanisms of oligodendrocytes during evolution and how such mechanisms are associated with neuropsychiatric disorders.

scholarly journals Accelerated evolution of oligodendrocytes in human brain

2019 ◽  
Author(s):  
Stefano Berto ◽  
Isabel Mendizabal ◽  
Noriyoshi Usui ◽  
Kazuya Toriumi ◽  
Paramita Chatterjee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Brain ◽  
Rhesus Macaques ◽  
Brain Evolution ◽  
Cell Types ◽  
Specific Expression ◽  
Accelerated Evolution ◽  
Human Brain Evolution ◽  
Cell Type Specific Expression ◽  
Human Specific

SUMMARYRecent discussions of human brain evolution have largely focused on increased neuron numbers and changes in their connectivity and expression. However, it is increasingly appreciated that oligodendrocytes play important roles in cognitive function and disease. Whether both cell-types follow similar or distinctive evolutionary trajectories is not known. We examined the transcriptomes of neurons and oligodendrocytes in the frontal cortex of humans, chimpanzees, and rhesus macaques. We identified human-specific trajectories of gene expression in neurons and oligodendrocytes and show that both cell-types exhibit human-specific upregulation. Moreover, oligodendrocytes have undergone accelerated gene expression evolution in the human lineage compared to neurons. The signature of acceleration is enriched for cell type-specific expression alterations in schizophrenia. These results underscore the importance of oligodendrocytes in human brain evolution.

scholarly journals Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution

2018 ◽  
Author(s):  
Alex A Pollen ◽  
Aparna Bhaduri ◽  
Madeline G Andrews ◽  
Tomasz J Nowakowski ◽  
Olivia S Meyerson ◽  
...  
Keyword(s):  
Human Brain ◽  
Regulatory Networks ◽  
Radial Glia ◽  
Brain Size ◽  
Metabolic Stress ◽  
Brain Evolution ◽  
Cell Types ◽  
Segmental Duplications ◽  
Systematic Analysis ◽  
Human Specific

Direct comparisons of human and non-human primate brain tissue have the potential to reveal molecular pathways underlying remarkable specializations of the human brain. However, chimpanzee tissue is largely inaccessible during neocortical neurogenesis when differences in brain size first appear. To identify human-specific features of cortical development, we leveraged recent innovations that permit generating pluripotent stem cell-derived cerebral organoids from chimpanzee. First, we systematically evaluated the fidelity of organoid models to primary human and macaque cortex, finding organoid models preserve gene regulatory networks related to cell types and developmental processes but exhibit increased metabolic stress. Second, we identified 261 genes differentially expressed in human compared to chimpanzee organoids and macaque cortex. Many of these genes overlap with human-specific segmental duplications and a subset suggest increased PI3K/AKT/mTOR activation in human outer radial glia. Together, our findings establish a platform for systematic analysis of molecular changes contributing to human brain development and evolution.

MO262THE SINGLE-CELL TRANSCRIPTOMICS OF HUMAN IGA NEPHROPATHY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Yong Zhong ◽  
Xiangcheng Xiao
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Signaling Pathways ◽  
Iga Nephropathy ◽  
Molecular Mechanisms ◽  
Mesangial Cells ◽  
Therapeutic Targets ◽  
Cell Types ◽  
Receptor Crosstalk ◽  
Overt Proteinuria

Abstract Background and Aims The exact molecular mechanisms underlying IgA nephropathy (IgAN) remains incompletely defined. Therefore, it is necessary to further elucidate the mechanism of IgA nephropathy and find novel therapeutic targets. Method Single-cell RNA sequencing (scRNA-seq) was applied to kidney biopsies from 4 IgAN and 1 control subjects to define the transcriptomic landscape at the single-cell resolution. Unsupervised clustering analysis of kidney specimens was used to identify distinct cell clusters. Differentially expressed genes and potential signaling pathways involved in IgAN were also identified. Results Our analysis identified 14 cell subsets in kidney biopsies from IgAN patients, and analyzed changing gene expression in distinct renal cell types. We found increased mesangial expression of several novel genes including MALAT1, GADD45B, SOX4 and EDIL3, which were related to proliferation and matrix accumulation and have not been reported in IgAN previously. The overexpressed genes in tubule cells of IgAN were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling and NOD-like receptor signaling. Moreover, the receptor-ligand crosstalk analysis revealed potential interactions between mesangial cells and other cells in IgAN. Specifically, IgAN with overt proteinuria displayed elevated genes participating in several signaling pathways which may be involved in pathogenesis of progression of IgAN. Conclusion The comprehensive analysis of kidney biopsy specimen demonstrated different gene expression profile, potential pathologic ligand-receptor crosstalk, signaling pathways in human IgAN. These results offer new insight into pathogenesis and identify new therapeutic targets for patients with IgA nephropathy.

scholarly journals Genetic control of age-related gene expression and complex traits in the human brain

2017 ◽  
Author(s):  
Trevor Martin ◽  
Hunter B. Fraser
Keyword(s):  
Gene Expression ◽  
Human Brain ◽  
Neurodegenerative Diseases ◽  
Genetic Variants ◽  
Complex Traits ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Expression Patterns ◽  
Related Gene ◽  
Age Related

AbstractAge is the primary risk factor for many of the most common human diseases—particularly neurodegenerative diseases—yet we currently have a very limited understanding of how each individual’s genome affects the aging process. Here we introduce a method to map genetic variants associated with age-related gene expression patterns, which we call temporal expression quantitative trait loci (teQTL). We found that these loci are markedly enriched in the human brain and are associated with neurodegenerative diseases such as Alzheimer’s disease and Creutzfeldt-Jakob disease. Examining potential molecular mechanisms, we found that age-related changes in DNA methylation can explain some cis-acting teQTLs, and that trans-acting teQTLs can be mediated by microRNAs. Our results suggest that genetic variants modifying age-related patterns of gene expression, acting through both cis- and trans-acting molecular mechanisms, could play a role in the pathogenesis of diverse neurological diseases.

scholarly journals Proteolytic Activation of Human-specific Olduvai Domains by the Furin Protease

2021 ◽  
Author(s):  
Ashley Pacheco ◽  
Aaron Issaian ◽  
Jonathan Davis ◽  
Nathan Anderson ◽  
Travis Nemkov ◽  
...  
Keyword(s):  
Human Brain ◽  
Copy Number ◽  
Brain Size ◽  
Active Agent ◽  
Brain Evolution ◽  
Variable Number ◽  
Coding Region ◽  
Proteolytic Activation ◽  
Highly Correlated ◽  
Human Specific

Olduvai protein domains (formerly DUF1220) show the greatest human-specific increase in copy number of any coding region in the genome and are highly correlated with human brain evolution and cognitive disease. The majority of human copies are found within four NBPF genes organized in a variable number of a tandemly arranged three-domain blocks called Olduvai triplets. Here we show that these human-specific Olduvai domains are posttranslationally processed by the furin protease, with a cleavage site occurring once at each triplet. These findings suggest that all expanded human-specific NBPF genes encode proproteins consisting of many independent Olduvai triplet proteins which are activated by furin processing. The exceptional correlation of Olduvai copy number and brain size taken together with our new furin data, indicates the ultimate target of selection was a rapid increase in dosage of autonomously functioning Olduvai triplet proteins, and that these proteins are the primary active agent underlying Olduvai's role in human brain expansion.

scholarly journals Modeling Reveals Human–Rodent Differences in H-Current Kinetics Influencing Resonance in Cortical Layer 5 Neurons

2020 ◽  
Author(s):  
Scott Rich ◽  
Homeira Moradi Chameh ◽  
Vladislav Sekulic ◽  
Taufik A Valiante ◽  
Frances K Skinner
Keyword(s):  
Human Brain ◽  
Cell Model ◽  
Model Development ◽  
Compartment Model ◽  
Cell Types ◽  
Cortical Layer ◽  
Neuron Models ◽  
Cellular Models ◽  
Human Neurons ◽  
Human Specific

Abstract While our understanding of human neurons is often inferred from rodent data, inter-species differences between neurons can be captured by building cellular models specifically from human data. This includes understanding differences at the level of ion channels and their implications for human brain function. Thus, we here present a full spiking, biophysically detailed multi-compartment model of a human layer 5 (L5) cortical pyramidal cell. Model development was primarily based on morphological and electrophysiological data from the same human L5 neuron, avoiding confounds of experimental variability. Focus was placed on describing the behavior of the hyperpolarization-activated cation (h-) channel, given increasing interest in this channel due to its role in pacemaking and differentiating cell types. We ensured that the model exhibited post-inhibitory rebound spiking considering its relationship with the h-current, along with other general spiking characteristics. The model was validated against data not used in its development, which highlighted distinctly slower kinetics of the human h-current relative to the rodent setting. We linked the lack of subthreshold resonance observed in human L5 neurons to these human-specific h-current kinetics. This work shows that it is possible and necessary to build human-specific biophysical neuron models in order to understand human brain dynamics.

Inducible cAMP early repressor suppresses gastrin-mediated activation of cyclin D1 and c-fos gene expression

2007 ◽  
Vol 292 (4) ◽  
pp. G1062-G1069 ◽  
Author(s):  
Tonje S. Steigedal ◽  
Torunn Bruland ◽  
Kristine Misund ◽  
Liv Thommesen ◽  
Astrid Lægreid
Keyword(s):  
Gene Expression ◽  
Cyclin D1 ◽  
Cell Line ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Neuroendocrine Cells ◽  
Cell Cycle Gene ◽  
Pancreatic Cell ◽  
Inducible Camp Early Repressor

The gastric hormone gastrin and its precursors promote proliferation in several gastrointestinal cell types. Here we show that gastrin induces transcription of cell cycle gene cyclin D1 and protooncogene c- fos in the neuroendocrine pancreatic cell line AR42J and that this gastrin response is inhibited by endogenous inducible cAMP early repressor (ICER). The transcriptional repressor ICER is known to downregulate both its own expression and the expression of other genes containing cAMP-responsive elements (CREs). Using siRNA, we also show that CRE promoter elements are the targets of endogenous ICER in AR42J cells as well as in the neuroendocrine cell line RIN5F. Our results suggest that ICER plays an important role in molecular mechanisms governing gastrin-mediated growth by modulating gastrin's transcriptional activation of growth-related genes. Our finding that ICER modulates pituitary adenylate cyclase-activating polypeptide-activated gene expression also indicates a regulatory effect of ICER in the responses of neuroendocrine cells to peptides other than gastrin.

scholarly journals A deconvolution method and its application in analyzing the cellular fractions in acute myeloid leukemia samples

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Huamei Li ◽  
Amit Sharma ◽  
Wenglong Ming ◽  
Xiao Sun ◽  
Hongde Liu
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Bulk Sample ◽  
Marker Genes ◽  
Benchmark Datasets ◽  
Multiple Conditions ◽  
Acute Myeloid

Abstract Background The identification of cell type-specific genes (markers) is an essential step for the deconvolution of the cellular fractions, primarily, from the gene expression data of a bulk sample. However, the genes with significant changes identified by pair-wise comparisons cannot indeed represent the specificity of gene expression across multiple conditions. In addition, the knowledge about the identification of gene expression markers across multiple conditions is still paucity. Results Herein, we developed a hybrid tool, LinDeconSeq, which consists of 1) identifying marker genes using specificity scoring and mutual linearity strategies across any number of cell types, and 2) predicting cellular fractions of bulk samples using weighted robust linear regression with the marker genes identified in the first stage. On multiple publicly available datasets, the marker genes identified by LinDeconSeq demonstrated better accuracy and reproducibility compared to MGFM and RNentropy. Among deconvolution methods, LinDeconSeq showed low average deviations (≤0.0958) and high average Pearson correlations (≥0.8792) between the predicted and actual fractions on the benchmark datasets. Importantly, the cellular fractions predicted by LinDeconSeq appear to be relevant in the diagnosis of acute myeloid leukemia (AML). The distinct cellular fractions in granulocyte-monocyte progenitor (GMP), lymphoid-primed multipotent progenitor (LMPP) and monocytes (MONO) were found to be closely associated with AML compared to the healthy samples. Moreover, the heterogeneity of cellular fractions in AML patients divided these patients into two subgroups, differing in both prognosis and mutation patterns. GMP fraction was the most pronounced between these two subgroups, particularly, in SubgroupA, which was strongly associated with the better AML prognosis and the younger population. Totally, the identification of marker genes by LinDeconSeq represents the improved feature for deconvolution. The data processing strategy with regard to the cellular fractions used in this study also showed potential for the diagnosis and prognosis of diseases. Conclusions Taken together, we developed a freely-available and open-source tool LinDeconSeq (https://github.com/lihuamei/LinDeconSeq), which includes marker identification and deconvolution procedures. LinDeconSeq is comparable to other current methods in terms of accuracy when applied to benchmark datasets and has broad application in clinical outcome and disease-specific molecular mechanisms.

Identification of dysregulated genes in lymphocytes from children with Down syndrome

Genome ◽  
2008 ◽  
Vol 51 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Cesar A. Sommer ◽  
Erika C. Pavarino-Bertelli ◽  
Eny M. Goloni-Bertollo ◽  
Flavio Henrique-Silva
Keyword(s):  
Gene Expression ◽  
Down Syndrome ◽  
Trisomy 21 ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cell Receptor ◽  
Chromosome 21 ◽  
Global Changes ◽  
Real Time Quantitative Pcr ◽  
Functional Classes

The molecular mechanisms by which trisomy of human chromosome 21 disrupts normal development are not well understood. Global transcriptome studies attempting to analyze the consequences of trisomy in Down syndrome (DS) tissues have reported conflicting results, which have led to the suggestion that the analysis of specific tissues or cell types may be more productive. In the present study, we set out to analyze global changes of gene expression in lymphocytes from children with trisomy 21 by means of the serial analysis of gene expression (SAGE) methodology. Two SAGE libraries were constructed using pooled RNA of normal and Down syndrome children. Comparison between DS and normal profiles revealed that most of the transcripts were expressed at similar levels and functional classes of abundant genes were equally represented. Among the 242 significantly differentially expressed SAGE tags, several transcripts downregulated in DS code for proteins involved in T-cell and B-cell receptor signaling (e.g., PI3Kδ, RGS2, LY6E, FOS, TAGAP, CD46). The SAGE data and interindividual variability were validated by real-time quantitative PCR. Our results indicate that trisomy 21 induces a modest dysregulation of disomic genes that may be related to the immunological perturbations seen in DS.

scholarly journals Telomere associated gene expression as well as TERT protein level and telomerase activity are altered in the ovarian follicles of aged mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Esra Gozde Kosebent ◽  
Saffet Ozturk
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Structural Integrity ◽  
Cell Types ◽  
Telomerase Activity ◽  
Ovarian Follicles ◽  
Biological Aging ◽  
Aged Mice ◽  
Protein Levels ◽  
Ovarian Aging

AbstractTelomeres cap the ends of eukaryotic chromosomes to maintain genomic stability and integrity during an organism’s lifespan. The length of telomeres inevitably shortens due to DNA replication, genotoxic agents, and biological aging. A limited number of cell types, e.g., stem cells, germline cells, and early embryos can elongate shortened telomeres via the enzymatic action of telomerase, which is composed of telomerase reverse transcriptase (TERT) and telomerase RNA component (Terc). Additionally, telomere-associated proteins including telomeric repeat binding factor 1 (TRF1) and 2 (TRF2), as well as protection of telomeres 1a (POT1a), bind to telomeres to maintain their structural integrity and length. During ovarian aging in mammals, telomeres progressively shorten, accompanied by fertility loss; however, the molecular mechanism underlying this attrition during follicle development remains unclear. In this study, the primary, secondary, preantral, and antral follicles were obtained either from 6-week-old adult (n = 19) or 52-week-old aged (n = 12) mice. We revealed that the Tert, Terc, Trf1, Trf2, and Pot1a gene expression (P < 0.001) and TERT protein (P < 0.01) levels significantly decreased in certain ovarian follicles of the aged group when compared to those of the adult group. Also, telomerase activity exhibited remarkable changes in the follicles of both groups. Consequently, altered telomere-associated gene expression and reduced TERT protein levels in the follicles of aged mice may be a determinant of telomere shortening during ovarian aging, and infertility appearing in the later decades of reproductive lifespan. Further investigations are required to determine the molecular mechanisms underlying these alterations in the follicles during ovarian aging.

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