scholarly journals Robust inference of positive selection on regulatory sequences in the human brain

2020 ◽  
Vol 6 (48) ◽  
pp. eabc9863
Author(s):  
Jialin Liu ◽  
Marc Robinson-Rechavi
Keyword(s):  
Human Brain ◽  
Positive Selection ◽  
Binding Sites ◽  
A Priori ◽  
Cell Types ◽  
Ctcf Binding ◽  
Regulatory Sequences ◽  
Accelerated Evolution ◽  
Mouse Tissues ◽  
Affinity Change

A longstanding hypothesis is that divergence between humans and chimpanzees might have been driven more by regulatory level adaptations than by protein sequence adaptations. This has especially been suggested for regulatory adaptations in the evolution of the human brain. We present a new method to detect positive selection on transcription factor binding sites on the basis of measuring predicted affinity change with a machine learning model of binding. Unlike other methods, this approach requires neither defining a priori neutral sites nor detecting accelerated evolution, thus removing major sources of bias. We scanned the signals of positive selection for CTCF binding sites in 29 human and 11 mouse tissues or cell types. We found that human brain–related cell types have the highest proportion of positive selection. This result is consistent with the view that adaptive evolution to gene regulation has played an important role in evolution of the human brain.

scholarly journals Robust inference of positive selection on regulatory sequences in human brain

2020 ◽  
Author(s):  
Jialin Liu ◽  
Marc Robinson-Rechavi
Keyword(s):  
Human Brain ◽  
Positive Selection ◽  
Binding Sites ◽  
A Priori ◽  
Cell Types ◽  
Ctcf Binding ◽  
Sign Test ◽  
Regulatory Sequences ◽  
Accelerated Evolution ◽  
Mouse Tissues

AbstractA long standing hypothesis is that divergence between humans and chimpanzees might have been driven more by regulatory level adaptions than by protein sequence adaptations. This has especially been suggested for regulatory adaptions in the evolution of the human brain. There is some support for this hypothesis, but it has been limited by the lack of a reliable and powerful way to detect positive selection on regulatory sequences. We present a new method to detect positive selection on transcription factor binding sites, based on Orr’s sign test applied to a machine learning model of binding. Unlike other methods, this requires neither defining a priori neutral sites, nor detecting accelerated evolution, thus removing major sources of bias. The method is validated in flies, mice, and primates, by a McDonald-Kreitman-like measure of polymorphism vs. divergence, by experimental binding site gains and losses, and by changes in expression levels. We scanned the signals of positive selection for CTCF binding sites in 29 human and 11 mouse tissues or cell types. We found that human brain related cell types have the highest proportion of positive selection. This is consistent with the importance of adaptive evolution on gene regulation in the evolution of the human brain.

scholarly journals Functional Interactions between NURF and Ctcf Regulate Gene Expression

2014 ◽  
Vol 35 (1) ◽  
pp. 224-237 ◽  
Author(s):  
Zhijun Qiu ◽  
Carolyn Song ◽  
Navid Malakouti ◽  
Daniel Murray ◽  
Aymen Hariz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Sites ◽  
Nucleosome Occupancy ◽  
Cell Types ◽  
Ctcf Binding ◽  
Nucleosome Remodeling ◽  
Functional Interactions ◽  
Chromatin Remodeling Complexes ◽  
Reporter Assays

Gene expression frequently requires chromatin-remodeling complexes, and it is assumed that these complexes have common gene targets across cell types. Contrary to this belief, we show by genome-wide expression profiling that Bptf, an essential and unique subunit of the nucleosome-remodeling factor (NURF), predominantly regulates the expression of a unique set of genes between diverse cell types. Coincident with its functions in gene expression, we observed that Bptf is also important for regulating nucleosome occupancy at nucleosome-free regions (NFRs), many of which are located at sites occupied by the multivalent factors Ctcf and cohesin. NURF function at Ctcf binding sites could be direct, because Bptf occupies Ctcf binding sitesin vivoand has physical interactions with CTCF and the cohesin subunit SA2. Assays of several Ctcf binding sites using reporter assays showed that their regulatory activity requires Bptf in two different cell types. Focused studies atH2-K1showed that Bptf regulates the ability of Klf4 to bind near an upstream Ctcf site, possibly influencing gene expression. In combination, these studies demonstrate that gene expression as regulated by NURF occurs partly through physical and functional interactions with the ubiquitous and multivalent factors Ctcf and cohesin.

scholarly journals Effects of DNA Methylation on TFs in Human Embryonic Stem Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Ximei Luo ◽  
Tianjiao Zhang ◽  
Yixiao Zhai ◽  
Fang Wang ◽  
Shumei Zhang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Binding Sites ◽  
Embryonic Stem ◽  
Cell Types ◽  
Epigenetic Mechanism ◽  
Ctcf Binding ◽  
Sequence Specificity ◽  
Sequencing Data ◽  
Methylated Dna

DNA methylation is an important epigenetic mechanism for gene regulation. The conventional view of DNA methylation is that DNA methylation could disrupt protein-DNA interactions and repress gene expression. Several recent studies reported that DNA methylation could alter transcription factors (TFs) binding sequence specificity in vitro. Here, we took advantage of the large sets of ChIP-seq data for TFs and whole-genome bisulfite sequencing data in many cell types to perform a systematic analysis of the protein-DNA methylation in vivo. We observed that many TFs could bind methylated DNA regions, especially in H1-hESC cells. By locating binding sites, we confirmed that some TFs could bind to methylated CpGs directly. The different proportion of CpGs at TF binding specificity motifs in different methylation statuses shows that some TFs are sensitive to methylation and some could bind to the methylated DNA with different motifs, such as CEBPB and CTCF. At the same time, TF binding could interactively alter local DNA methylation. The TF hypermethylation binding sites extensively overlap with enhancers. And we also found that some DNase I hypersensitive sites were specifically hypermethylated in H1-hESC cells. At last, compared with TFs’ binding regions in multiple cell types, we observed that CTCF binding to high methylated regions in H1-hESC were not conservative. These pieces of evidence indicate that TFs that bind to hypermethylation DNA in H1-hESC cells may associate with enhancers to regulate special biological functions.

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 Positional specificity of different transcription factor classes within enhancers

2018 ◽  
Vol 115 (30) ◽  
pp. E7222-E7230 ◽  
Author(s):  
Sharon R. Grossman ◽  
Jesse Engreitz ◽  
John P. Ray ◽  
Tung H. Nguyen ◽  
Nir Hacohen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Binding Sites ◽  
Cell Types ◽  
Regulatory Sequences ◽  
Functional Characteristics ◽  
Positional Specificity ◽  
Chromatin Remodelers ◽  
Positional Bias

Gene expression is controlled by sequence-specific transcription factors (TFs), which bind to regulatory sequences in DNA. TF binding occurs in nucleosome-depleted regions of DNA (NDRs), which generally encompass regions with lengths similar to those protected by nucleosomes. However, less is known about where within these regions specific TFs tend to be found. Here, we characterize the positional bias of inferred binding sites for 103 TFs within ∼500,000 NDRs across 47 cell types. We find that distinct classes of TFs display different binding preferences: Some tend to have binding sites toward the edges, some toward the center, and some at other positions within the NDR. These patterns are highly consistent across cell types, suggesting that they may reflect TF-specific intrinsic structural or functional characteristics. In particular, TF classes with binding sites at NDR edges are enriched for those known to interact with histones and chromatin remodelers, whereas TFs with central enrichment interact with other TFs and cofactors such as p300. Our results suggest distinct regiospecific binding patterns and functions of TF classes within enhancers.

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 Topologically associating domain (TAD) boundaries stable across diverse cell types are evolutionarily constrained and enriched for heritability

2020 ◽  
Author(s):  
Evonne McArthur ◽  
John A. Capra
Keyword(s):  
Genetic Variation ◽  
Association Studies ◽  
3D Structure ◽  
Complex Trait ◽  
Cell Types ◽  
Ctcf Binding ◽  
Evolutionary Constraint ◽  
Regulatory Sequences ◽  
Specific Cell ◽  
Genome Wide Association Studies

ABSTRACTTopologically associating domains (TADs) are fundamental units of three-dimensional (3D) nuclear organization. The regions bordering TADs—TAD boundaries—contribute to the regulation of gene expression by restricting interactions of cis-regulatory sequences to their target genes. TAD and TAD boundary disruption have been implicated in rare disease pathogenesis; however, we have a limited framework for integrating TADs and their variation across cell types into the interpretation of common trait-associated variants. Here, we investigate an attribute of 3D genome architecture—the stability of TAD boundaries across cell types—and demonstrate its relevance to understanding how genetic variation in TADs contribute to complex disease. By synthesizing TAD maps across 37 diverse cell types with 41 genome-wide association studies (GWAS), we investigate the differences in functionality and evolutionary pressure on variation in TADs versus TAD boundaries. We quantify their contribution to trait heritability and sequence-level evolutionary constraint and demonstrate that genetic variation in TAD boundaries contributes more to complex trait heritability, especially for immunologic, hematologic, and metabolic traits. We also show that TAD boundaries are more evolutionarily constrained than TADs. Next, stratifying boundaries by their stability across cell types, we find substantial differences. Boundaries stable across cell types are further enriched for complex trait heritability, evolutionary constraint, CTCF binding, and housekeeping genes compared to boundaries unique to a specific cell type. This suggests greater functional importance for stable boundaries. Thus, considering TAD boundary stability across cell types provides valuable context for understanding the genome’s functional landscape and enabling 3D-structure aware variant interpretation.

scholarly journals Single-cell atlas of early human brain development highlights heterogeneity of human neuroepithelial cells and early radial glia

2021 ◽  
Author(s):  
Ugomma C. Eze ◽  
Aparna Bhaduri ◽  
Maximilian Haeussler ◽  
Tomasz J. Nowakowski ◽  
Arnold R. Kriegstein
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Single Cell ◽  
Radial Glia ◽  
Cortical Development ◽  
Cell Types ◽  
Human Cortex ◽  
Early Stages ◽  
Human Brain Development ◽  
Neuroepithelial Cells

AbstractThe human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex. To characterize the earliest stages of human brain development, we performed single-cell RNA-sequencing across regions of the developing human brain, including the telencephalon, diencephalon, midbrain, hindbrain and cerebellum. We identify nine progenitor populations physically proximal to the telencephalon, suggesting more heterogeneity than previously described, including a highly prevalent mesenchymal-like population that disappears once neurogenesis begins. Comparison of human and mouse progenitor populations at corresponding stages identifies two progenitor clusters that are enriched in the early stages of human cortical development. We also find that organoid systems display low fidelity to neuroepithelial and early radial glia cell types, but improve as neurogenesis progresses. Overall, we provide a comprehensive molecular and spatial atlas of early stages of human brain and cortical development.

Characterization and quantification of 125I-bolton hunter substance P binding sites in human brain

1991 ◽  
Vol 18 (3) ◽  
pp. 399-404 ◽  
Author(s):  
Lars Nilsson ◽  
Bengt Winblad ◽  
Inga Volkmann ◽  
Irina Alafuzoff ◽  
Lena Bergström
Keyword(s):  
Substance P ◽  
Human Brain ◽  
Binding Sites

Glycosylation of developing human glomeruli: lectin binding sites during cell induction and maturation.

1987 ◽  
Vol 35 (1) ◽  
pp. 33-37 ◽  
Author(s):  
H Holthöfer ◽  
I Virtanen
Keyword(s):  
Binding Sites ◽  
Mesangial Cells ◽  
Ricinus Communis ◽  
Lectin Binding ◽  
Helix Pomatia ◽  
Cell Types ◽  
Basement Membranes ◽  
Phenotypic Change ◽  
Neuraminidase Treatment ◽  
Nephron Development

Expression of cellular glycoconjugates during differentiation of human fetal kidney was studied using fluorochrome-labeled lectins. Each lectin revealed a characteristic binding pattern during the phenotypic change of the nephrogenic mesenchyme and during distinct stages of nephron development. The uninduced mesenchymal cells were positive for Pisum sativum (PSA), Concanavalin A (ConA), Wistaria floribunda (WGA), and Ricinus communis (RCA-I) lectins. However, these lectins failed to react with the uninduced cells of the S-shaped bodies, whereas Maclura pomifera (MPA), Triticum vulgaris (WGA) and, after neuraminidase treatment, Arachis hypogaea (PNA) agglutinins bound intensely to the presumptive podocytes. During later stages of nephrogenesis, MPA positively on the podocytes weakened and could not be observed in adult kidney glomeruli. Binding sites for Helix pomatia (HPA) agglutinin in glomeruli were also expressed only transiently during nephrogenesis. During further development PSA, ConA, WFA, and RCA-I reacted with mesangial cells in addition to the glomerular basement membranes. The segment-specific lectin binding patterns of the tubuli emerged in parallel with the appearance of brush border and Tamm-Horsfall antigens of the proximal and distal tubuli. The results show that nephron site-specific saccharides appear in a developmentally regulated manner and in parallel with morphologic maturation of the nephron. Lectins therefore appear to be useful tools for study of induction and maturation of various nephron cell types.

Sign in / Sign up

Export Citation Format

Share Document