scholarly journals Dynamic genetic regulation of gene expression during cellular differentiation

Science ◽  
2019 ◽  
Vol 364 (6447) ◽  
pp. 1287-1290 ◽  
Author(s):  
B. J. Strober ◽  
R. Elorbany ◽  
K. Rhodes ◽  
N. Krishnan ◽  
K. Tayeb ◽  
...  
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Specific Gene ◽  
Genetic Associations ◽  
Sequencing Data ◽  
Using Data ◽  
Induced Pluripotent

Genetic regulation of gene expression is dynamic, as transcription can change during cell differentiation and across cell types. We mapped expression quantitative trait loci (eQTLs) throughout differentiation to elucidate the dynamics of genetic effects on cell type–specific gene expression. We generated time-series RNA sequencing data, capturing 16 time points during the differentiation of induced pluripotent stem cells to cardiomyocytes, in 19 human cell lines. We identified hundreds of dynamic eQTLs that change over time, with enrichment in enhancers of relevant cell types. We also found nonlinear dynamic eQTLs, which affect only intermediate stages of differentiation and cannot be found by using data from mature tissues. These fleeting genetic associations with gene regulation may explain some of the components of complex traits and disease. We highlight one example of a nonlinear eQTL that is associated with body mass index.

scholarly journals On Using Local Ancestry to Characterize the Genetic Architecture of Human Phenotypes: Genetic Regulation of Gene Expression in Multiethnic or Admixed Populations as a Model

2018 ◽  
Author(s):  
Yizhen Zhong ◽  
Minoli Perera ◽  
Eric R. Gamazon
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Type I ◽  
Eqtl Mapping ◽  
Entire Genome ◽  
Local Ancestry ◽  
Heritability Estimation

AbstractBackgroundUnderstanding the nature of the genetic regulation of gene expression promises to advance our understanding of the genetic basis of disease. However, the methodological impact of use of local ancestry on high-dimensional omics analyses, including most prominently expression quantitative trait loci (eQTL) mapping and trait heritability estimation, in admixed populations remains critically underexplored.ResultsHere we develop a statistical framework that characterizes the relationships among the determinants of the genetic architecture of an important class of molecular traits. We estimate the trait variance explained by ancestry using local admixture relatedness between individuals. Using National Institute of General Medical Sciences (NIGMS) and Genotype-Tissue Expression (GTEx) datasets, we show that use of local ancestry can substantially improve eQTL mapping and heritability estimation and characterize the sparse versus polygenic component of gene expression in admixed and multiethnic populations respectively. Using simulations of diverse genetic architectures to estimate trait heritability and the level of confounding, we show improved accuracy given individual-level data and evaluate a summary statistics based approach. Furthermore, we provide a computationally efficient approach to local ancestry analysis in eQTL mapping while increasing control of type I and type II error over traditional approaches.ConclusionOur study has important methodological implications on genetic analysis of omics traits across a range of genomic contexts, from a single variant to a prioritized region to the entire genome. Our findings highlight the importance of using local ancestry to better characterize the heritability of complex traits and to more accurately map genetic associations.

scholarly journals Inducible cell-specific mouse models for paired epigenetic and transcriptomic studies of microglia and astroglia

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Ana J. Chucair-Elliott ◽  
Sarah R. Ocañas ◽  
David R. Stanford ◽  
Victor A. Ansere ◽  
Kyla B. Buettner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Affinity Purification ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Tissue Level ◽  
Cell Phenotype ◽  
Specific Gene ◽  
Cell Type ◽  
A Cell ◽  
Cell Type Specific

AbstractEpigenetic regulation of gene expression occurs in a cell type-specific manner. Current cell-type specific neuroepigenetic studies rely on cell sorting methods that can alter cell phenotype and introduce potential confounds. Here we demonstrate and validate a Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) approach for temporally controlled labeling and isolation of ribosomes and nuclei, and thus RNA and DNA, from specific central nervous system cell types. Analysis of gene expression and DNA modifications in astrocytes or microglia from the same animal demonstrates differential usage of DNA methylation and hydroxymethylation in CpG and non-CpG contexts that corresponds to cell type-specific gene expression. Application of this approach in LPS treated mice uncovers microglia-specific transcriptome and epigenome changes in inflammatory pathways that cannot be detected with tissue-level analysis. The NuTRAP model and the validation approaches presented can be applied to any brain cell type for which a cell type-specific cre is available.

scholarly journals Genetic, parental and lifestyle factors influence telomere length

2021 ◽  
Author(s):  
Sergio Andreu-Sanchez ◽  
Geraldine Aubert ◽  
Aida Ripoll-Cladellas ◽  
Sandra Henkelman ◽  
Daria V. Zhernakova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Average Length ◽  
Cell Types ◽  
Paternal Age ◽  
Specific Gene ◽  
Cell Type ◽  
Sequencing Data ◽  
Nonsense Mediated Decay ◽  
Cell Type Specific ◽  
Telomere Biology

The average length of telomere repeats (TL) declines with age and is considered to be a marker of biological ageing. Here, we measured TL in six blood cell types from 1,046 individuals using the clinically validated Flow-FISH method. We identified remarkable cell-type-specific variations in TL. Host genetics, environmental, parental and intrinsic factors such as sex, parental age, and smoking are associated to variations in TL. By analysing the genome-wide methylation patterns, we identified that the association of maternal, but not paternal, age to TL is mediated by epigenetics. Coupling these measurements to single-cell RNA-sequencing data for 62 participants revealed differential gene expression in T-cells. Genes negatively associated with TL were enriched for pathways related to translation and nonsense-mediated decay. Altogether, this study addresses cell-type-specific differences in telomere biology and its relation to cell-type-specific gene expression and highlights how perinatal factors play a role in determining TL, on top of genetics and lifestyle.

scholarly journals Inducible cell-specific mouse models for paired epigenetic and transcriptomic studies of microglia and astroglia

2019 ◽  
Author(s):  
Ana J. Chucair-Elliott ◽  
Sarah R. Ocañas ◽  
David R. Stanford ◽  
Victor A. Ansere ◽  
Kyla B. Buettner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Tissue Level ◽  
Cell Phenotype ◽  
Specific Gene ◽  
Cell Type ◽  
Current Cell ◽  
A Cell ◽  
Cell Type Specific

AbstractEpigenetic regulation of gene expression occurs in a cell type-specific manner. Current cell-type specific neuroepigenetic studies rely on cell sorting methods that can alter cell phenotype and introduce potential confounds. Here we demonstrate and validate a Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) approach for temporally controlled labeling and isolation of ribosomes and nuclei, and thus RNA and DNA, from specific CNS cell types. Paired analysis of the transcriptome and DNA modifications in astrocytes and microglia demonstrates differential usage of DNA methylation and hydroxymethylation in CG and non-CG contexts that corresponds to cell type-specific gene expression. Application of this approach in LPS treated mice uncovers microglia-specific transcriptome and epigenome changes in inflammatory pathways that cannot be detected with tissue-level analysis. The NuTRAP model and the validation approaches presented can be applied to any CNS cell type for which a cell type-specific cre is available.

scholarly journals Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Anthony S Findley ◽  
Alan Monziani ◽  
Allison L Richards ◽  
Katherine Rhodes ◽  
Michelle C Ward ◽  
...  
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Cell System ◽  
Genetic Effects ◽  
Evolutionary Features ◽  
Multiple Cell ◽  
Multiple Treatments ◽  
Induced Pluripotent

Genetic effects on gene expression and splicing can be modulated by cellular and environmental factors; yet interactions between genotypes, cell type and treatment have not been comprehensively studied together. We used an induced pluripotent stem cell system to study multiple cell types derived from the same individuals and exposed them to a large panel of treatments. Cellular responses involved different genes and pathways for gene expression and splicing, and were highly variable across contexts. For thousands of genes, we identified variable allelic expression across contexts and characterized different types of gene-environment interactions, many of which are associated with complex traits. Promoter functional and evolutionary features distinguished genes with elevated allelic imbalance mean and variance. On average half of the genes with dynamic regulatory interactions were missed by large eQTL mapping studies, indicating the importance of exploring multiple treatments to reveal previously unrecognized regulatory loci that may be important for disease.

scholarly journals Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood

2018 ◽  
Author(s):  
Ting Qi ◽  
Yang Wu ◽  
Jian Zeng ◽  
Futao Zhang ◽  
Angli Xue ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Genetic Effects ◽  
Sample Sizes ◽  
Specific Effects ◽  
The Difference ◽  
Highly Correlated ◽  
Using Data ◽  
Larger Sample

AbstractUnderstanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes associated with brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top associated cis-expression (cis-eQTLs or cis-mQTLs) between brain and blood for genes expressed (or CpG sites methylated) in both tissues, while accounting for errors in their estimated effects (rb). Using publicly available data (n = 72 to l,366), we find that the genetic effects of cis-eQTLs (PeQTL < 5×10−8) or mQTLs (PmQTL < 1×10−10) are highly correlated between independent brain and blood samples ( with SE = 0.015 for cis-eQTL and with SE = 0.006 for cis-mQTLs). Using meta-analyzed brain eQTL/mQTL data (n = 526 to 1,194), we identify 61 genes and 167 DNA methylation (DNAm) sites associated with 4 brain-related traits and disorders. Most of these associations are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = l,980 to 14,115). We further find that cis-eQTLs with tissue-specific effects are approximately uniformly distributed across all the functional annotation categories, and that mean difference in gene expression level between brain and blood is almost independent of the difference in the corresponding cis-eQTL effect. Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL or cis-mQTL data with large sample sizes.

scholarly journals An atlas of lamina-associated chromatin across thirteen human cell types reveals cell-type-specific and multiple subtypes of peripheral heterochromatin

2020 ◽  
Author(s):  
Kathleen C. Keough ◽  
Parisha P. Shah ◽  
Nadeera M. Wickramasinghe ◽  
Carolyn E. Dundes ◽  
Angela Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Cell ◽  
Regulation Of Gene Expression ◽  
Nuclear Periphery ◽  
Cell Types ◽  
Specific Gene ◽  
Cell Type ◽  
Cell Type Specific ◽  
Cellular Identity ◽  
Peripheral Heterochromatin

AbstractThree-dimensional genome organization, specifically organization of heterochromatin at the nuclear periphery, coordinates cell type-specific gene regulation. While defining various histone modifications and chromatin-associated proteins in multiple cell types has provided important insights into epigenetic regulation of gene expression and cellular identity, peripheral heterochromatin has not been mapped comprehensively and relatively few examples have emerged detailing the role of peripheral heterochromatin in cellular identity, cell fate choices, and/or organogenesis. In this study, we define nuclear peripheral heterochromatin organization signatures based on association with LAMIN B1 and/or dimethylation of lysine 9 on H3 (H3K9me2) across thirteen human cell types encompassing pluripotent stem cells, intermediate progenitors and differentiated cells from all three germ layers. Genomic analyses across this atlas reveal that lamin-associated chromatin is organized into at least two different compartments, defined by differences in genome coverage, chromatin accessibility, residence of transposable elements, replication timing domains, and gene complements. Our datasets reveal that only a small subset of lamin-associated chromatin domains are cell type invariant, underscoring the complexity of peripheral heterochromatin organization. Moreover, by integrating peripheral chromatin maps with transcriptional data, we find evidence of cooperative shifts between chromatin structure and gene expression associated with each cell type. This atlas of peripheral chromatin provides the largest resource to date for peripheral chromatin organization and a deeper appreciation for how this organization may impact the establishment and maintenance of cellular identity.

scholarly journals Mechanisms of tissue-specific genetic regulation revealed by latent factors across eQTLs

2019 ◽  
Author(s):  
Yuan He ◽  
Surya B. Chhetri ◽  
Marios Arvanitis ◽  
Kaushik Srinivasan ◽  
François Aguet ◽  
...  
Keyword(s):  
Matrix Factorization ◽  
Tissue Specificity ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Genetic Effect ◽  
Cell Types ◽  
Tissue Expression ◽  
Specific Gene ◽  
Disease Etiology ◽  
Tissue Specific

AbstractBackgroundGenetic regulation of gene expression, revealed by expression quantitative trait loci (eQTLs), varies across tissues in complex patterns ranging from highly tissue-specific effects to effects shared across many or all tissues. Improved characterization of these patterns may allow us to better understand the biological mechanisms that underlie tissue-specific gene regulation and disease etiology.ResultsWe develop a constrained matrix factorization model to learn patterns of tissue sharing and tissue specificity of eQTLs across 49 human tissues from the Genotype-Tissue Expression (GTEx) project. The learned factors include patterns reflecting tissues with known biological similarity or shared cell types, in addition to a dense factor representing a universal genetic effect across all tissues. To explore the regulatory mechanisms that generate tissue-specific patterns of expression, we evaluate chromatin state enrichment and identify specific transcription factors with binding sites enriched for eQTLs from each factor.ConclusionsOur results demonstrate that matrix factorization can be applied to learn the tissue specificity pattern of eQTLs and that it exhibits better biological interpretability than heuristic methods. We present a framework to characterize the tissue specificity of eQTLs, and we identify examples of tissue-specific eQTLs that may be driven by tissue-specific transcription factor (TF) binding, with relevance to interpretation of disease association.

Spatial associations of centromeres in the nuclei of hematopoietic cells: evidence for cell-type-specific organizational patterns

Blood ◽  
2000 ◽  
Vol 95 (5) ◽  
pp. 1608-1615 ◽  
Author(s):  
Isabel Alcobia ◽  
Rui Dilão ◽  
Leonor Parreira
Keyword(s):  
Gene Expression ◽  
Regulation Of Gene Expression ◽  
Hematopoietic Cells ◽  
Cell Types ◽  
Epigenetic Mechanism ◽  
Centromeric Heterochromatin ◽  
Specific Gene ◽  
Cell Type ◽  
Spatial Associations ◽  
Cell Type Specific

It is believed that the 3-dimensional organization of centromeric heterochromatin in interphase may be of functional relevance as an epigenetic mechanism for the regulation of gene expression. Accordingly, a likely possibility is that the centromeres that spatially associate into the heterochromatic structures (chromocenters) observed in the G1 phase of the cell cycle will differ in different cells. We sought to address this issue using, as a model, the chromocenters observed in quiescent normal human hematopoietic cells and primary fibroblasts. To do this, we analyzed the spatial relationships among different human centromeres in 3-D preserved cells using nonisotopic in situ hybridization and confocal microscopy. We showed quantitatively that chromocenters in all cell types do indeed represent nonrandom spatial associations of certain centromeres. Furthermore, the observed patterns of centromere association indicate that the chromocenters in these cell types are made of different combinations of specific centromeres, that hematopoietic cells are strikingly different from fibroblasts as to the composition of their chromocenters and that centromeres in peripheral blood cells appear to aggregate into distinct “myeloid” (present in monocytes and granulocytes) and “lymphoid” (present in lymphocytes) spatial patterns. These findings support the idea that the chromocenters formed in the nucleus of quiescent hematopoietic cells might represent heterochromatic nuclear compartments involved in the regulation of cell-type-specific gene expression, further suggesting that the spatial arrangement of centromeric heterochromatin in interphase is ontogenically determined during hematopoietic differentiation.

scholarly journals Cell type–specific genetic regulation of gene expression across human tissues

Science ◽  
2020 ◽  
Vol 369 (6509) ◽  
pp. eaaz8528 ◽  
Author(s):  
Sarah Kim-Hellmuth ◽  
François Aguet ◽  
Meritxell Oliva ◽  
Manuel Muñoz-Aguirre ◽  
Silva Kasela ◽  
...  
Keyword(s):  
Complex Traits ◽  
Functional Characterization ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Human Tissues ◽  
Genetic Associations ◽  
Cell Type ◽  
Wide Range ◽  
Type Interaction ◽  
Bulk Tissue

The Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci in cis (QTLs) for the majority of genes across a wide range of human tissues. However, the functional characterization of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. We mapped interactions between computational estimates of cell type abundance and genotype to identify cell type–interaction QTLs for seven cell types and show that cell type–interaction expression QTLs (eQTLs) provide finer resolution to tissue specificity than bulk tissue cis-eQTLs. Analyses of genetic associations with 87 complex traits show a contribution from cell type–interaction QTLs and enables the discovery of hundreds of previously unidentified colocalized loci that are masked in bulk tissue.

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