scholarly journals Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Matthew Jensen ◽  
Anastasia Tyryshkina ◽  
Lucilla Pizzo ◽  
Corrine Smolen ◽  
Maitreya Das ◽  
...  
Keyword(s):  
Gene Expression ◽  
Developmental Delay ◽  
Gene Networks ◽  
Phenotypic Variability ◽  
Specific Interaction ◽  
Loss Of Function ◽  
Specific Expression ◽  
Second Hit ◽  
Complex Disorders ◽  
Variable Expressivity

Abstract Background Recent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in > 90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional “second-hit” variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown. Methods We performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We identified contributions of the 16p12.1 deletion and “second-hit” variants towards a range of expression changes in deletion carriers and their family members, including differential expression, outlier expression, alternative splicing, allele-specific expression, and expression quantitative trait loci analyses. Results We found that the deletion dysregulates multiple autism and brain development genes such as FOXP1, ANK3, and MEF2. Carrier children also showed an average of 5323 gene expression changes compared with one or both parents, which matched with 33/39 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of “second-hit” variants in genes with expression changes, where 4/25 variant classes were only enriched when inherited from the noncarrier parent, including loss-of-function SNVs and large duplications. In 11 instances, including for ZEB2 and SYNJ1, gene expression was synergistically altered by both the deletion and inherited “second-hits” in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying “second-hits” and genes with transcriptome alterations in deletion carriers. Conclusions Our results suggest a potential mechanism for how “second-hit” variants modulate expressivity of complex disorders such as the 16p12.1 deletion through transcriptomic perturbation of gene networks important for early development. Our work further shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders.

scholarly journals Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion

2021 ◽  
Author(s):  
Matthew Jensen ◽  
Anastasia Tyryshkina ◽  
Lucilla Pizzo ◽  
Corrine Smolen ◽  
Maitreya Das ◽  
...  
Keyword(s):  
Gene Expression ◽  
Developmental Delay ◽  
De Novo ◽  
Phenotypic Variability ◽  
Specific Interaction ◽  
Specific Expression ◽  
Strong Connectivity ◽  
Second Hit ◽  
Complex Disorders ◽  
Variable Expressivity

ABSTRACTRecent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in >90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional “second-hit” variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown. We performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We found that the deletion dysregulates multiple autism and brain development genes such as FOXP1, ANK3, and MEF2. Carrier children also showed expression changes that were inherited as well as de novo compared with their parents, which matched with 39/47 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of “second-hit” variants in genes with expression changes, where 7/25 variant classes were only enriched when inherited from the non-carrier parent, including missense SNVs and large deletions. In 11 instances, including for ZEB2 and SYNJ1, gene expression was synergistically altered by both the deletion and inherited “second-hits” in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying “second-hits” and genes with transcriptome alterations, including differential expression, alternative splicing, and allele-specific expression. Our study shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders.

scholarly journals Auxin methylation is required for differential growth inArabidopsis

2018 ◽  
Vol 115 (26) ◽  
pp. 6864-6869 ◽  
Author(s):  
Mohamad Abbas ◽  
Jorge Hernández-García ◽  
Stephan Pollmann ◽  
Sophia L. Samodelov ◽  
Martina Kolb ◽  
...  
Keyword(s):  
Gene Expression ◽  
Auxin Transport ◽  
Polar Auxin Transport ◽  
Asymmetric Distribution ◽  
Loss Of Function ◽  
Differential Growth ◽  
Specific Expression ◽  
Auxin Homeostasis ◽  
Auxin Distribution ◽  
Gene Expression Levels

Asymmetric auxin distribution is instrumental for the differential growth that causes organ bending on tropic stimuli and curvatures during plant development. Local differences in auxin concentrations are achieved mainly by polarized cellular distribution of PIN auxin transporters, but whether other mechanisms involving auxin homeostasis are also relevant for the formation of auxin gradients is not clear. Here we show that auxin methylation is required for asymmetric auxin distribution across the hypocotyl, particularly during its response to gravity. We found that loss-of-function mutants inArabidopsis IAA CARBOXYL METHYLTRANSFERASE1(IAMT1) prematurely unfold the apical hook, and that their hypocotyls are impaired in gravitropic reorientation. This defect is linked to an auxin-dependent increase inPINgene expression, leading to an increased polar auxin transport and lack of asymmetric distribution of PIN3 in theiamt1mutant. Gravitropic reorientation in theiamt1mutant could be restored with either endodermis-specific expression ofIAMT1or partial inhibition of polar auxin transport, which also results in normalPINgene expression levels. We propose that IAA methylation is necessary in gravity-sensing cells to restrict polar auxin transport within the range of auxin levels that allow for differential responses.

Systematic assessment of the human osteoblast transcriptome in resting and induced primary cells

2008 ◽  
Vol 33 (3) ◽  
pp. 301-311 ◽  
Author(s):  
Elin Grundberg ◽  
Helena Brändström ◽  
Kevin C. L. Lam ◽  
Scott Gurd ◽  
Bing Ge ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Biology ◽  
Gene Networks ◽  
Cell Function ◽  
Expression Profiles ◽  
Bone Cell ◽  
Specific Gene ◽  
Molecular Physiology ◽  
Specific Expression ◽  
Vast Number

Osteoblasts are key players in bone remodeling. The accessibility of human primary osteoblast-like cells (HObs) from bone explants makes them a lucrative model for studying molecular physiology of bone turnover, for discovering novel anabolic therapeutics, and for mesenchymal cell biology in general. Relatively little is known about resting and dynamic expression profiles of HObs, and to date no studies have been conducted to systematically assess the osteoblast transcriptome. The aim of this study was to characterize HObs and investigate signaling cascades and gene networks with genomewide expression profiling in resting and bone morphogenic protein (BMP)-2- and dexamethasone-induced cells. In addition, we compared HOb gene expression with publicly available samples from the Gene Expression Omnibus. Our data show a vast number of genes and networks expressed predominantly in HObs compared with closely related cells such as fibroblasts or chondrocytes. For instance, genes in the insulin-like growth factor (IGF) signaling pathway were enriched in HObs ( P = 0.003) and included the binding proteins (IGFBP-1, -2, -5) and IGF-II and its receptor. Another HOb-specific expression pattern included leptin and its receptor ( P < 10−8). Furthermore, after stimulation of HObs with BMP-2 or dexamethasone, the expression of several interesting genes and pathways was observed. For instance, our data support the role of peripheral leptin signaling in bone cell function. In conclusion, we provide the landscape of tissue-specific and dynamic gene expression in HObs. This resource will allow utilization of osteoblasts as a model to study specific gene networks and gene families related to human bone physiology and diseases.

scholarly journals A Drosophila natural variation screen identifies NKCC1 as a substrate of NGLY1 deglycosylation and a modifier of NGLY1 deficiency

2020 ◽  
Author(s):  
Dana M. Talsness ◽  
Katie G. Owings ◽  
Emily Coelho ◽  
Gaelle Mercenne ◽  
John M. Pleinis ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Natural Variation ◽  
Evolutionary Rate ◽  
Phenotypic Variability ◽  
Loss Of Function ◽  
Ion Transporter ◽  
Phenotypic Spectrum ◽  
Mouse Cells ◽  
Covariation Analysis ◽  
Insight Into

AbstractN-Glycanase 1 (NGLY1) is a cytoplasmic deglycosylating enzyme. Loss-of-function mutations in the NGLY1 gene cause NGLY1 deficiency, which is characterized by developmental delay, seizures, and a lack of sweat and tears. To model the phenotypic variability observed among patients, we crossed a Drosophila model of NGLY1 deficiency onto a panel of genetically diverse strains. The resulting progeny showed a phenotypic spectrum from 0-100% lethality. Association analysis on the lethality phenotype as well as an evolutionary rate covariation analysis generated lists of modifying genes, providing insight into NGLY1 function and disease. The top association hit was Ncc69 (human NKCC1/2), a conserved ion transporter. Analyses in NGLY1 -/- mouse cells demonstrated that NKCC1 is misglycosylated and has reduced function, making it only the second confirmed NGLY1 enzymatic substrate. The misregulation of this ion transporter may explain the observed defects in secretory epithelium function in NGLY1 deficiency patients.

scholarly journals Predicting tissue-specific gene expression from whole blood transcriptome

2020 ◽  
Author(s):  
Mahashweta Basu ◽  
Kun Wang ◽  
Eytan Ruppin ◽  
Sridhar Hannenhalli
Keyword(s):  
Gene Expression ◽  
Whole Blood ◽  
Specific Gene ◽  
Specific Expression ◽  
Tissue Specific ◽  
Complex Disorders ◽  
Tissue Specific Gene ◽  
Tissue Specific Expression ◽  
Specific Gene Expression ◽  
Blood Transcriptome

AbstractComplex diseases are systemic, largely mediated via transcriptional dysregulation in multiple tissues. Thus, knowledge of tissue-specific transcriptome in an individual can provide important information about an individual’s health. Unfortunately, with a few exceptions such as blood, skin, and muscle, an individual’s tissue-specific transcriptome is not accessible through non-invasive means. However, due to shared genetics and regulatory programs between tissues, the transcriptome in blood may be predictive of those in other tissues, at least to some extent. Here, based on GTEx data, we address this question in a rigorous, systematic manner, for the first time. We find that an individual’s whole blood gene expression and splicing profile can predict tissue-specific expression levels in a significant manner (beyond demographic variables) for many genes. On average, across 32 tissues, the expression of about 60% of the genes is predictable from blood expression in a significant manner, with a maximum of 81% of the genes for the musculoskeletal tissue. Remarkably, the tissue-specific expression inferred from the blood transcriptome is almost as good as the actual measured tissue expression in predicting disease state for six different complex disorders, including Hypertension and Type 2 diabetes, substantially surpassing predictors built directly from the blood transcriptome. The code for our pipeline for tissue-specific gene expression prediction – TEEBoT, is provided, enabling others to study its potential translational value in other indications.

Spatially specific expression of Hoxb4 is dependent on the ubiquitous transcription factor NFY

Development ◽  
2002 ◽  
Vol 129 (16) ◽  
pp. 3887-3899 ◽  
Author(s):  
Jonathan Gilthorpe ◽  
Marie Vandromme ◽  
Tim Brend ◽  
Alejandro Gutman ◽  
Dennis Summerbell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Sites ◽  
Specific Interaction ◽  
Transcriptional Regulators ◽  
Heterologous Promoter ◽  
Specific Expression ◽  
Enhancer Activity ◽  
Hox Gene ◽  
Two Factors ◽  
Enhancer Function

Understanding how boundaries and domains of Hox gene expression are determined is critical to elucidating the means by which the embryo is patterned along the anteroposterior axis. We have performed a detailed analysis of the mouse Hoxb4 intron enhancer to identify upstream transcriptional regulators. In the context of an heterologous promoter, this enhancer can establish the appropriate anterior boundary of mesodermal expression but is unable to maintain it, showing that a specific interaction with its own promoter is important for maintenance. Enhancer function depends on a motif that contains overlapping binding sites for the transcription factors NFY and YY1. Specific mutations that either abolish or reduce NFY binding show that it is crucial for enhancer activity. The NFY/YY1 motif is reiterated in the Hoxb4 promoter and is known to be required for its activity. As these two factors are able to mediate opposing transcriptional effects by reorganizing the local chromatin environment, the relative levels of NFY and YY1 binding could represent a mechanism for balancing activation and repression of Hoxb4 through the same site.

scholarly journals Cis- and Trans-Regulatory Variations in the Domestication of the Chili Pepper Fruit

2020 ◽  
Vol 37 (6) ◽  
pp. 1593-1603 ◽  
Author(s):  
Erik Díaz-Valenzuela ◽  
Ruairidh H Sawers ◽  
Angélica Cibrián-Jaramillo
Keyword(s):  
Gene Expression ◽  
Chili Pepper ◽  
Loss Of Function ◽  
Morphological Transformation ◽  
Specific Expression ◽  
Network Analyses ◽  
Regulatory Variants ◽  
Regulatory Cascades ◽  
In The Wild ◽  
Cis And Trans

Abstract The process of domestication requires the rapid transformation of the wild morphology into the cultivated forms that humans select for. This process often takes place through changes in the regulation of genes, yet, there is no definite pattern on the role of cis- and trans-acting regulatory variations in the domestication of the fruit among crops. Using allele-specific expression and network analyses, we characterized the regulatory patterns and the inheritance of gene expression in wild and cultivated accessions of chili pepper, a crop with remarkable fruit morphological variation. We propose that gene expression differences associated to the cultivated form are best explained by cis-regulatory hubs acting through trans-regulatory cascades. We show that in cultivated chili, the expression of genes associated with fruit morphology is partially recessive with respect to those in the wild relative, consistent with the hybrid fruit phenotype. Decreased expression of fruit maturation and growth genes in cultivated chili suggest that selection for loss-of-function took place in its domestication. Trans-regulatory changes underlie the majority of the genes showing regulatory divergence and had larger effect sizes on gene expression than cis-regulatory variants. Network analysis of selected cis-regulated genes, including ARP9 and MED25, indicated their interaction with many transcription factors involved in organ growth and fruit ripening. Differentially expressed genes linked to cis-regulatory variants and their interactions with downstream trans-acting genes have the potential to drive the morphological differences observed between wild and cultivated fruits and provide an attractive mechanism of morphological transformation during the domestication of the chili pepper.

scholarly journals Selection at the pathway level drives the evolution of gene-specific transcriptional noise

2017 ◽  
Author(s):  
Gustavo Valadares Barroso ◽  
Natasa Puzovic ◽  
Julien Y Dutheil
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Gene Networks ◽  
Phenotypic Variability ◽  
Published Data ◽  
Evolutionary Constraint ◽  
Stochastic Gene Expression ◽  
Transcriptional Noise ◽  
Evolutionary Forces ◽  
A Genome

ABSTRACTBiochemical reactions within individual cells result from the interactions of molecules, typically in small numbers. Consequently, the inherent stochasticity of binding and diffusion processes generate noise along the cascade that leads to the synthesis of a protein from its encoding gene. As a result, isogenic cell populations display phenotypic variability even in homogeneous environments. The extent and consequences of this stochastic gene expression have only recently been assessed on a genome-wide scale, in particular owing to the advent of single cell transcriptomics. However, the evolutionary forces shaping this stochasticity have yet to be unraveled. We take advantage of two recently published data sets of the single-cell transcriptome of the domestic mouse Mus musculus in order to characterize the effect of natural selection on gene-specific transcriptional stochasticity. We show that noise levels in the mRNA distributions (a.k.a. transcriptional noise) significantly correlate with three-dimensional nuclear domain organization, evolutionary constraint on the encoded protein and gene age. The position of the encoded protein in biological pathways, however, is the main factor that explains observed levels of transcriptional noise, in agreement with models of noise propagation within gene networks. Because transcriptional noise is under widespread selection, we argue that it constitutes an important component of the phenotype and that variance of expression is a potential target of adaptation. Stochastic gene expression should therefore be considered together with mean expression level in functional and evolutionary studies of gene expression.

scholarly journals Predicting tissue-specific gene expression from whole blood transcriptome

2021 ◽  
Vol 7 (14) ◽  
pp. eabd6991
Author(s):  
Mahashweta Basu ◽  
Kun Wang ◽  
Eytan Ruppin ◽  
Sridhar Hannenhalli
Keyword(s):  
Gene Expression ◽  
Whole Blood ◽  
Specific Gene ◽  
Specific Expression ◽  
Tissue Specific ◽  
Complex Disorders ◽  
Tissue Specific Gene ◽  
Tissue Specific Expression ◽  
Specific Gene Expression ◽  
Blood Transcriptome

Complex diseases are mediated via transcriptional dysregulation in multiple tissues. Thus, knowing an individual’s tissue-specific gene expression can provide critical information about her health. Unfortunately, for most tissues, the transcriptome cannot be obtained without invasive procedures. Could we, however, infer an individual’s tissue-specific expression from her whole blood transcriptome? Here, we rigorously address this question. We find that an individual’s whole blood transcriptome can significantly predict tissue-specific expression levels for ~60% of the genes on average across 32 tissues, with up to 81% of the genes in skeletal muscle. The tissue-specific expression inferred from the blood transcriptome is almost as good as the actual measured tissue expression in predicting disease state for six different complex disorders, including hypertension and type 2 diabetes, substantially surpassing the blood transcriptome. The code for tissue-specific gene expression prediction, TEEBoT, is provided, enabling others to study its potential translational value in other indications.

scholarly journals Cis-Repression of Foxq1 Expression Affects Foxf2-Mediated Gene Expression in Palate Development

2021 ◽  
Vol 9 ◽  
Author(s):  
Jingyue Xu ◽  
Han Liu ◽  
Yu Lan ◽  
Rulang Jiang
Keyword(s):  
Gene Expression ◽  
Cleft Palate ◽  
Chromatin Domain ◽  
Loss Of Function ◽  
Specific Expression ◽  
Palate Development ◽  
Domain Specific ◽  
Conditional Allele ◽  
Or Gene ◽  
Conserved Gene

Disruption of FOXF2, encoding a member of the Forkhead family transcription factors, has been associated with cleft palate in humans and mice. FOXF2 is located in a conserved gene cluster containing FOXQ1, FOXF2, and FOXC1. We found that expression of Foxq1 is dramatically upregulated in the embryonic palatal mesenchyme in Foxf2–/– mouse embryos. We show here that the Foxf2 promoter-deletion mutation caused dramatically increased expression of the cis-linked Foxq1 allele but had little effect on the Foxq1 allele in trans. We analyzed effects of the Foxf2 mutation on the expression of other neighboring genes and compared those effects with the chromatin domain structure and recently identified enhancer-promoter associations as well as H3K27ac ChIP-seq data. We show that the Foxf2 mutation resulted in significantly increased expression of the Foxq1 and Exoc2 genes located in the same topologically associated domain with Foxf2 but not the expression of the Foxc1 and Gmds genes located in the adjacent chromatin domain. We inactivated the Foxq1 gene in mice homozygous for a Foxf2 conditional allele using CRISPR genome editing and generated (Foxf2/Foxq1)+/– mice with loss-of-function mutations in Foxf2 and Foxq1 in cis. Whereas the (Foxf2/Foxq1)–/– mice exhibited cleft palate at birth similar as in the Foxf2–/– mice, systematic expression analyses of a large number of Foxf2-dependent genes revealed that the (Foxf2/Foxq1)–/– embryos exhibited distinct effects on the domain-specific expression of several important genes, including Foxf1, Shox2, and Spon1, in the developing palatal shelves compared with Foxf2–/– embryos. These results identify a novel cis-regulatory effect of the Foxf2 mutation and demonstrate that cis-regulation of Foxq1 contributed to alterations in palatal gene expression in Foxf2–/– embryos. These results have important implications for interpretation of results and mechanisms from studies of promoter- or gene-deletion alleles. In addition, the unique mouse lines generated in this study provide a valuable resource for understanding the cross-regulation and combinatorial functions of the Foxf2 and Foxq1 genes in development and disease.

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