scholarly journals Imprinted gene expression at the Dlk1-Dio3 cluster is controlled by both maternal and paternal IG-DMRs in a tissue-specific fashion

2019 ◽  
Author(s):  
Katherine A. Alexander ◽  
María J. García-García
Keyword(s):  
Gene Expression ◽  
Regulatory Elements ◽  
Enhancer Activity ◽  
Enhancer Element ◽  
Tissue Specific ◽  
Imprinted Gene ◽  
Imprinting Control Region ◽  
Regulatory Landscape ◽  
Insight Into ◽  
Different Tissues

ABSTRACTImprinting at the Dlk1-Dio3 cluster is controlled by the IG-DMR, an imprinting control region differentially methylated between maternal and paternal chromosomes. The maternal IG-DMR is essential for imprinting control, functioning as a cis enhancer element. Meanwhile, DNA methylation at the paternal IG-DMR is thought to prevent enhancer activity. To explore whether suppression of enhancer activity at the methylated IG-DMR requires the transcriptional repressor TRIM28, we analyzed Trim28chatwo embryos and performed epistatic experiments with IG-DMR deletion mutants. We found that while TRIM28 regulates the enhancer properties of the paternal IG-DMR, it also controls imprinting through other mechanisms. Additionally, we found that the paternal IG-DMR, previously deemed dispensable for imprinting, is required in certain tissues, demonstrating that imprinting is regulated in a tissue-specific manner. Using PRO-seq to analyze nascent transcription, we identified 30 novel transcribed regulatory elements, including 23 that are tissue-specific. These results demonstrate that different tissues have a distinctive regulatory landscape at the Dlk1-Dio3 cluster and provide insight into potential mechanisms of tissue-specific imprinting control. Together, our findings challenge the premise that Dlk1-Dio3 imprinting is regulated through a single mechanism and demonstrate that different tissues use distinct strategies to accomplish imprinted gene expression.

scholarly journals Complexity and conservation of regulatory landscapes underlie evolutionary resilience of mammalian gene expression

2017 ◽  
Author(s):  
Camille Berthelot ◽  
Diego Villar ◽  
Julie E. Horvath ◽  
Duncan T. Odom ◽  
Paul Flicek
Keyword(s):  
Gene Expression ◽  
Regulatory Elements ◽  
List Type ◽  
Enhancer Activity ◽  
Expression Levels ◽  
Mammalian Gene ◽  
Highly Expressed Genes ◽  
Regulatory Landscape ◽  
Regulatory Landscapes ◽  
Mammalian Gene Expression

AbstractTo gain insight into how mammalian gene expression is controlled by rapidly evolving regulatory elements, we jointly analysed promoter and enhancer activity with downstream transcription levels in liver samples from twenty species. Genes associated with complex regulatory landscapes generally exhibit high expression levels that remain evolutionarily stable. While the number of regulatory elements is the key driver of transcriptional output and resilience, regulatory conservation matters: elements active across mammals most effectively stabilise gene expression. In contrast, recently-evolved enhancers typically contribute weakly, consistent with their high evolutionary plasticity. These effects are observed across the entire mammalian clade and robust to potential confounders, such as gene expression level. Overall, our results illuminate how the evolutionary stability of gene expression is profoundly entwined with both the number and conservation of surrounding promoters and enhancers.HighlightsGene expression levels and stability are linked to the number of elements in the regulatory landscape.Conserved regulatory elements associate with tightly controlled, highly expressed genes.Recently evolved enhancers weakly influence gene expression, but promoters are similarly active regardless of conservation.The interplay between complexity of the regulatory landscape and conservation of individual promoters and enhancers shapes gene expression in mammals.

scholarly journals Dissection of a Complex Enhancer Element: Maintenance of Keratinocyte Specificity but Loss of Differentiation Specificity

2002 ◽  
Vol 22 (12) ◽  
pp. 4293-4308 ◽  
Author(s):  
Charles K. Kaufman ◽  
Satrajit Sinha ◽  
Diana Bolotin ◽  
Jie Fan ◽  
Elaine Fuchs
Keyword(s):  
Gene Expression ◽  
Specific Activity ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Regulatory Sequence ◽  
Open Chromatin ◽  
Specific Expression ◽  
Enhancer Activity ◽  
Enhancer Element

ABSTRACT In this report, we explored the mechanisms underlying keratinocyte-specific and differentiation-specific gene expression in the skin. We have identified five keratinocyte-specific, open chromatin regions that exist within the 6 kb of 5′ upstream regulatory sequence known to faithfully recapitulate the strong endogenous keratin 5 (K5) promoter and/or enhancer activity. One of these, DNase I-hypersensitive site (HSs) 4, was unique in that it acted independently to drive abundant and keratinocyte-specific reporter gene activity in culture and in transgenic mice, despite the fact that it was not essential for K5 enhancer activity. We have identified evolutionarily conserved regulatory elements and a number of their associated proteins that bind to this compact and complex enhancer element. The 125-bp 3′ half of this element (referred to as 4.2) is by far the smallest known strong enhancer element possessing keratinocyte-specific activity in vivo. Interestingly, its activity is restricted to a subset of progeny of K5-expressing cells located within the sebaceous gland. The other half of HSs 4 (termed 4.1) possesses activity to suppress sebocyte-specific expression and induce expression in the channel (inner root sheath) cells surrounding the hair shaft. Our findings lead us to a view of keratinocyte gene expression which is determined by multiple regulatory modules, many of which contain AP-2 and/or Sp1/Sp3 binding sites for enhancing expression in skin epithelium, but which also harbor one or more unique sites for the binding of factors which determine specificity. Through mixing and matching of these modules, additional levels of specificity are obtained, indicating that both transcriptional repressors and activators govern the specificity.

scholarly journals T cell receptor beta gene has two downstream DNase I hypersensitive regions. Possible mechanisms of tissue- and stage-specific gene regulation.

1989 ◽  
Vol 169 (6) ◽  
pp. 2097-2107 ◽  
Author(s):  
Y Hashimoto
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Cell Lines ◽  
Regulatory Elements ◽  
Dnase I ◽  
The Other ◽  
Specific Gene ◽  
Enhancer Element ◽  
Tissue Specific ◽  
T Cell Lines

Two DNase I-hypersensitive regions were identified downstream of the TCR gene constant region. One of these regions is located at the site of a putative enhancer element and was observed only in T cell lines and not in cell lines derived from other tissues. The other DNase-hypersensitive region was also detected only in T cell lines but only in those expressing TCR-beta RNA. Thus, the first region is probably tissue specific, while the second region is probably tissue and stage specific. The DNA sequence of the second DNase I-hypersensitive region revealed several stretches of nucleotides that are characteristic of consensus sequences for regulatory elements. These results, together with the observations in transgenic mice that indicate a requirement for two distinct regions for optimal TCR gene expression, suggest the presence of at least two regulatory regions downstream of the C-beta-2 region; one is an enhancer region and the other is a transcriptionally related regulatory region. The tissue/stage specificity of these DNase I-hypersensitive regions supports the notion that changes in chromatin structure control tissue-specific gene expression.

Regulation of the twist target gene tinman by modular cis-regulatory elements during early mesoderm development

Development ◽  
1997 ◽  
Vol 124 (24) ◽  
pp. 4971-4982 ◽  
Author(s):  
Z. Yin ◽  
X.L. Xu ◽  
M. Frasch
Keyword(s):  
Homeobox Gene ◽  
Regulatory Elements ◽  
Bhlh Protein ◽  
Expression Domain ◽  
Enhancer Activity ◽  
Enhancer Element ◽  
Mesoderm Development ◽  
Visceral Mesoderm

The Drosophila tinman homeobox gene has a major role in early mesoderm patterning and determines the formation of visceral mesoderm, heart progenitors, specific somatic muscle precursors and glia-like mesodermal cells. These functions of tinman are reflected in its dynamic pattern of expression, which is characterized by initial widespread expression in the trunk mesoderm, then refinement to a broad dorsal mesodermal domain, and finally restricted expression in heart progenitors. Here we show that each of these phases of expression is driven by a discrete enhancer element, the first being active in the early mesoderm, the second in the dorsal mesoderm and the third in cardioblasts. We provide evidence that the early-active enhancer element is a direct target of twist, a gene encoding a basic helix-loop-helix (bHLH) protein, which is necessary for tinman activation. This 180 bp enhancer includes three E-box sequences which bind Twist protein in vitro and are essential for enhancer activity in vivo. Ectodermal misexpression of twist causes ectopic activation of this enhancer in ectodermal cells, indicating that twist is the only mesoderm-specific activator of early tinman expression. We further show that the 180 bp enhancer also includes negatively acting sequences. Binding of Even-skipped to these sequences appears to reduce twist-dependent activation in a periodic fashion, thus producing a striped tinman pattern in the early mesoderm. In addition, these sequences prevent activation of tinman by twist in a defined portion of the head mesoderm that gives rise to hemocytes. We find that this repression requires the function of buttonhead, a head-patterning gene, and that buttonhead is necessary for normal activation of the hematopoietic differentiation gene serpent in the same area. Together, our results show that tinman is controlled by an array of discrete enhancer elements that are activated successively by differential genetic inputs, as well as by closely linked activator and repressor binding sites within an early-acting enhancer, which restrict twist activity to specific areas within the twist expression domain.

scholarly journals Tissue-specific sex differences in human gene expression

2019 ◽  
Vol 28 (17) ◽  
pp. 2976-2986 ◽  
Author(s):  
Irfahan Kassam ◽  
Yang Wu ◽  
Jian Yang ◽  
Peter M Visscher ◽  
Allan F McRae
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Complex Traits ◽  
Tissue Expression ◽  
Regulatory Elements ◽  
Tissue Specific ◽  
Significance Threshold ◽  
Expression Of Genes ◽  
Causal Variants ◽  
Similar Distance

Abstract Despite extensive sex differences in human complex traits and disease, the male and female genomes differ only in the sex chromosomes. This implies that most sex-differentiated traits are the result of differences in the expression of genes that are common to both sexes. While sex differences in gene expression have been observed in a range of different tissues, the biological mechanisms for tissue-specific sex differences (TSSDs) in gene expression are not well understood. A total of 30 640 autosomal and 1021 X-linked transcripts were tested for heterogeneity in sex difference effect sizes in n = 617 individuals across 40 tissue types in Genotype–Tissue Expression (GTEx). This identified 65 autosomal and 66 X-linked TSSD transcripts (corresponding to unique genes) at a stringent significance threshold. Results for X-linked TSSD transcripts showed mainly concordant direction of sex differences across tissues and replicate previous findings. Autosomal TSSD transcripts had mainly discordant direction of sex differences across tissues. The top cis-expression quantitative trait loci (eQTLs) across tissues for autosomal TSSD transcripts are located a similar distance away from the nearest androgen and estrogen binding motifs and the nearest enhancer, as compared to cis-eQTLs for transcripts with stable sex differences in gene expression across tissue types. Enhancer regions that overlap top cis-eQTLs for TSSD transcripts, however, were found to be more dispersed across tissues. These observations suggest that androgen and estrogen regulatory elements in a cis region may play a common role in sex differences in gene expression, but TSSD in gene expression may additionally be due to causal variants located in tissue-specific enhancer regions.

scholarly journals Chromatin state signatures associated with tissue-specific gene expression and enhancer activity in the embryonic limb

2012 ◽  
Vol 22 (6) ◽  
pp. 1069-1080 ◽  
Author(s):  
Justin Cotney ◽  
Jing Leng ◽  
Sunghee Oh ◽  
Laura E. DeMare ◽  
Steven K. Reilly ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin State ◽  
Specific Gene ◽  
Enhancer Activity ◽  
Tissue Specific ◽  
Tissue Specific Gene ◽  
Specific Gene Expression ◽  
Embryonic Limb

scholarly journals Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders

2016 ◽  
Vol 113 (16) ◽  
pp. 4434-4439 ◽  
Author(s):  
Aoi Wakabayashi ◽  
Jacob C. Ulirsch ◽  
Leif S. Ludwig ◽  
Claudia Fiorini ◽  
Makiko Yasuda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Activity ◽  
Regulatory Elements ◽  
Binding Motif ◽  
Targeted Disruption ◽  
Altered Gene Expression ◽  
Whole Exome ◽  
Altered Gene ◽  
Insight Into

Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptional cis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders.

scholarly journals Starvation resistance and tissue-specific gene expression of stress-related genes in a naturally inbred ant population

2016 ◽  
Vol 3 (4) ◽  
pp. 160062 ◽  
Author(s):  
Nick Bos ◽  
Unni Pulliainen ◽  
Liselotte Sundström ◽  
Dalial Freitak
Keyword(s):  
Gene Expression ◽  
Stress Responses ◽  
Specific Gene ◽  
Starvation Resistance ◽  
Specific Expression ◽  
Tissue Specific ◽  
Trade Offs ◽  
Stress Related Genes ◽  
The Individual ◽  
Different Tissues

Starvation is one of the most common and severe stressors in nature. Not only does it lead to death if not alleviated, it also forces the starved individual to allocate resources only to the most essential processes. This creates energetic trade-offs which can lead to many secondary challenges for the individual. These energetic trade-offs could be exacerbated in inbred individuals, which have been suggested to have a less efficient metabolism. Here, we studied the effect of inbreeding on starvation resistance in a natural population of Formica exsecta ants, with a focus on survival and tissue-specific expression of stress, metabolism and immunity-related genes. Starvation led to large tissue-specific changes in gene expression, but inbreeding had little effect on most of the genes studied. Our results illustrate the importance of studying stress responses in different tissues instead of entire organisms.

scholarly journals A non-coding genetic variant maximally associated with serum urate levels is functionally linked to HNF4A-dependent PDZK1 expression

2018 ◽  
Author(s):  
Sarada Ketharnathan ◽  
Megan Leask ◽  
James Boocock ◽  
Amanda J. Phipps-Green ◽  
Jisha Antony ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepg2 Cells ◽  
Molecular Mechanisms ◽  
Genetic Variant ◽  
Fluorescent Protein ◽  
Serum Urate ◽  
Specific Gene ◽  
Specific Expression ◽  
Enhancer Activity ◽  
Tissue Specific

ABSTRACTSeveral dozen genetic variants associate with serum urate levels, but the precise molecular mechanisms by which they affect serum urate are unknown. Here we tested for functional linkage of the maximally-associated genetic variant rs1967017 at the PDZK1 locus to elevated PDZK1 expression.We performed expression quantitative trait locus (eQTL) and likelihood analyses followed by gene expression assays. Zebrafish were used to determine the ability of rs1967017 to direct tissue-specific gene expression. Luciferase assays in HEK293 and HepG2 cells measured the effect of rs1967017 on transcription amplitude.PAINTOR analysis revealed rs1967017 as most likely to be causal and rs1967017 was an eQTL for PDZK1 in the intestine. The region harboring rs1967017 was capable of directly driving green fluorescent protein expression in the kidney, liver and intestine of zebrafish embryos, consistent with a conserved ability to confer tissue-specific expression. The urate-increasing T-allele of rs1967017 strengthens a binding site for the transcription factor HNF4A. siRNA depletion of HNF4A reduced endogenous PDZK1 expression in HepG2 cells. Luciferase assays showed that the T-allele of rs1967017 gains enhancer activity relative to the urate-decreasing C-allele, with T-allele enhancer activity abrogated by HNF4A depletion. HNF4A physically binds the rs1967017 region, suggesting direct transcriptional regulation of PDZK1 by HNF4A.With other reports our data predict that the urate-raising T-allele of rs1967017 enhances HNF4A binding to the PDZK1 promoter, thereby increasing PDZK1 expression. As PDZK1 is a scaffold protein for many ion channel transporters, increased expression can be predicted to increase activity of urate transporters and alter excretion of urate.

scholarly journals Analysis of putative cis-regulatory elements regulating blood pressure variation

2019 ◽  
Author(s):  
Priyanka Nandakumar ◽  
Dongwon Lee ◽  
Thomas J. Hoffmann ◽  
Georg B. Ehret ◽  
Dan Arking ◽  
...  
Keyword(s):  
Gene Expression ◽  
Blood Pressure ◽  
Cell Types ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Genome Wide Association Studies ◽  
Cell Type ◽  
Functional Scores ◽  
Cell Type Specific ◽  
Different Tissues

AbstractHundreds of loci have been associated with blood pressure traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ∼100,000 Genetic Epidemiology Research on Aging (GERA) study participants. In the present study, we subsequently focused on determining putative regulatory regions for these and other tissues of relevance to blood pressure, to both fine-map these loci by pinpointing genes and variants of functional interest within them, and to identify any novel genes.We constructed maps of putative cis-regulatory elements using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Sequence variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. In order to identify genes of interest, we aggregate these variants in these putative cis-regulatory elements within 50Kb of the start or end of genes considered as “expressed” in these tissues or cell types using publicly available gene expression data, and use the deltaSVM scores as weights in the well-known group-wise sequence kernel association test (SKAT). We test for association with both blood pressure traits as well as expression within these tissues or cell types of interest, and identify several genes, including MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B, and PPCDC. Although our study centers on blood pressure traits, we additionally examined two known genes, SCN5A and NOS1AP involved in the cardiac trait QT interval, in the Atherosclerosis Risk in Communities Study (ARIC), as a positive control, and observed an expected heart-specific effect. Thus, our method may be used to identify variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.Author SummarySequence change in genes (“variants”) are linked to the presence and severity of different traits or diseases. However, as genes may be expressed in different tissues and at different times and degrees, using this information is expected to more accurately identify genes of interest. Variants within the genes are essential, but also in the sequences (“regulatory elements”) that control the genes’ expression in different tissues or cell types. In this study, we aim to use this information about expression and variants potentially involved in gene expression regulation to better pinpoint genes and variants in regulatory elements of interest for blood pressure regulation. We do so by taking advantage of such data that are publicly available, and use methods to combine information about variants in aggregate within a gene’s putative regulatory elements in tissues thought to be relevant for blood pressure, and identify several genes, meant to enable experimental follow-up.

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