scholarly journals Epigenomic atlas in wheat reveals regulatory elements specifying sub-genome divergence

2021 ◽  
Author(s):  
Sunil Kumar Kenchanmane Raju
Keyword(s):  
Genetic Diversity ◽  
Regulatory Elements ◽  
Flowering Plant ◽  
Dependent Manner ◽  
Ongoing Research ◽  
Genome Complexity ◽  
Gene Copies ◽  
Modulation Of Gene Expression ◽  
Genome Divergence ◽  
Epigenomic Reprogramming

Abstract Whole-genome duplication or polyploidy is widespread throughout eukaryotes but is most prevalent in flowering plant lineages. The evolutionary processes following polyploidization, such as genome downsizing, biased fractionation, modulation of gene expression, and epigenomic reprogramming, can profoundly affect genome complexity and generate evolutionarily beneficial genetic diversity. Compared to its diploid and tetraploid progenitors, the allohexaploid common wheat (Triticum aestivum, AABBDD) displays remarkable genome plasticity and broader adaptability, attributed in part to the creation of new genetic diversity following allopolyploidy. How gene copies in the three different subgenomes of wheat are regulated and coordinate molecular responses through combinatorial and dosage-dependent manner is a matter of ongoing research.

scholarly journals A gain-of-function single nucleotide variant creates a new promoter which acts as an orientation-dependent enhancer-blocker

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yavor K. Bozhilov ◽  
Damien J. Downes ◽  
Jelena Telenius ◽  
A. Marieke Oudelaar ◽  
Emmanuel N. Olivier ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Diseases ◽  
Regulatory Elements ◽  
Base Change ◽  
Dependent Manner ◽  
Globin Genes ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Super Enhancer ◽  
Single Base Change

AbstractMany single nucleotide variants (SNVs) associated with human traits and genetic diseases are thought to alter the activity of existing regulatory elements. Some SNVs may also create entirely new regulatory elements which change gene expression, but the mechanism by which they do so is largely unknown. Here we show that a single base change in an otherwise unremarkable region of the human α-globin cluster creates an entirely new promoter and an associated unidirectional transcript. This SNV downregulates α-globin expression causing α-thalassaemia. Of note, the new promoter lying between the α-globin genes and their associated super-enhancer disrupts their interaction in an orientation-dependent manner. Together these observations show how both the order and orientation of the fundamental elements of the genome determine patterns of gene expression and support the concept that active genes may act to disrupt enhancer-promoter interactions in mammals as in Drosophila. Finally, these findings should prompt others to fully evaluate SNVs lying outside of known regulatory elements as causing changes in gene expression by creating new regulatory elements.

scholarly journals Influence of Quaternary environmental changes on mole populations inferred from mitochondrial sequences and evolutionary rate estimation

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Azusa Nakamoto ◽  
Masashi Harada ◽  
Reiko Mitsuhashi ◽  
Kimiyuki Tsuchiya ◽  
Alexey P. Kryukov ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Environmental Changes ◽  
Late Quaternary ◽  
Population Expansion ◽  
Rapid Expansion ◽  
Dependent Manner ◽  
Distribution Analysis ◽  
Land Bridge ◽  
Mismatch Distribution Analysis ◽  
Expansion Event

AbstractQuaternary environmental changes fundamentally influenced the genetic diversity of temperate-zone terrestrial animals, including those in the Japanese Archipelago. The genetic diversity of present-day populations is taxon- and region-specific, but its determinants are poorly understood. Here, we analyzed cytochrome b gene (Cytb) sequences (1140 bp) of mitochondrial DNA (mtDNA) to elucidate the factors determining the genetic variation in three species of large moles: Mogera imaizumii and Mogera wogura, which occur in central and southern mainland Japan (Honshu, Shikoku, and Kyushu), and Mogera robusta, which occurs on the nearby Asian continent. Network construction with the Cytb sequences revealed 10 star-shaped clusters with apparent geographic affinity. Mismatch distribution analysis showed that modes of pairwise nucleotide differences (τ values) were grouped into five classes in terms of the level, implying the occurrence of five stages for rapid expansion. It is conceivable that severe cold periods and subsequent warm periods during the late Quaternary were responsible for the population expansion events. The first and third oldest events included island-derived haplotypes, indicative of the involvement of land bridge formation between remote islands, hence suggesting an association of the ends of the penultimate (PGM, ca. 130,000 years ago) and last (LGM, ca. 15,000 years ago) glacial maxima, respectively. Since the third event was followed by the fourth, it is plausible that the termination of the Younger Dryas and subsequent abrupt warming ca. 11,500 years ago facilitated the fourth expansion event. The second event most likely corresponded to early marine isotope stage (MIS) 3 (ca. 53,000 years ago) when the glaciation and subsequent warming period were predicted to have influenced biodiversity. Utilization of the critical times of 130,000, 53,000, 15,000, and 11,500 years ago as calibration points yielded evolutionary rates of 0.03, 0.045, 0.10 and 0.10 substitutions/site/million years, respectively, showing a time-dependent manner whose pattern was similar to that seen in small rodents reported in our previous studies. The age of the fifth expansion event was calculated to be 5800 years ago with a rate of 0.10 substitutions/site/million years ago during the mid-Holocene, suggestive of the influence of humans or other unspecified reasons, such as the Jomon marine transgression.

scholarly journals An integrative transcriptional logic model of hepatic insulin resistance

2021 ◽  
Author(s):  
TAKUMI KITAMOTO ◽  
Taiyi Kuo ◽  
Atsushi Okabe ◽  
Atsushi Kaneda ◽  
Domenico Accili
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Regulatory Elements ◽  
Hepatic Insulin Resistance ◽  
Dependent Manner ◽  
Metabolic Genes ◽  
Target Sites ◽  
Common Pathogenesis ◽  
Glucose Abnormalities

Abnormalities of lipid/lipoprotein and glucose metabolism are hallmarks of hepatic insulin resistance in type 2 diabetes. The former antedate the latter, but the latter become progressively refractory to treatment and contribute to therapeutic failures. It's unclear whether the two processes share a common pathogenesis and what underlies their progressive nature. In this study, we investigated the hypothesis that genes in the lipid/lipoprotein pathway and those in the glucose metabolic pathway are governed by different transcriptional logics that affect their response to physiologic (fasting/refeeding) as well as pathophysiologic cues (insulin resistance and hyperglycemia). To this end, we obtained genomic and transcriptomic maps of the key insulin-regulated transcription factor, FoxO1, and integrated them with those of CREB, PPARα, and glucocorticoid receptor. We found an enrichment of glucose metabolic genes among those regulated by intergenic and promoter enhancers in a fasting-dependent manner, while lipid genes were enriched among fasting-dependent intron enhancers and fasting-independent enhancer-less introns. Glucose genes also showed a remarkable transcriptional resiliency, i.e., an enrichment of active marks at shared PPARα/FoxO1 regulatory elements when FoxO1 was inactivated. Surprisingly, the main features associated with insulin resistance and hyperglycemia were a ″spreading″ of FoxO1 binding to enhancers, and the emergence of target sites unique to this condition. We surmise that this unusual pattern correlates with the progressively intractable nature of hepatic insulin resistance. This transcriptional logic provides an integrated model to interpret the combined lipid and glucose abnormalities of type 2 diabetes.

scholarly journals Cardiac Cell Type-Specific Gene Regulatory Programs and Disease Risk Association

2020 ◽  
Author(s):  
James D. Hocker ◽  
Olivier B. Poirion ◽  
Fugui Zhu ◽  
Justin Buchanan ◽  
Kai Zhang ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Cell Types ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Dependent Manner ◽  
Cardiac Cell ◽  
Risk Variants ◽  
Gene Regulatory

ABSTRACTBackgroundCis-regulatory elements such as enhancers and promoters are crucial for directing gene expression in the human heart. Dysregulation of these elements can result in many cardiovascular diseases that are major leading causes of morbidity and mortality worldwide. In addition, genetic variants associated with cardiovascular disease risk are enriched within cis-regulatory elements. However, the location and activity of these cis-regulatory elements in individual cardiac cell types remains to be fully defined.MethodsWe performed single nucleus ATAC-seq and single nucleus RNA-seq to define a comprehensive catalogue of candidate cis-regulatory elements (cCREs) and gene expression patterns for the distinct cell types comprising each chamber of four non-failing human hearts. We used this catalogue to computationally deconvolute dynamic enhancers in failing hearts and to assign cardiovascular disease risk variants to cCREs in individual cardiac cell types. Finally, we applied reporter assays, genome editing and electrophysiogical measurements in in vitro differentiated human cardiomyocytes to validate the molecular mechanisms of cardiovascular disease risk variants.ResultsWe defined >287,000 candidate cis-regulatory elements (cCREs) in human hearts at single-cell resolution, which notably revealed gene regulatory programs controlling specific cell types in a cardiac region/structure-dependent manner and during heart failure. We further report enrichment of cardiovascular disease risk variants in cCREs of distinct cardiac cell types, including a strong enrichment of atrial fibrillation variants in cardiomyocyte cCREs, and reveal 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Two such risk variants residing within a cardiomyocyte-specific cCRE at the KCNH2/HERG locus resulted in reduced enhancer activity compared to the non-risk allele. Finally, we found that deletion of the cCRE containing these variants decreased KCNH2 expression and prolonged action potential repolarization in an enhancer dosage-dependent manner.ConclusionsThis comprehensive atlas of human cardiac cCREs provides the foundation for not only illuminating cell type-specific gene regulatory programs controlling human hearts during health and disease, but also interpreting genetic risk loci for a wide spectrum of cardiovascular diseases.

scholarly journals Evaluation of Analgesic and Anti-inflammatory Activities of Polyalthia simiarum (Hook. F. &Thomson)

2019 ◽  
Vol 5 (1) ◽  
pp. 18-23
Author(s):  
Selina Kabir ◽  
Ronok Zahan ◽  
Abdullah Mohammad Sarwaruddin Chowdhury ◽  
Choudhury Mahmood Hasan ◽  
Mohammad Abdur Rashid
Keyword(s):  
Acetic Acid ◽  
Analgesic Activity ◽  
Biological Activities ◽  
Dependent Manner ◽  
Paw Edema ◽  
Immersion Method ◽  
Ongoing Research ◽  
Tail Immersion ◽  
Anti Inflammatory ◽  
Dose Dependent

Background: Polyalthia simiarum (Hook. F. &Thomson) exhibits different effects in human body. Objective: As a part of ongoing research on medicinal plants of Bangladesh, the present study is focused to investigate the analgesic and anti-inflammatory activities of stem bark of Polyalthia simiarum (Annonaceae). Methodology: The ethyl acetate (EA) and petroleum ether (PE) extracts were subjected to qualitative chemical investigation for the identification of different phytoconstituents. The analgesic activity was determined for its central and peripheral pharmacological actions using tail immersion method and acetic acid-induced writhing test. The anti-inflammatory activity was evaluated by carrageenan induced paw edema in rats. Analgesic and anti-inflammatory data were evaluated statistically analysed by Dunnett’s-T test. Result: Both extracts at the dose of 50- and 100 mg/kg b.w., produced significant increase in pain threshold in tail immersion method whereas significantly reduced the writhing caused by acetic acid in a dose dependent manner. The EA and PE extracts showed anti-inflammatory activities at 50- and 100 mg/kg body weight. Among all the extracts, the EA extract showed a dose dependent and comparable analgesic activity in all the tested methods and also reduced the paw edema considerably (27.5% and 39.1% inhibition after 4h), in dose dependent manner when compared to carrageenan induced control rat. Conclusion: Therefore, the EA and PE extracts of Polyalthia simiarum were capable to exhibit moderate analgesic and anti-inflammatory activities. This is the first report of analgesic and anti-inflammatory potential of Polyalthia simiarum and can be further investigated to isolate the active compounds responsible for the biological activities. Journal of National Institute of Neurosciences Bangladesh, 2019;5(1): 18-23

scholarly journals Epigenomic landscape of enhancer elements during Hydra head organizer formation

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Puli Chandramouli Reddy ◽  
Akhila Gungi ◽  
Suyog Ubhe ◽  
Sanjeev Galande
Keyword(s):  
Gene Expression ◽  
Wnt Signaling ◽  
Histone Modifications ◽  
Specific Inhibitor ◽  
Regulatory Elements ◽  
The Body ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Chromatin Architecture ◽  
Ectopic Activation

Abstract Background Axis patterning during development is accompanied by large-scale gene expression changes. These are brought about by changes in the histone modifications leading to dynamic alterations in chromatin architecture. The cis regulatory DNA elements also play an important role towards modulating gene expression in a context-dependent manner. Hydra belongs to the phylum Cnidaria where the first asymmetry in the body plan was observed and the oral-aboral axis originated. Wnt signaling has been shown to determine the head organizer function in the basal metazoan Hydra. Results To gain insights into the evolution of cis regulatory elements and associated chromatin signatures, we ectopically activated the Wnt signaling pathway in Hydra and monitored the genome-wide alterations in key histone modifications. Motif analysis of putative intergenic enhancer elements from Hydra revealed the conservation of bilaterian cis regulatory elements that play critical roles in development. Differentially regulated enhancer elements were identified upon ectopic activation of Wnt signaling and found to regulate many head organizer specific genes. Enhancer activity of many of the identified cis regulatory elements was confirmed by luciferase reporter assay. Quantitative chromatin immunoprecipitation analysis upon activation of Wnt signaling further confirmed the enrichment of H3K27ac on the enhancer elements of Hv_Wnt5a, Hv_Wnt11 and head organizer genes Hv_Bra1, CnGsc and Hv_Pitx1. Additionally, perturbation of the putative H3K27me3 eraser activity using a specific inhibitor affected the ectopic activation of Wnt signaling indicating the importance of the dynamic changes in the H3K27 modifications towards regulation of the genes involved in the head organizer activity. Conclusions The activation-associated histone marks H3K4me3, H3K27ac and H3K9ac mark chromatin in a similar manner as seen in bilaterians. We identified intergenic cis regulatory elements which harbor sites for key transcription factors involved in developmental processes. Differentially regulated enhancers exhibited motifs for many zinc-finger, T-box and ETS related TFs whose homologs have a head specific expression in Hydra and could be a part of the pioneer TF network in the patterning of the head. The ability to differentially modify the H3K27 residue is critical for the patterning of Hydra axis revealing a dynamic acetylation/methylation switch to regulate gene expression and chromatin architecture.

scholarly journals UV regulates the expression of phenylpropanoid biosynthesis genes in cucumber (Cucumis sativus L.) in an organ and spectrum dependent manner

2019 ◽  
Vol 18 (2) ◽  
pp. 424-433 ◽  
Author(s):  
Minjie Qian ◽  
Irina Kalbina ◽  
Eva Rosenqvist ◽  
Marcel A. K. Jansen ◽  
Yuanwen Teng ◽  
...  
Keyword(s):  
Cucumis Sativus ◽  
Regulatory Elements ◽  
Dependent Manner ◽  
Cucumis Sativus L ◽  
Phenylpropanoid Biosynthesis ◽  
Enhanced Expression

A combination of a substantial number of cis-acting regulatory elements (MREs, ACEs, and G-boxes) is present in promoters of copies of phenylpropanoid biosynthesis genes that show strongly enhanced expression under UV-B-containing light in Cucumis sativus.

scholarly journals Transposable elements as a potent source of diverse cis -regulatory sequences in mammalian genomes

2020 ◽  
Vol 375 (1795) ◽  
pp. 20190347 ◽  
Author(s):  
Vasavi Sundaram ◽  
Joanna Wysocka
Keyword(s):  
Gene Regulation ◽  
Transposable Elements ◽  
Regulatory Networks ◽  
Regulatory Elements ◽  
Regulatory Function ◽  
Specific Gene ◽  
Regulatory Sequences ◽  
Dependent Manner ◽  
Unique Contribution ◽  
Regulatory Potential

Eukaryotic gene regulation is mediated by cis -regulatory elements, which are embedded within the vast non-coding genomic space and recognized by the transcription factors in a sequence- and context-dependent manner. A large proportion of eukaryotic genomes, including at least half of the human genome, are composed of transposable elements (TEs), which in their ancestral form carried their own cis -regulatory sequences able to exploit the host trans environment to promote TE transcription and facilitate transposition. Although not all present-day TE copies have retained this regulatory function, the preexisting regulatory potential of TEs can provide a rich source of cis -regulatory innovation for the host. Here, we review recent evidence documenting diverse contributions of TE sequences to gene regulation by functioning as enhancers, promoters, silencers and boundary elements. We discuss how TE-derived enhancer sequences can rapidly facilitate changes in existing gene regulatory networks and mediate species- and cell-type-specific regulatory innovations, and we postulate a unique contribution of TEs to species-specific gene expression divergence in pluripotency and early embryogenesis. With advances in genome-wide technologies and analyses, systematic investigation of TEs' cis -regulatory potential is now possible and our understanding of the biological impact of genomic TEs is increasing. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.

scholarly journals Towards a reference genome that captures global genetic diversity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Karen H. Y. Wong ◽  
Walfred Ma ◽  
Chun-Yu Wei ◽  
Erh-Chan Yeh ◽  
Wan-Jia Lin ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Reference Genome ◽  
Regulatory Elements ◽  
Human Populations ◽  
Single Individual ◽  
Rna Seq ◽  
Human Reference Genome ◽  
Reference Sequences ◽  
Genome Annotations ◽  
Unmapped Reads

Abstract The current human reference genome is predominantly derived from a single individual and it does not adequately reflect human genetic diversity. Here, we analyze 338 high-quality human assemblies of genetically divergent human populations to identify missing sequences in the human reference genome with breakpoint resolution. We identify 127,727 recurrent non-reference unique insertions spanning 18,048,877 bp, some of which disrupt exons and known regulatory elements. To improve genome annotations, we linearly integrate these sequences into the chromosomal assemblies and construct a Human Diversity Reference. Leveraging this reference, an average of 402,573 previously unmapped reads can be recovered for a given genome sequenced to ~40X coverage. Transcriptomic diversity among these non-reference sequences can also be directly assessed. We successfully map tens of thousands of previously discarded RNA-Seq reads to this reference and identify transcription evidence in 4781 gene loci, underlining the importance of these non-reference sequences in functional genomics. Our extensive datasets are important advances toward a comprehensive reference representation of global human genetic diversity.

scholarly journals Convergent evolution of caffeine in plants by co-option of exapted ancestral enzymes

2016 ◽  
Vol 113 (38) ◽  
pp. 10613-10618 ◽  
Author(s):  
Ruiqi Huang ◽  
Andrew J. O’Donnell ◽  
Jessica J. Barboline ◽  
Todd J. Barkman
Keyword(s):  
Genetic Diversity ◽  
Plant Defense ◽  
Plant Species ◽  
Convergent Evolution ◽  
Flowering Plant ◽  
Phylogenetic Relatedness ◽  
Future Studies ◽  
Biochemical Pathways ◽  
Caffeine Synthase ◽  
Caffeine Biosynthesis

Convergent evolution is a process that has occurred throughout the tree of life, but the historical genetic and biochemical context promoting the repeated independent origins of a trait is rarely understood. The well-known stimulant caffeine, and its xanthine alkaloid precursors, has evolved multiple times in flowering plant history for various roles in plant defense and pollination. We have shown that convergent caffeine production, surprisingly, has evolved by two previously unknown biochemical pathways in chocolate, citrus, and guaraná plants using either caffeine synthase- or xanthine methyltransferase-like enzymes. However, the pathway and enzyme lineage used by any given plant species is not predictable from phylogenetic relatedness alone. Ancestral sequence resurrection reveals that this convergence was facilitated by co-option of genes maintained over 100 million y for alternative biochemical roles. The ancient enzymes of the Citrus lineage were exapted for reactions currently used for various steps of caffeine biosynthesis and required very few mutations to acquire modern-day enzymatic characteristics, allowing for the evolution of a complete pathway. Future studies aimed at manipulating caffeine content of plants will require the use of different approaches given the metabolic and genetic diversity revealed by this study.

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