scholarly journals Ancestral and derived transcriptional enhancers share regulatory sequence and a pleiotropic site affecting chromatin accessibility

2020 ◽  
Vol 117 (34) ◽  
pp. 20636-20644 ◽  
Author(s):  
Yaqun Xin ◽  
Yann Le Poul ◽  
Liucong Ling ◽  
Mariam Museridze ◽  
Bettina Mühling ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Regulatory Region ◽  
Gene Expression Pattern ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Regulatory Sequence ◽  
The Novel ◽  
Regulatory Activity ◽  
Dna Accessibility ◽  
Multicellular Organisms

The diversity of forms in multicellular organisms originates largely from the spatial redeployment of developmental genes [S. B. Carroll,Cell134, 25–36 (2008)]. Several scenarios can explain the emergence ofcis-regulatory elements that govern novel aspects of a gene expression pattern [M. Rebeiz, M. Tsiantis,Curr. Opin. Genet. Dev.45, 115–123 (2017)]. One scenario, enhancer co-option, holds that a DNA sequence producing an ancestral regulatory activity also becomes the template for a new regulatory activity, sharing regulatory information. While enhancer co-option might fuel morphological diversification, it has rarely been documented [W. J. Glassford et al.,Dev. Cell34, 520–531 (2015)]. Moreover, if two regulatory activities are borne from the same sequence, their modularity, considered a defining feature of enhancers [J. Banerji, L. Olson, W. Schaffner,Cell33, 729–740 (1983)], might be affected by pleiotropy. Sequence overlap may thereby play a determinant role in enhancer function and evolution. Here, we investigated this problem with two regulatory activities of theDrosophilageneyellow, the novelspotenhancer and the ancestralwing bladeenhancer. We used precise and comprehensive quantification of each activity inDrosophilawings to systematically map their sequences along the locus. We show that thespotenhancer has co-opted the sequences of thewing bladeenhancer. We also identified a pleiotropic site necessary for DNA accessibility of a shared regulatory region. While the evolutionary steps leading to the derived activity are still unknown, such pleiotropy suggests that enhancer accessibility could be one of the molecular mechanisms seeding evolutionary co-option.

scholarly journals Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Karolina Stępniak ◽  
Magdalena A. Machnicka ◽  
Jakub Mieczkowski ◽  
Anna Macioszek ◽  
Bartosz Wojtaś ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Molecular Mechanisms ◽  
Genome Mapping ◽  
Malignant Gliomas ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Multiple Tumor ◽  
Genes Encoding ◽  
Methylation Patterns

AbstractChromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.

scholarly journals Transcription of the Human 5-Hydroxytryptamine Receptor 2B (HTR2B) Gene Is under the Regulatory Influence of the Transcription Factors NFI and RUNX1 in Human Uveal Melanoma

2018 ◽  
Vol 19 (10) ◽  
pp. 3272 ◽  
Author(s):  
Manel Benhassine ◽  
Sylvain Guérin
Keyword(s):  
Transcription Factors ◽  
Uveal Melanoma ◽  
Serotonin Receptor ◽  
Molecular Mechanisms ◽  
Regulatory Region ◽  
Gene Signature ◽  
Regulatory Elements ◽  
Gene Encoding ◽  
Aberrant Expression ◽  
Factor I

Because it accounts for 70% of all eye cancers, uveal melanoma (UM) is therefore the most common primary ocular malignancy. In this study, we investigated the molecular mechanisms leading to the aberrant expression of the gene encoding the serotonin receptor 2B (HTR2B), one of the most discriminating among the candidates from the class II gene signature, in metastatic and non-metastatic UM cell lines. Transfection analyses revealed that the upstream regulatory region of the HTR2B gene contains a combination of alternative positive and negative regulatory elements functional in HTR2B− but not in HTR23B+ UM cells. We demonstrated that both the transcription factors nuclear factor I (NFI) and Runt-related transcription factor I (RUNX1) interact with regulatory elements from the HTR2B gene to either activate (NFI) or repress (RUNX1) HTR2B expression in UM cells. The results of this study will help understand better the molecular mechanisms accounting for the abnormal expression of the HTR2B gene in uveal melanoma.

scholarly journals Quantitative dissection of transcription in development yields evidence for transcription factor-driven chromatin accessibility

2020 ◽  
Author(s):  
Elizabeth Eck ◽  
Jonathan Liu ◽  
Maryam Kazemzadeh-Atoufi ◽  
Sydney Ghoreishi ◽  
Shelby Blythe ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Predictive Power ◽  
Molecular Mechanisms ◽  
Thermal Fluctuations ◽  
Chromatin Accessibility ◽  
Dna Accessibility ◽  
Transcriptional Regulatory ◽  
Regulatory Dynamics ◽  
Predictive Understanding ◽  
Developmental Decision

AbstractThermodynamic models of gene regulation can predict transcriptional regulation in bacteria, but in eukaryotes chromatin accessibility and energy expenditure may call for a different framework. Here we systematically tested the predictive power of models of DNA accessibility based on the Monod-Wyman-Changeux (MWC) model of allostery, which posits that chromatin fluctuates between accessible and inaccessible states. We dissected the regulatory dynamics of hunchback by the activator Bicoid and the pioneer-like transcription factor Zelda in living Drosophila embryos and showed that no thermodynamic or non-equilibrium MWC model can recapitulate hunchback transcription. Therefore, we explored a model where DNA accessibility is not the result of thermal fluctuations but is catalyzed by Bicoid and Zelda, possibly through histone acetylation, and found that this model can predict hunchback dynamics. Thus, our theory-experiment dialogue uncovered potential molecular mechanisms of transcriptional regulatory dynamics, a key step toward reaching a predictive understanding of developmental decision-making.

scholarly journals Chromatin accessibility analysis uncovers regulatory element landscape in prostate cancer progression

2020 ◽  
Author(s):  
Joonas Uusi-Mäkelä ◽  
Ebrahim Afyounian ◽  
Francesco Tabaro ◽  
Tomi Häkkinen ◽  
Alessandro Lussana ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cancer Progression ◽  
Regulatory Element ◽  
Regulatory Region ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Prostate Cancer Progression ◽  
Accessibility Analysis ◽  
A Genome

AbstractAberrant oncogene functions and structural variation alter the chromatin structure in cancer cells. While gene regulation by chromatin states has been studied extensively, chromatin accessibility and its relevance in aberrant gene expression during prostate cancer progression is not well understood. Here, we report a genome-wide chromatin accessibility analysis of clinical tissue samples of benign prostatic hyperplasia (BPH), untreated primary prostate cancer (PC) and castration-resistant prostate cancer (CRPC) and integrative analysis with transcriptome, methylome, and proteome profiles of the same samples to uncover disease-relevant regulatory elements and their association to altered gene expression during prostate cancer progression. While promoter accessibility is consistent during disease initiation and progression, at distal sites chromatin accessibility is variable enabling transcription factors (TFs) binding patterns that are differently activated in different patients and disease stages. We identify consistent progression-related chromatin alterations during the progression to CRPC. By studying the TF binding patterns, we demonstrate the activation and suppression of androgen receptor-driven regulatory programs during PC progression and identify complementary TF regulatory modules characterized by e.g. MYC and glucocorticoid receptor. By correlation analysis we assign at least one putative regulatory region for 62% of genes and 85% of proteins differentially expressed during prostate cancer progression. Taken together, our analysis of the chromatin landscape in PC identifies putative regulatory elements for the majority of cancer-associated genes and characterizes their impact on the cancer phenotype.

Control of segmental expression of the cardiac-restricted ankyrin repeat protein gene by distinct regulatory pathways in murine cardiogenesis

Development ◽  
1999 ◽  
Vol 126 (19) ◽  
pp. 4223-4234 ◽  
Author(s):  
H. Kuo ◽  
J. Chen ◽  
P. Ruiz-Lozano ◽  
Y. Zou ◽  
M. Nemer ◽  
...  
Keyword(s):  
Transgene Expression ◽  
Molecular Mechanisms ◽  
Regulatory Region ◽  
Regulatory Elements ◽  
Ankyrin Repeat ◽  
Specific Marker ◽  
Sequence Element ◽  
Regulatory Pathways ◽  
Repeat Protein ◽  
Ankyrin Repeat Protein

Although accumulating evidence suggests that the heart develops in a segmental fashion, the molecular mechanisms that control regional specification of cardiomyocytes in the developing heart remain largely unknown. In this study, we have used the mouse cardiac-restricted ankyrin repeat protein (CARP) gene as a model system to study these mechanisms. The CARP gene encodes a nuclear co-regulator for cardiac gene expression, which lies downstream of the cardiac homeobox gene, Nkx 2.5, and is an early marker of the cardiac muscle cell lineage. We have demonstrated that the expression of the gene is developmentally down regulated and dramatically induced as part of the embryonic gene program during cardiac hypertrophy. Using a lacZ/knock-in mouse and three lines of transgenic mouse harboring various CARP promoter/lacZ reporters, we have identified distinct 5′ cis regulatory elements of the gene that can direct heart segment-specific transgene expression, such as atrial versus ventricular and left versus right. Most interestingly, a 213 base pair sequence element of the gene was found to confer conotruncal segment-specific transgene expression. Using the transgene as a conotruncal segment-specific marker, we were able to document the developmental fate of a subset of cardiomyocytes in the conotruncus during cardiogenesis. In addition, we have identified an essential GATA-4 binding site in the proximal upstream regulatory region of the gene and cooperative transcriptional regulation mediated by Nkx2.5 and GATA-4. We have shown that this cooperative regulation is dependent on binding of GATA-4 to its cognate DNA sequence in the promoter, which suggests that Nkx2.5 controls CARP expression, at least in part, through GATA-4.

scholarly journals Deep learning of immune cell differentiation

2020 ◽  
Vol 117 (41) ◽  
pp. 25655-25666 ◽  
Author(s):  
Alexandra Maslova ◽  
Ricardo N. Ramirez ◽  
Ke Ma ◽  
Hugo Schmutz ◽  
Chendi Wang ◽  
...  
Keyword(s):  
Deep Learning ◽  
Cell Differentiation ◽  
Dna Sequences ◽  
Immune Cell ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Regulatory Sequence ◽  
B Lineage ◽  
Additional Support

Although we know many sequence-specific transcription factors (TFs), how the DNA sequence of cis-regulatory elements is decoded and orchestrated on the genome scale to determine immune cell differentiation is beyond our grasp. Leveraging a granular atlas of chromatin accessibility across 81 immune cell types, we asked if a convolutional neural network (CNN) could learn to infer cell type-specific chromatin accessibility solely from regulatory DNA sequences. With a tailored architecture and an ensemble approach to CNN parameter interpretation, we show that our trained network (“AI-TAC”) does so by rediscovering ab initio the binding motifs for known regulators and some unknown ones. Motifs whose importance is learned virtually as functionally important overlap strikingly well with positions determined by chromatin immunoprecipitation for several TFs. AI-TAC establishes a hierarchy of TFs and their interactions that drives lineage specification and also identifies stage-specific interactions, like Pax5/Ebf1 vs. Pax5/Prdm1, or the role of different NF-κB dimers in different cell types. AI-TAC assigns Spi1/Cebp and Pax5/Ebf1 as the drivers necessary for myeloid and B lineage fates, respectively, but no factors seemed as dominantly required for T cell differentiation, which may represent a fall-back pathway. Mouse-trained AI-TAC can parse human DNA, revealing a strikingly similar ranking of influential TFs and providing additional support that AI-TAC is a generalizable regulatory sequence decoder. Thus, deep learning can reveal the regulatory syntax predictive of the full differentiative complexity of the immune system.

scholarly journals A reference map of murine cardiac transcription factor chromatin occupancy identifies dynamic and conserved enhancers

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Brynn N. Akerberg ◽  
Fei Gu ◽  
Nathan J. VanDusen ◽  
Xiaoran Zhang ◽  
Rui Dong ◽  
...  
Keyword(s):  
Heart Development ◽  
Molecular Mechanisms ◽  
Developmental Stages ◽  
Transcriptional Regulatory Network ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Mouse Heart ◽  
Transcriptional Enhancer ◽  
Enhancer Activity

Abstract Mapping the chromatin occupancy of transcription factors (TFs) is a key step in deciphering developmental transcriptional programs. Here we use biotinylated knockin alleles of seven key cardiac TFs (GATA4, NKX2-5, MEF2A, MEF2C, SRF, TBX5, TEAD1) to sensitively and reproducibly map their genome-wide occupancy in the fetal and adult mouse heart. These maps show that TF occupancy is dynamic between developmental stages and that multiple TFs often collaboratively occupy the same chromatin region through indirect cooperativity. Multi-TF regions exhibit features of functional regulatory elements, including evolutionary conservation, chromatin accessibility, and activity in transcriptional enhancer assays. H3K27ac, a feature of many enhancers, incompletely overlaps multi-TF regions, and multi-TF regions lacking H3K27ac retain conservation and enhancer activity. TEAD1 is a core component of the cardiac transcriptional network, co-occupying cardiac regulatory regions and controlling cardiomyocyte-specific gene functions. Our study provides a resource for deciphering the cardiac transcriptional regulatory network and gaining insights into the molecular mechanisms governing heart development.

scholarly journals Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jessica L. Haigh ◽  
Anna Adhikari ◽  
Nycole A. Copping ◽  
Tyler Stradleigh ◽  
A. Ayanna Wade ◽  
...  
Keyword(s):  
Regulatory Element ◽  
Transcriptional Start Site ◽  
Regulatory Region ◽  
Regulatory Elements ◽  
Dravet Syndrome ◽  
Regulatory Sequence ◽  
Functional Requirements ◽  
Transgenic Mouse Line ◽  
Gene And Protein Expression ◽  
Promoter Mutations

Abstract Background Genes with multiple co-active promoters appear common in brain, yet little is known about functional requirements for these potentially redundant genomic regulatory elements. SCN1A, which encodes the NaV1.1 sodium channel alpha subunit, is one such gene with two co-active promoters. Mutations in SCN1A are associated with epilepsy, including Dravet syndrome (DS). The majority of DS patients harbor coding mutations causing SCN1A haploinsufficiency; however, putative causal non-coding promoter mutations have been identified. Methods To determine the functional role of one of these potentially redundant Scn1a promoters, we focused on the non-coding Scn1a 1b regulatory region, previously described as a non-canonical alternative transcriptional start site. We generated a transgenic mouse line with deletion of the extended evolutionarily conserved 1b non-coding interval and characterized changes in gene and protein expression, and assessed seizure activity and alterations in behavior. Results Mice harboring a deletion of the 1b non-coding interval exhibited surprisingly severe reductions of Scn1a and NaV1.1 expression throughout the brain. This was accompanied by electroencephalographic and thermal-evoked seizures, and behavioral deficits. Conclusions This work contributes to functional dissection of the regulatory wiring of a major epilepsy risk gene, SCN1A. We identified the 1b region as a critical disease-relevant regulatory element and provide evidence that non-canonical and seemingly redundant promoters can have essential function.

scholarly journals Epigenetic reprogramming rewires transcription during the alternation of generations in Arabidopsis

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Michael Borg ◽  
Ranjith K Papareddy ◽  
Rodolphe Dombey ◽  
Elin Axelsson ◽  
Michael D Nodine ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Life Form ◽  
Regulatory Elements ◽  
Life Forms ◽  
Chromatin Accessibility ◽  
Life Cycles ◽  
Dna Demethylation ◽  
Epigenetic Reprogramming ◽  
Dynamic Relationship ◽  
Alternation Of Generations

Alternation between morphologically distinct haploid and diploid life forms is a defining feature of most plant and algal life cycles, yet the underlying molecular mechanisms that govern these transitions remain unclear. Here, we explore the dynamic relationship between chromatin accessibility and epigenetic modifications during life form transitions in Arabidopsis. The diploid-to-haploid life form transition is governed by the loss of H3K9me2 and DNA demethylation of transposon-associated cis-regulatory elements. This event is associated with dramatic changes in chromatin accessibility and transcriptional reprogramming. In contrast, the global loss of H3K27me3 in the haploid form shapes a chromatin accessibility landscape that is poised to re-initiate the transition back to diploid life after fertilization. Hence, distinct epigenetic reprogramming events rewire transcription through major reorganization of the regulatory epigenome to guide the alternation of generations in flowering plants.

scholarly journals The development of reporter system for the investigation of molecular mechanisms of ecdysone response

2019 ◽  
Vol 485 (4) ◽  
pp. 515-518
Author(s):  
M. Yu. Mazina ◽  
A. N. Krasnov ◽  
P. G. Georgiev ◽  
N. E. Vorobyeva
Keyword(s):  
Transcriptional Regulation ◽  
Molecular Mechanisms ◽  
Fluorescent Protein ◽  
Regulatory Region ◽  
Regulatory Elements ◽  
Reporter System ◽  
Genetic Construct ◽  
Genome Wide ◽  
Early Late

To study the mechanisms of transcriptional regulation, a convenient experimental approach is to use the artificial chimeric constructs, carrying the regulatory elements of interest. In the present work, we describe the creation and characterization of a novel genetic construct, which makes possible to study the transcriptional regulation of the early-late gene of the ecdysone cascade. Using the data of genome-wide experiments, we have isolated the main regulatory region of the hr4 gene, which was successfully used to create a chimeric reporter construct expressing a fluorescent protein upon the treatment with the ecdysone hormone. This reporter system can be used to study the mechanisms of the ecdysone response, both in cell culture and in tissues, at various stages of the Drosophila development.

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