scholarly journals Chromatin accessibility and histone acetylation in the regulation of competence in early development

2019 ◽  
Author(s):  
Melody Esmaeili ◽  
Shelby A. Blythe ◽  
John W. Tobias ◽  
Kai Zhang ◽  
Jing Yang ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Neural Crest ◽  
Target Genes ◽  
Gene Activation ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Histone Deacetylase Inhibition ◽  
Inductive Signals

AbstractAs development proceeds, inductive cues are interpreted by competent tissues in a spatially and temporally restricted manner. While key inductive signaling pathways within competent cells are well-described at a molecular level, the mechanisms by which tissues lose responsiveness to inductive signals are not well understood. Localized activation of Wnt signaling before zygotic gene activation in Xenopus laevis leads to dorsal development, but competence to induce dorsal genes in response to Wnts is lost by the late blastula stage. We hypothesize that loss of competence is mediated by changes in histone modifications leading to a loss of chromatin accessibility at the promoters of Wnt target genes. We use ATAC-seq to evaluate genome-wide changes in chromatin accessibility across several developmental stages. Based on overlap with p300 binding, we identify thousands of putative cis-regulatory elements at the gastrula stage, including sites that lose accessibility by the end of gastrulation and are enriched for pluripotency factor binding motifs. Dorsal Wnt target gene promoters are not accessible after the loss of competence in the early gastrula while genes involved in mesoderm and neural crest development maintain accessibility at their promoters. Inhibition of histone deacetylases increases acetylation at the promoters of dorsal Wnt target genes and extends competence for dorsal gene induction by Wnt signaling. Histone deacetylase inhibition, however, is not sufficient to extend competence for mesoderm or neural crest induction. These data suggest that chromatin state regulates the loss of competence to inductive signals in a context-dependent manner.

Androgen receptor: acting in the three-dimensional chromatin landscape of prostate cancer cells

2011 ◽  
Vol 5 (1) ◽  
Author(s):  
Harri Makkonen ◽  
Jorma J. Palvimo
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Binding Sites ◽  
Target Genes ◽  
Three Dimensional ◽  
Regulatory Elements ◽  
Gene Promoters ◽  
Loop Formation ◽  
Prostate Cancer Cells

AbstractAndrogen receptor (AR) acts as a hormone-controlled transcription factor that conveys the messages of both natural and synthetic androgens to the level of genes and gene programs. Defective AR signaling leads to a wide array of androgen insensitivity disorders, and deregulated AR function, in particular overexpression of AR, is involved in the growth and progression of prostate cancer. Classic models of AR action view AR-binding sites as upstream regulatory elements in gene promoters or their proximity. However, recent wider genomic screens indicate that AR target genes are commonly activated through very distal chromatin-binding sites. This highlights the importance of long-range chromatin regulation of transcription by the AR, shifting the focus from the linear gene models to three-dimensional models of AR target genes and gene programs. The capability of AR to regulate promoters from long distances in the chromatin is particularly important when evaluating the role of AR in the regulation of genes in malignant prostate cells that frequently show striking genomic aberrations, especially gene fusions. Therefore, in addition to the mechanisms of DNA loop formation between the enhancer bound ARs and the transcription apparatus at the target core promoter, the mechanisms insulating distally bound ARs from promiscuously making contacts and activating other than their normal target gene promoters are critical for proper physiological regulation and thus currently under intense investigation. This review discusses the current knowledge about the AR action in the context of gene aberrations and the three-dimensional chromatin landscape of prostate cancer cells.

scholarly journals ASC proneural transcription factors mediate the timely initiation of the neural program during neuroectodermal to neuroblast transition ensuring progeny fidelity

2021 ◽  
Author(s):  
Vasiliki Theodorou ◽  
Aikaterini Stefanaki ◽  
Minas Drakos ◽  
Dafne Triantafyllou ◽  
Christos Delidakis
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Cis Elements ◽  
Enhancer Activity ◽  
Timely Initiation ◽  
Chromatin Dynamics ◽  
Neural Fate ◽  
Neural Specification

Background: ASC/ASCL proneural transcription factors are oncogenic and exhibit impressive reprogramming and pioneer activities. In both Drosophila and mammals, these factors are central in the early specification of the neural fate, where they act in opposition to Notch signalling. However, the role of ASC on the chromatin during CNS neural stem cells birth remains elusive. Results: We investigated the chromatin changes accompanying neural commitment using an integrative genetics and genomics methodology. We found that ASC factors bind equally strongly to two distinct classes of cis-regulatory elements: open regions remodeled earlier during maternal to zygotic transition by Zelda and Zelda-independent, less accessible regions. Both classes cis-elements exhibit enhanced chromatin accessibility during neural specification and correlate with transcriptional regulation of genes involved in many biological processes necessary for neuroblast function. We identified an ASC-Notch regulated TF network that most likely act as the prime regulators of neuroblast function. Using a cohort of ASC target genes, we report that ASC null neuroblasts are defectively specified, remaining initially stalled, lacking expression of many proneural targets and unable to divide. When they eventually start proliferating, they produce compromised progeny. Generation of lacZ reporter lines driven by proneural-bound elements display enhancer activity within neuroblasts and proneural dependency. Therefore, the partial neuroblast identity seen in the absence of ASC genes is driven by other, proneural-independent, cis-elements. Neuroblast impairment and the late differentiation defects of ASC mutants are corrected by ectodermal induction of individual ASC genes but not by individual members of the TF network downstream of ASC. However, in wild type embryos induction of individual members of this network induces CNS hyperplasia, suggesting that they synergize with the activating function of ASC to establish the chromatin dynamics that promote neural specification. Conclusion: ASC factors bind a large number of enhancers to orchestrate the timely activation of the neural chromatin program during neuroectodermal to neuroblast transition. This early chromatin remodeling is crucial for both neuroblast homeostasis as well as future progeny fidelity.

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 Integrative transcriptome and chromatin landscape analysis reveals distinct epigenetic regulations in human memory B cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Justin B. Moroney ◽  
Anusha Vasudev ◽  
Alexander Pertsemlidis ◽  
Hong Zan ◽  
Paolo Casali
Keyword(s):  
B Cells ◽  
Target Genes ◽  
Human Memory ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Memory B Cells ◽  
Transcriptional Signature ◽  
Integrative Analyses ◽  
Health And Disease ◽  
Variable Gene

Abstract Memory B cells (MBCs) are long-lived and produce high-affinity, generally, class-switched antibodies. Here, we use a multiparameter approach involving CD27 to segregate naïve B cells (NBC), IgD+ unswitched (unsw)MBCs and IgG+ or IgA+ class-switched (sw)MBCs from humans of different age, sex and race. Conserved antibody variable gene expression indicates that MBCs emerge through unbiased selection from NBCs. Integrative analyses of mRNAs, miRNAs, lncRNAs, chromatin accessibility and cis-regulatory elements uncover a core mRNA-ncRNA transcriptional signature shared by IgG+ and IgA+ swMBCs and distinct from NBCs, while unswMBCs display a transitional transcriptome. Some swMBC transcriptional signature loci are accessible but not expressed in NBCs. Profiling miRNAs reveals downregulated MIR181, and concomitantly upregulated MIR181 target genes such as RASSF6, TOX, TRERF1, TRPV3 and RORα, in swMBCs. Finally, lncRNAs differentially expressed in swMBCs cluster proximal to the IgH chain locus on chromosome 14. Our findings thus provide new insights into MBC transcriptional programs and epigenetic regulation, opening new investigative avenues on these critical cell elements in human health and disease.

scholarly journals CDK-Mediator and FBXL19 prime developmental genes for activation by promoting atypical regulatory interactions

2020 ◽  
Vol 48 (6) ◽  
pp. 2942-2955 ◽  
Author(s):  
Angelika Feldmann ◽  
Emilia Dimitrova ◽  
Alexander Kenney ◽  
Anna Lastuvkova ◽  
Robert J Klose
Keyword(s):  
Cpg Island ◽  
Gene Activation ◽  
Embryonic Stem ◽  
Regulatory Elements ◽  
Gene Induction ◽  
Gene Promoters ◽  
Developmental Gene ◽  
Gene Regulatory Elements ◽  
Gene Regulatory ◽  
Distal Regulatory Elements

Abstract Appropriate developmental gene regulation relies on the capacity of gene promoters to integrate inputs from distal regulatory elements, yet how this is achieved remains poorly understood. In embryonic stem cells (ESCs), a subset of silent developmental gene promoters are primed for activation by FBXL19, a CpG island binding protein, through its capacity to recruit CDK-Mediator. How mechanistically these proteins function together to prime genes for activation during differentiation is unknown. Here we discover that in mouse ESCs FBXL19 and CDK-Mediator support long-range interactions between silent gene promoters that rely on FBXL19 for their induction during differentiation and gene regulatory elements. During gene induction, these distal regulatory elements behave in an atypical manner, in that the majority do not acquire histone H3 lysine 27 acetylation and no longer interact with their target gene promoter following gene activation. Despite these atypical features, we demonstrate by targeted deletions that these distal elements are required for appropriate gene induction during differentiation. Together these discoveries demonstrate that CpG-island associated gene promoters can prime genes for activation by communicating with atypical distal gene regulatory elements to achieve appropriate gene expression.

scholarly journals Hepatocyte nuclear factor 1β suppresses canonical Wnt signaling through transcriptional repression of lymphoid enhancer–binding factor 1

2020 ◽  
Vol 295 (51) ◽  
pp. 17560-17572
Author(s):  
Siu Chiu Chan ◽  
Sachin S. Hajarnis ◽  
Sophia M. Vrba ◽  
Vishal Patel ◽  
Peter Igarashi
Keyword(s):  
Wnt Signaling ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Regulatory Elements ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Canonical Wnt Signaling ◽  
H3k27 Trimethylation ◽  
Binding Factor ◽  
Canonical Wnt

Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1β produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells results in activation of β-catenin and increased expression of lymphoid enhancer–binding factor 1 (LEF1), a downstream effector in the canonical Wnt signaling pathway. Increased expression and nuclear localization of LEF1 are also observed in cystic kidneys from Hnf1b mutant mice. Expression of dominant-negative mutant HNF-1β in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. WT HNF-1β binds to two evolutionarily conserved sites located 94 and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1β decreases H3K27 trimethylation repressive marks and increases β-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, WT HNF-1β recruits the polycomb-repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the β-catenin–binding domain of LEF1 in HNF-1β–deficient cells abolishes the increase in Lef1 transcription and decreases the expression of downstream Wnt target genes. The canonical Wnt target gene, Axin2, is also a direct transcriptional target of HNF-1β through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1β regulates canonical Wnt target genes through long-range effects on histone methylation at Wnt enhancers and reveal a new mode of active transcriptional repression by HNF-1β.

scholarly journals Modeling gene regulation from paired expression and chromatin accessibility data

2017 ◽  
Vol 114 (25) ◽  
pp. E4914-E4923 ◽  
Author(s):  
Zhana Duren ◽  
Xi Chen ◽  
Rui Jiang ◽  
Yong Wang ◽  
Wing Hung Wong
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Transcriptional Regulatory Network ◽  
Joint Modeling ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Exciting Opportunity ◽  
Transcriptional Regulatory ◽  
Dna Elements ◽  
Context Specific

The rapid increase of genome-wide datasets on gene expression, chromatin states, and transcription factor (TF) binding locations offers an exciting opportunity to interpret the information encoded in genomes and epigenomes. This task can be challenging as it requires joint modeling of context-specific activation of cis-regulatory elements (REs) and the effects on transcription of associated regulatory factors. To meet this challenge, we propose a statistical approach based on paired expression and chromatin accessibility (PECA) data across diverse cellular contexts. In our approach, we model (i) the localization to REs of chromatin regulators (CRs) based on their interaction with sequence-specific TFs, (ii) the activation of REs due to CRs that are localized to them, and (iii) the effect of TFs bound to activated REs on the transcription of target genes (TGs). The transcriptional regulatory network inferred by PECA provides a detailed view of how trans- and cis-regulatory elements work together to affect gene expression in a context-specific manner. We illustrate the feasibility of this approach by analyzing paired expression and accessibility data from the mouse Encyclopedia of DNA Elements (ENCODE) and explore various applications of the resulting model.

scholarly journals Promyelocytic Leukemia Protein Isoform II Promotes Transcription Factor Recruitment To Activate Interferon Beta and Interferon-Responsive Gene Expression

2015 ◽  
Vol 35 (10) ◽  
pp. 1660-1672 ◽  
Author(s):  
Yixiang Chen ◽  
Jordan Wright ◽  
Xueqiong Meng ◽  
Keith N. Leppard
Keyword(s):  
Target Genes ◽  
Gene Activation ◽  
Promyelocytic Leukemia ◽  
Type I ◽  
Gene Promoters ◽  
Creb Binding Protein ◽  
Terminal Domain ◽  
Efficient Induction ◽  
Transcription Complexes ◽  
Transcriptional Complex

To trigger type I interferon (IFN) responses, pattern recognition receptors activate signaling cascades that lead to transcription of IFN and IFN-stimulated genes (ISGs). The promyelocytic leukemia (PML) protein has been implicated in these responses, although its role has not been defined. Here, we show that PML isoform II (PML-II) is specifically required for efficient induction of IFN-β transcription and of numerous ISGs, acting at the point of transcriptional complex assembly on target gene promoters. PML-II associated with specific transcription factors NF-κB and STAT1, as well as the coactivator CREB-binding protein (CBP), to facilitate transcriptional complex formation. The absence of PML-II substantially reduced binding of these factors and IFN regulatory factor 3 (IRF3) to IFN-β or ISGs promoters and sharply reduced gene activation. The unique C-terminal domain of PML-II was essential for its activity, while the N-terminal RBCC motif common to all PML isoforms was dispensable. We propose a model in which PML-II contributes to the transcription of multiple genes via the association of its C-terminal domain with relevant transcription complexes, which promotes the stable assembly of these complexes at promoters/enhancers of target genes, and that in this way PML-II plays a significant role in the development of type I IFN responses.

scholarly journals Chromatin accessibility and regulatory vocabulary across indicine cattle tissues

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Pâmela A. Alexandre ◽  
Marina Naval-Sánchez ◽  
Moira Menzies ◽  
Loan T. Nguyen ◽  
Laercio R. Porto-Neto ◽  
...  
Keyword(s):  
Motif Discovery ◽  
Target Genes ◽  
Developmental Stages ◽  
Bos Taurus ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Model Organisms ◽  
Open Chromatin ◽  
Health And Disease ◽  
Collaborative Efforts

Abstract Background Spatiotemporal changes in the chromatin accessibility landscape are essential to cell differentiation, development, health, and disease. The quest of identifying regulatory elements in open chromatin regions across different tissues and developmental stages is led by large international collaborative efforts mostly focusing on model organisms, such as ENCODE. Recently, the Functional Annotation of Animal Genomes (FAANG) has been established to unravel the regulatory elements in non-model organisms, including cattle. Now, we can transition from prediction to validation by experimentally identifying the regulatory elements in tropical indicine cattle. The identification of regulatory elements, their annotation and comparison with the taurine counterpart, holds high promise to link regulatory regions to adaptability traits and improve animal productivity and welfare. Results We generate open chromatin profiles for liver, muscle, and hypothalamus of indicine cattle through ATAC-seq. Using robust methods for motif discovery, motif enrichment and transcription factor binding sites, we identify potential master regulators of the epigenomic profile in these three tissues, namely HNF4, MEF2, and SOX factors, respectively. Integration with transcriptomic data allows us to confirm some of their target genes. Finally, by comparing our results with Bos taurus data we identify potential indicine-specific open chromatin regions and overlaps with indicine selective sweeps. Conclusions Our findings provide insights into the identification and analysis of regulatory elements in non-model organisms, the evolution of regulatory elements within two cattle subspecies as well as having an immediate impact on the animal genetics community in particular for a relevant productive species such as tropical cattle.

scholarly journals TBX3 acts as tissue-specific component of the Wnt/β-catenin transcriptional complex

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Dario Zimmerli ◽  
Costanza Borrelli ◽  
Amaia Jauregi-Miguel ◽  
Simon Söderholm ◽  
Salome Brütsch ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Target Genes ◽  
Regulatory Elements ◽  
Dependent Manner ◽  
Independent Manner ◽  
Tissue Specific ◽  
Colorectal Cancer Cells ◽  
Transcriptional Complex

BCL9 and PYGO are β-catenin cofactors that enhance the transcription of Wnt target genes. They have been proposed as therapeutic targets to diminish Wnt signaling output in intestinal malignancies. Here we find that, in colorectal cancer cells and in developing mouse forelimbs, BCL9 proteins sustain the action of β-catenin in a largely PYGO-independent manner. Our genetic analyses implied that BCL9 necessitates other interaction partners in mediating its transcriptional output. We identified the transcription factor TBX3 as a candidate tissue-specific member of the β-catenin transcriptional complex. In developing forelimbs, both TBX3 and BCL9 occupy a large number of Wnt-responsive regulatory elements, genome-wide. Moreover, mutations in Bcl9 affect the expression of TBX3 targets in vivo, and modulation of TBX3 abundance impacts on Wnt target genes transcription in a β-catenin- and TCF/LEF-dependent manner. Finally, TBX3 overexpression exacerbates the metastatic potential of Wnt-dependent human colorectal cancer cells. Our work implicates TBX3 as context-dependent component of the Wnt/β-catenin-dependent transcriptional complex.

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