scholarly journals Combinatorial chromatin dynamics foster accurate cardiopharyngeal fate choices

2019 ◽  
Author(s):  
Claudia Racioppi ◽  
Keira A Wiechecki ◽  
Lionel Christiaen
Keyword(s):  
Gene Expression ◽  
Specific Activity ◽  
Expression Profiles ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Control Gene ◽  
Specific Expression ◽  
Pharyngeal Muscle ◽  
Control Gene Expression ◽  
Multipotent Progenitors

ABSTRACTIn embryos, lineage-specific profiles of chromatin accessibility control gene expression by modulating transcription, and thus impact multipotent progenitor states and subsequent fate choices. Subsets of cardiac and pharyngeal/head muscles share a common origin in the cardiopharyngeal mesoderm, but the chromatin landscapes that govern multipotent progenitors’ competence and early fate choices remain largely elusive. Here, we leveraged the simplicity of the chordate model Ciona to profile chromatin accessibility through stereotyped transitions from naive Mesp+ mesoderm to distinct fate-restricted heart and pharyngeal muscle precursors. An FGF-Foxf pathway acts in multipotent progenitors to establish cardiopharyngeal-specific patterns of accessibility, which govern later heart vs. pharyngeal muscle-specific expression profiles, demonstrating extensive spatiotemporal decoupling between early cardiopharyngeal enhancer accessibility and late cell-type-specific activity. Combinations of cis-regulatory elements with distinct chromatin accessibility profiles are required to activate of Ebf and Tbx1/10, two key determinants of cardiopharyngeal fate choices. We propose that this higher order combinatorial logic increases the repertoire of regulatory inputs that control gene expression, through either accessibility and/or activity, thus fostering spatially and temporally accurate fate choices.

scholarly journals Combinatorial chromatin dynamics foster accurate cardiopharyngeal fate choices

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Claudia Racioppi ◽  
Keira A Wiechecki ◽  
Lionel Christiaen
Keyword(s):  
Gene Expression ◽  
Specific Activity ◽  
Expression Profiles ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Specific Expression ◽  
Pharyngeal Muscle ◽  
Chromatin Dynamics ◽  
Multipotent Progenitors

During embryogenesis, chromatin accessibility profiles control lineage-specific gene expression by modulating transcription, thus impacting multipotent progenitor states and subsequent fate choices. Subsets of cardiac and pharyngeal/head muscles share a common origin in the cardiopharyngeal mesoderm, but the chromatin landscapes that govern multipotent progenitors competence and early fate choices remain largely elusive. Here, we leveraged the simplicity of the chordate model Ciona to profile chromatin accessibility through stereotyped transitions from naive Mesp+ mesoderm to distinct fate-restricted heart and pharyngeal muscle precursors. An FGF-Foxf pathway acts in multipotent progenitors to establish cardiopharyngeal-specific patterns of accessibility, which govern later heart vs. pharyngeal muscle-specific expression profiles, demonstrating extensive spatiotemporal decoupling between early cardiopharyngeal enhancer accessibility and late cell-type-specific activity. We found that multiple cis-regulatory elements, with distinct chromatin accessibility profiles and motif compositions, are required to activate Ebf and Tbx1/10, two key determinants of cardiopharyngeal fate choices. We propose that these ‘combined enhancers’ foster spatially and temporally accurate fate choices, by increasing the repertoire of regulatory inputs that control gene expression, through either accessibility and/or activity.

scholarly journals Cis-regulatory elements used to control gene expression in plants

2016 ◽  
Vol 127 (2) ◽  
pp. 269-287 ◽  
Author(s):  
Róża Biłas ◽  
Katarzyna Szafran ◽  
Katarzyna Hnatuszko-Konka ◽  
Andrzej K. Kononowicz
Keyword(s):  
Gene Expression ◽  
Regulatory Elements ◽  
Control Gene ◽  
Control Gene Expression

scholarly journals Virus-Induced Changes in mRNA Secondary Structure Uncover cis-Regulatory Elements that Directly Control Gene Expression

2018 ◽  
Vol 72 (5) ◽  
pp. 862-874.e5 ◽  
Author(s):  
Orel Mizrahi ◽  
Aharon Nachshon ◽  
Alina Shitrit ◽  
Idit A. Gelbart ◽  
Martina Dobesova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Secondary Structure ◽  
Regulatory Elements ◽  
Mrna Secondary Structure ◽  
Control Gene ◽  
Control Gene Expression ◽  
Induced Changes

scholarly journals Deciphering programs of transcriptional regulation by combined deconvolution of multiple omics layers

2017 ◽  
Author(s):  
Daniel Hüebschmann ◽  
Nils Kurzawa ◽  
Sebastian Steinhauser ◽  
Philipp Rentzsch ◽  
Stephen Krämer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Developmental Stages ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Cell Type ◽  
Specific Expression ◽  
Input Size ◽  
Human Blood Cells ◽  
Cell Type Specific Expression

AbstractMetazoans are crucially dependent on multiple layers of gene regulatory mechanisms which allow them to control gene expression across developmental stages, tissues and cell types. Multiple recent research consortia have aimed to generate comprehensive datasets to profile the activity of these cell type- and condition-specific regulatory landscapes across many different cell lines and primary cells. However, extraction of genes or regulatory elements specific to certain entities from these datasets remains challenging. We here propose a novel method based on non-negative matrix factorization for disentangling and associating huge multi-assay datasets including chromatin accessibility and gene expression data. Taking advantage of implementations of NMF algorithms in the GPU CUDA environment full datasets composed of tens of thousands of genes as well as hundreds of samples can be processed without the need for prior feature selection to reduce the input size. Applying this framework to multiple layers of genomic data derived from human blood cells we unravel mechanisms of regulation of cell type-specific expression in T-cells and monocytes.

Building the heart piece by piece: modularity of cis-elements regulating Nkx2-5 transcription

Development ◽  
1999 ◽  
Vol 126 (19) ◽  
pp. 4187-4192 ◽  
Author(s):  
R.J. Schwartz ◽  
E.N. Olson
Keyword(s):  
Gene Expression ◽  
Homeobox Gene ◽  
Regulatory Elements ◽  
Mouse Heart ◽  
Cis Elements ◽  
Control Gene ◽  
Control Gene Expression ◽  
Developing Heart ◽  
Heart Formation ◽  
Vertebrate Embryos

Heart formation in Drosophila is dependent on the homeobox gene tinman. The homeobox gene Nkx2-5 is closely related to tinman and is the earliest known marker for cardiogenesis in vertebrate embryos. Recent studies of cis-regulatory elements required for Nkx2-5 expression in the developing mouse heart have revealed an extraordinary array of independent cardiac enhancers, and associated negative regulatory elements, that direct transcription in distinct regions of the embryonic heart. These studies demonstrate the modularity in cardiac transcription, in which different regulatory elements respond to distinct sets of transcription factors to control gene expression in different compartments of the developing heart. We consider the potential mechanisms underlying such transcriptional complexity, its possible significance for cardiac function, and the implications for evolution of the multichambered heart.

scholarly journals Discovery of gene regulatory elements through a new bioinformatics analysis of haploid genetic screens

2018 ◽  
Author(s):  
Bhaven B. Patel ◽  
Andres M. Lebensohn ◽  
Jan E. Carette ◽  
Julia Salzman ◽  
Rajat Rohatgi
Keyword(s):  
Gene Expression ◽  
Wnt Signaling ◽  
Insertional Mutagenesis ◽  
Bioinformatics Analysis ◽  
Regulatory Elements ◽  
Gene Trap ◽  
Genetic Screens ◽  
Control Gene ◽  
Protein Coding ◽  
Control Gene Expression

AbstractThe systematic identification of regulatory elements that control gene expression remains a challenge. Genetic screens that use untargeted mutagenesis have the potential to identify protein-coding genes, non-coding RNAs and regulatory elements, but their analysis has mainly focused on identifying the former two. To identify regulatory elements, we conducted a new bioinformatics analysis of insertional mutagenesis screens interrogating WNT signaling in haploid human cells. We searched for specific patterns of retroviral gene trap integrations (used as mutagens in haploid screens) in short genomic intervals overlapping with introns and regions upstream of genes. We uncovered atypical patterns of gene trap insertions that were not predicted to disrupt coding sequences, but caused changes in the expression of two key regulators of WNT signaling, suggesting the presence of cis-regulatory elements. Our methodology extends the scope of haploid genetic screens by enabling the identification of regulatory elements that control gene expression.

scholarly journals Titrating gene expression with series of systematically compromised CRISPR guide RNAs

2019 ◽  
Author(s):  
Marco Jost ◽  
Daniel A. Santos ◽  
Reuben A. Saunders ◽  
Max A. Horlbeck ◽  
John S. Hawkins ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Biology ◽  
Large Scale ◽  
Control Gene ◽  
Specific Expression ◽  
Expression Phenotype ◽  
Control Gene Expression ◽  
Human Genes ◽  
A Genome ◽  
Multiple Cell

AbstractBiological phenotypes arise from the degrees to which genes are expressed, but the lack of tools to precisely control gene expression limits our ability to evaluate the underlying expression-phenotype relationships. Here, we describe a readily implementable approach to titrate expression of human genes using series of systematically compromised sgRNAs and CRISPR interference. We empirically characterize the activities of compromised sgRNAs using large-scale measurements across multiple cell models and derive the rules governing sgRNA activity using deep learning, enabling construction of a compact sgRNA library to titrate expression of ∼2,400 genes involved in central cell biology and a genome-wide in silico library. Staging cells along a continuum of gene expression levels combined with rich single-cell RNA-seq readout reveals gene-specific expression-phenotype relationships with expression level-specific responses. Our work provides a general tool to control gene expression, with applications ranging from tuning biochemical pathways to identifying suppressors for diseases of dysregulated gene expression.

scholarly journals Recapitulation-like developmental transitions of chromatin accessibility in vertebrates

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Masahiro Uesaka ◽  
Shigeru Kuratani ◽  
Hiroyuki Takeda ◽  
Naoki Irie
Keyword(s):  
Gene Expression ◽  
Developmental Stages ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Regulatory Elements ◽  
Evolutionary Developmental Biology ◽  
Chromatin Accessibility ◽  
Putative Gene ◽  
A Genome ◽  
Conserved Gene

AbstractThe relationship between development and evolution has been a central theme in evolutionary developmental biology. Across the vertebrates, the most highly conserved gene expression profiles are found at mid-embryonic, organogenesis stages, whereas those at earlier and later stages are more diverged. This hourglass-like pattern of divergence does not necessarily rule out the possibility that gene expression profiles that are more evolutionarily derived appear at later stages of development; however, no molecular-level evidence of such a phenomenon has been reported. To address this issue, we compared putative gene regulatory elements among different species within a phylum. We made a genome-wide assessment of accessible chromatin regions throughout embryogenesis in three vertebrate species (mouse, chicken, and medaka) and estimated the evolutionary ages of these regions to define their evolutionary origins on the phylogenetic tree. In all the three species, we found that genomic regions tend to become accessible in an order that parallels their phylogenetic history, with evolutionarily newer gene regulations activated at later developmental stages. This tendency was restricted only after the mid-embryonic, phylotypic periods. Our results imply a phylogenetic hierarchy of putative regulatory regions, in which their activation parallels the phylogenetic order of their appearance. One evolutionary mechanism that may explain this phenomenon is that newly introduced regulatory elements are more likely to survive if activated at later stages of embryogenesis. Possible relationships between this phenomenon and the so-called recapitulation are discussed.

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.

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