Mammalian transcriptional hotspots are enriched for tissue specific enhancers near cell type specific highly expressed genes and are predicted to act as transcriptional activator hubs

Abstract Stratification of enhancers by signal strength in ChIP-seq assays has resulted in the establishment of super-enhancers as a widespread and useful tool for identifying cell type-specific, highly expressed genes and associated pathways. We examine a distinct method of stratification that focuses on peak breadth, termed hyperacetylated chromatin domains (HCDs), which classifies broad regions exhibiting histone modifications associated with gene activation. We find that this analysis serves to identify genes that are both more highly expressed and more closely aligned to cell identity than super-enhancer analysis does using multiple data sets. Moreover, genetic manipulations of selected gene loci suggest that some enhancers located within HCDs work at least in part via a distinct mechanism involving the modulation of histone modifications across domains and that this activity can be imported into a heterologous gene locus. In addition, such genetic dissection reveals that the super-enhancer concept can obscure important functions of constituent elements.

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Differentiation: the selective potentiation of chromatin domains

Development ◽

10.1242/dev.125.23.4749 ◽

1998 ◽

Vol 125 (23) ◽

pp. 4749-4755 ◽

Cited By ~ 1

Author(s):

J.A. Kramer ◽

J.R. McCarrey ◽

D. Djakiew ◽

S.A. Krawetz

Keyword(s):

Gene Expression ◽

Stem Cell ◽

Spermatogonial Stem Cell ◽

Specific Gene ◽

Cell Type ◽

Chromatin Domains ◽

Tissue Specific ◽

Specific Gene Expression ◽

Cell Type Specific ◽

Cellular Phenotypes

Potentiation is requisite for the expression of our genome. It is the mechanism of opening chromatin domains to render genes accessible to tissue-specific and ubiquitous transacting-factors that enables transcription. The results presented in this study demonstrate that modulation of stage- and cell-type-specific gene expression during mammalian spermatogenesis involves selective potentiation of testis-expressed genes that reverses their repressive state when present in the spermatogonial stem cell. This directly contrasts hematopoiesis, which acts to selectively restrict lineage potential during differentiation from its permissive stem cell. These results are key to understanding how differentiative pathways are controlled and cellular phenotypes determined. A window to their modulation is presented.

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The SNF5 protein of Saccharomyces cerevisiae is a glutamine- and proline-rich transcriptional activator that affects expression of a broad spectrum of genes

Molecular and Cellular Biology ◽

10.1128/mcb.10.11.5616-5625.1990 ◽

1990 ◽

Vol 10 (11) ◽

pp. 5616-5625

Author(s):

B C Laurent ◽

M A Treitel ◽

M Carlson

Keyword(s):

Saccharomyces Cerevisiae ◽

Nucleotide Sequence ◽

Fusion Protein ◽

Broad Spectrum ◽

Transcriptional Activator ◽

Binding Activity ◽

Cell Type ◽

Dna Binding Activity ◽

Cell Type Specific ◽

Beta Galactosidase

The Saccharomyces cerevisiae SNF5 gene affects expression of both glucose- and phosphate-regulated genes and appears to function in transcription. We report the nucleotide sequence, which predicts that SNF5 encodes a 102,536-dalton protein. The N-terminal third of the protein is extremely rich in glutamine and proline. Mutants carrying a deletion of the coding sequence were viable but grew slowly, indicating that the SNF5 gene is important but not essential. Evidence that SNF5 affects expression of the cell type-specific genes MF alpha 1 and BAR1 at the RNA level extends the known range of SNF5 function. SNF5 is apparently required for expression of a wide variety of differently regulated genes. A bifunctional SNF5-beta-galactosidase fusion protein was localized in the nucleus by immunofluorescence. No DNA-binding activity was detected for SNF5. A LexA-SNF5 fusion protein, when bound to a lexA operator, functioned as a transcriptional activator.

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A Single-copy Knock In Translating Ribosome ImmunoPrecipitation (SKI TRIP) tool kit for tissue specific profiling of actively translated mRNAs in C. elegans.

10.1101/2021.12.22.473890 ◽

2021 ◽

Author(s):

Laura E Wester ◽

Anne Lanjuin ◽

Emanuel H W Bruckisch ◽

Maria C Perez Matos ◽

Caroline Heintz ◽

...

Keyword(s):

Affinity Purification ◽

Ribosomal Subunit ◽

Mrna Translation ◽

Single Copy ◽

Specific Cell ◽

Cell Type ◽

Specific Expression ◽

Tissue Specific ◽

C Elegans ◽

Cell Type Specific

Translating Ribosome Affinity Purification (TRAP) methods have emerged as a powerful approach to profile actively translated transcripts in specific cell and tissue types. Epitope tagged ribosomal subunits are expressed in defined cell populations and used to pull down ribosomes and their associated mRNAs, providing a snapshot of cell type-specific translation occurring in that space and time. Current TRAP toolkits available to the C. elegans community have been built using multi-copy arrays, randomly integrated in the genome. Here we introduce a Single-copy Knock In Translating Ribosome ImmunoPrecipitation (SKI TRIP) tool kit, a collection of C. elegans strains engineered by CRISPR in which tissue specific expression of FLAG tagged ribosomal subunit protein RPL-22 is driven by cassettes present in single copy from defined sites in the genome. In depth characterization of the SKI TRIP strains and methodology shows that 3xFLAG tagged RPL-22 expressed from its endogenous locus or within defined cell types incorporates into actively translating ribosomes and can be used to efficiently and cleanly pull-down cell type specific transcripts without impacting overall mRNA translation or fitness of the animal. We propose SKI TRIP use for the study of processes that are acutely sensitive to changes in translation, such as aging.

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The SNF5 protein of Saccharomyces cerevisiae is a glutamine- and proline-rich transcriptional activator that affects expression of a broad spectrum of genes.

Molecular and Cellular Biology ◽

10.1128/mcb.10.11.5616 ◽

1990 ◽

Vol 10 (11) ◽

pp. 5616-5625 ◽

Cited By ~ 80

Author(s):

B C Laurent ◽

M A Treitel ◽

M Carlson

Keyword(s):

Saccharomyces Cerevisiae ◽

Nucleotide Sequence ◽

Fusion Protein ◽

Broad Spectrum ◽

Transcriptional Activator ◽

Binding Activity ◽

Cell Type ◽

Dna Binding Activity ◽

Cell Type Specific ◽

Beta Galactosidase

The Saccharomyces cerevisiae SNF5 gene affects expression of both glucose- and phosphate-regulated genes and appears to function in transcription. We report the nucleotide sequence, which predicts that SNF5 encodes a 102,536-dalton protein. The N-terminal third of the protein is extremely rich in glutamine and proline. Mutants carrying a deletion of the coding sequence were viable but grew slowly, indicating that the SNF5 gene is important but not essential. Evidence that SNF5 affects expression of the cell type-specific genes MF alpha 1 and BAR1 at the RNA level extends the known range of SNF5 function. SNF5 is apparently required for expression of a wide variety of differently regulated genes. A bifunctional SNF5-beta-galactosidase fusion protein was localized in the nucleus by immunofluorescence. No DNA-binding activity was detected for SNF5. A LexA-SNF5 fusion protein, when bound to a lexA operator, functioned as a transcriptional activator.

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Tissue-specific and cell type–specific RNA interference in vivo

Nature Protocols ◽

10.1038/nprot.2006.260 ◽

2006 ◽

Vol 1 (3) ◽

pp. 1494-1501 ◽

Cited By ~ 30

Author(s):

Manjeet K Rao ◽

Miles F Wilkinson

Keyword(s):

Rna Interference ◽

Cell Type ◽

Tissue Specific ◽

Cell Type Specific

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Tissue-specific ramp sequences correspond with increased gene expression in humans and SARS-CoV-2

10.21203/rs.3.rs-738082/v1 ◽

2021 ◽

Author(s):

Justin Miller ◽

Taylor Meurs ◽

Matthew Hodgman ◽

Benjamin Song ◽

Mark Ebbert ◽

...

Keyword(s):

Gene Expression ◽

Cell Types ◽

Regulatory Elements ◽

Targeted Therapeutics ◽

Cell Type ◽

Sequence Analyses ◽

Tissue Specific ◽

Cell Type Specific ◽

Viral Proliferation ◽

Increase Gene Expression

Abstract Translational ramp sequences are essential regulatory elements that have yet to be characterized in specific tissues. Ramp sequences increase gene expression by evenly spacing ribosomes and slowing initial translation. Therefore, the relative codon adaptiveness within different tissues changes the existence of a ramp sequence without altering the underlying genetic code. Here, we present the first comprehensive analysis of tissue and cell type-specific ramp sequences, and report 3,108 genes with ramp sequences that change between tissues and cell types. The Ramp Atlas (https://ramps.byu.edu/) is an accompanying web portal that allows researchers to query ramp sequences in 18,388 genes across 62 tissues and 66 cell types. We also identified seven SARS-CoV-2 genes and seven human SARS-CoV-2 entry factor genes with tissue-specific ramp sequences that may help explain viral proliferation within those tissues. We anticipate that The Ramp Atlas will facilitate future tissue-specific ramp sequence analyses to develop targeted therapeutics for human disease.

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Quantifying the Tissue-Specific Regulatory Information within Enhancer DNA Sequences

10.1101/2021.05.02.442309 ◽

2021 ◽

Author(s):

Philipp Benner ◽

Martin Vingron

Keyword(s):

Dna Sequences ◽

Cell Types ◽

Cell Type ◽

Regulate Gene Expression ◽

Tissue Specific ◽

Sequence Patterns ◽

Cell Type Specific ◽

Specific Regulation ◽

Different Cell Types ◽

Regulatory Landscape

AbstractRecent efforts to measure epigenetic marks across a wide variety of different cell types and tissues provide insights into the cell type-specific regulatory landscape. We use this data to study if there exists a correlate of epigenetic signals in the DNA sequence of enhancers and explore with computational methods to what degree such sequence patterns can be used to predict cell type-specific regulatory activity. By constructing classifiers that predict in which tissues enhancers are active, we are able to identify sequence features that might be recognized by the cell in order to regulate gene expression. While classification performances vary greatly between tissues, we show examples where our classifiers correctly predict tissue specific regulation from sequence alone. We also show that many of the informative patterns indeed harbor transcription factor footprints.

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Hyperacetylated Chromatin Domains Mark Cell Type-Specific Genes and Suggest Distinct Modes of Enhancer Function

10.1101/666784 ◽

2019 ◽

Author(s):

Sierra Fox ◽

Jacquelyn A. Myers ◽

Christina Davidson ◽

Michael Getman ◽

Paul D. Kingsley ◽

...

Keyword(s):

Histone Modifications ◽

Gene Activation ◽

Genetic Dissection ◽

Cell Type ◽

Chromatin Domains ◽

Genetic Manipulations ◽

Super Enhancer ◽

Highly Expressed Genes ◽

Cell Type Specific ◽

Constituent Elements

AbstractStratification of enhancers by relative signal strength in ChIP-seq assays has resulted in the establishment of super-enhancers as a widespread and useful tool for identifying cell type-specific, highly expressed genes and associated pathways. We have examined a distinct method of stratification that focuses on peak breadth, termed “hyperacetylated chromatin domains” (HCDs), which classifies broad regions exhibiting histone modifications associated with gene activation. We find that this analysis serves to identify genes that are both more highly expressed and more closely aligned to cell identity than super-enhancer analysis does when applied to multiple datasets. Moreover, genetic manipulations of selected gene loci suggest that at least some enhancers located within HCDs work at least in part via a distinct mechanism involving the modulation of covalent histone modifications across domains, and that this activity can be imported into a heterologous gene locus. In addition, such genetic dissection reveals that the super-enhancer concept can obscure important functions of constituent elements.

Download Full-text