Enhancer-dependence of gene expression increases with developmental age

SummaryHow overall principles of gene regulation (the “logic”) may change during ontogeny is largely unexplored. We compared transcriptomic, epigenomic and topological profiles in embryonic (EryP) and adult (EryD) erythroblasts. Despite reduced chromatin accessibility compared to EryP, distal chromatin of EryD is enriched in H3K27ac, Gata1 and Myb occupancy. In contrast to EryP-specific genes, which exhibit promoter-centric regulation through Gata1, EryD-specific genes employ distal enhancers for long-range regulation through enhancer-promoter looping, confirmed by Gata1 HiChIP. Genome editing demonstrated distal enhancers are required for gene expression in EryD but not in EryP. Applying a metric for enhancer-dependence of transcription, we observed a progressive reliance on enhancer control with increasing age of ontogeny among diverse primary cells and tissues of mouse and human origin. Our findings highlight fundamental and conserved differences in regulatory logic at distinct developmental stages, characterized by simpler promoter-centric regulation in embryonic cells and combinatorial enhancer-driven control in adult cells.HighlightsRegulation of embryonic-specific erythroid genes is promoter-centric through Gata1Adult-specific control is combinatorial enhancer-driven and requires MybAdult specific genes have increased enhancer-promoter chromatin interactionsEnhancer-dependence increases progressively with increasing developmental age

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Enhancer dependence of cell-type–specific gene expression increases with developmental age

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2008672117 ◽

2020 ◽

Vol 117 (35) ◽

pp. 21450-21458 ◽

Cited By ~ 1

Author(s):

Wenqing Cai ◽

Jialiang Huang ◽

Qian Zhu ◽

Bin E. Li ◽

Davide Seruggia ◽

...

Keyword(s):

Gene Expression ◽

Developmental Stages ◽

Three Dimensional ◽

Chromatin Accessibility ◽

Specific Gene ◽

Embryonic Cells ◽

Cell Type ◽

Cell Type Specific ◽

Specific Regulation ◽

Highly Correlated

How overall principles of cell-type–specific gene regulation (the “logic”) may change during ontogeny is largely unexplored. We compared transcriptomic, epigenomic, and three-dimensional (3D) genomic profiles in embryonic (EryP) and adult (EryD) erythroblasts. Despite reduced chromatin accessibility compared to EryP, distal chromatin of EryD is enriched in H3K27ac, Gata1, and Myb occupancy. EryP-/EryD-shared enhancers are highly correlated with red blood cell identity genes, whereas cell-type–specific regulation employs differentciselements in EryP and EryD cells. In contrast to EryP-specific genes, which exhibit promoter-centric regulation through Gata1, EryD-specific genes rely more on distal enhancers for regulation involving Myb-mediated enhancer activation. Gata1 HiChIP demonstrated an overall increased enhancer–promoter interactions at EryD-specific genes, whereas genome editing in selected loci confirmed distal enhancers are required for gene expression in EryD but not in EryP. Applying a metric for enhancer dependence of transcription, we observed a progressive reliance on cell-specific enhancers with increasing ontogenetic age among diverse tissues of mouse and human origin. Our findings highlight fundamental and conserved differences at distinct developmental stages, characterized by simpler promoter-centric regulation of cell-type–specific genes in embryonic cells and increased combinatorial enhancer-driven control in adult cells.

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

10.1101/199547 ◽

2017 ◽

Cited By ~ 5

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.

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Reconstructing the transcriptional ontogeny of maize and sorghum supports an inverse hourglass model of inflorescence development

10.1101/616235 ◽

2019 ◽

Author(s):

Samuel Leiboff ◽

Sarah Hake

Keyword(s):

Random Forest ◽

Developmental Stages ◽

List Type ◽

Inflorescence Development ◽

Closely Related Species ◽

Developmental Age ◽

Maize Tassel ◽

Rapid Divergence ◽

Hourglass Model ◽

Developmental Reprogramming

AbstractAssembling meaningful comparisons between species is a major limitation in studying the evolution of organismal form. To understand development in maize and sorghum, closely-related species with architecturally distinct inflorescences, we collected RNAseq profiles encompassing inflorescence body plan specification in both species. We reconstructed molecular ontogenies from 40 B73 maize tassels and 47 BT×623 sorghum panicles and separated them into transcriptional stages. To discover new markers of inflorescence development, we used random forest machine learning to determine stage by RNAseq. We used two descriptions of transcriptional conservation to identify hourglass-like developmental stages. Despite short evolutionary ancestry of 12 million years, we found maize and sorghum inflorescences are most different during their hourglass-like stages of development, following an ‘inverse-hourglass’ model of development. We discuss if agricultural selection may account for the rapid divergence signatures in these species and the observed separation of evolutionary pressure and developmental reprogramming.HighlightsTranscript dynamics identify maize tassel and sorghum panicle developmental stagesRandom forest predicts developmental age by gene expression, providing molecular markers and an in silico staging applicationMaize and sorghum inflorescences are most similar when committing stem cells to a determinant fateExpression conservation identifies hourglass-like stage, but transcriptomes diverge, similar to ‘inverse hourglass’ observations in cross-phyla animal embryo comparisons

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Chromatin information content landscapes inform transcription factor and DNA interactions

Nature Communications ◽

10.1038/s41467-021-21534-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ricardo D’Oliveira Albanus ◽

Yasuhiro Kyono ◽

John Hensley ◽

Arushi Varshney ◽

Peter Orchard ◽

...

Keyword(s):

Gene Expression ◽

Information Theory ◽

Transcription Factor ◽

Transcription Factors ◽

Genome Organization ◽

Specific Protein ◽

Chromatin Accessibility ◽

Dna Interactions ◽

Cell State ◽

Chromatin Interactions

AbstractInteractions between transcription factors and chromatin are fundamental to genome organization and regulation and, ultimately, cell state. Here, we use information theory to measure signatures of organized chromatin resulting from transcription factor-chromatin interactions encoded in the patterns of the accessible genome, which we term chromatin information enrichment (CIE). We calculate CIE for hundreds of transcription factor motifs across human samples and identify two classes: low and high CIE. The 10–20% of common and tissue-specific high CIE transcription factor motifs, associate with higher protein–DNA residence time, including different binding site subclasses of the same transcription factor, increased nucleosome phasing, specific protein domains, and the genetic control of both chromatin accessibility and gene expression. These results show that variations in the information encoded in chromatin architecture reflect functional biological variation, with implications for cell state dynamics and memory.

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Multi-level remodelling of chromatin underlying activation of human T cells

Scientific Reports ◽

10.1038/s41598-020-80165-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Naiara G. Bediaga ◽

Hannah D. Coughlan ◽

Timothy M. Johanson ◽

Alexandra L. Garnham ◽

Gaetano Naselli ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Chromatin Accessibility ◽

Chromatin Architecture ◽

Chromatin Interactions ◽

Human T Cells ◽

Multi Level

AbstractRemodelling of chromatin architecture is known to regulate gene expression and has been well characterized in cell lineage development but less so in response to cell perturbation. Activation of T cells, which triggers extensive changes in transcriptional programs, serves as an instructive model to elucidate how changes in chromatin architecture orchestrate gene expression in response to cell perturbation. To characterize coordinate changes at different levels of chromatin architecture, we analyzed chromatin accessibility, chromosome conformation and gene expression in activated human T cells. T cell activation was characterized by widespread changes in chromatin accessibility and interactions that were shared between activated CD4+ and CD8+ T cells, and with the formation of active regulatory regions associated with transcription factors relevant to T cell biology. Chromatin interactions that increased and decreased were coupled, respectively, with up- and down-regulation of corresponding target genes. Furthermore, activation was associated with disruption of long-range chromatin interactions and with partitioning of topologically associating domains (TADs) and remodelling of their TAD boundaries. Newly formed/strengthened TAD boundaries were associated with higher nucleosome occupancy and lower accessibility, linking changes in lower and higher order chromatin architecture. T cell activation exemplifies coordinate multi-level remodelling of chromatin underlying gene transcription.

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Untangling mechanisms of crude oil toxicity: linking gene expression, morphology and PAHs at two developmental stages in a cold-water fish

10.1101/2020.09.09.288852 ◽

2020 ◽

Author(s):

Elin Sørhus ◽

Carey E. Donald ◽

Denis da Silva ◽

Anders Thorsen ◽

Ørjan Karlsen ◽

...

Keyword(s):

Gene Expression ◽

Crude Oil ◽

Developmental Stages ◽

Cold Water ◽

Melanogrammus Aeglefinus ◽

List Type ◽

Short Term ◽

Oil Droplet ◽

Oil Toxicity ◽

Oil Exposure

AbstractEarly life stages of fish are highly sensitive to crude oil exposure and thus, short term exposures during critical developmental periods could have detrimental consequences for juvenile survival. Here we administered crude oil to Atlantic haddock (Melanogrammus aeglefinus) in short term (3-day) exposures at two developmental time periods: before first heartbeat, from gastrulation to cardiac cone stage (early), and from first heartbeat to one day before hatching (late). A frequent sampling regime enabled us to determine immediate PAH uptake, metabolite formation and gene expression changes. In general, the embryotoxic consequences of an oil exposure were more severe in the early exposure animals. Oil droplet fouling in the highest doses resulted in severe cardiac and craniofacial abnormalities. Gene expression changes of Cytochrome 1 a,b,c and d (cyp1a,b,c,d), Bone morphogenetic protein 10 (bmp10), ABC transporter b1 (abcb1) and Rh-associated G-protein (rhag) were linked to PAH uptake, occurrence of metabolites of phenanthrene and developmental and functional abnormalities. We detected circulation-independent, oil-induced gene expression changes and separated phenotypes linked to proliferation, growth and disruption of formation events at early and late developmental stages. Our study gives an increased knowledge about developmentally dependent effects of crude oil toxicity. Thus, providing more knowledge and detail to new and several existing adverse outcome pathways of crude oil toxicity.Graphical abstractHighlightsOil droplet fouling occurred in the whole water column and increased the oil toxicity.Early exposure resulted in higher PAH uptake due to lower metabolism resulting in more severe abnormalities.A rapid and circulation-indepenent regulation of bmp10 suggested a direct oil-induced effect on calcium homeostasis.Expression of rhag indicated a direct oil-induced effect on osmoregulatory cells and osmoregulation.Severe eye abnormalities especially in the late exposure was linked to inappropriate overexpression of cyp1b in the eyes.

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Chromatin information content landscapes inform transcription factor and DNA interactions

10.1101/777532 ◽

2019 ◽

Cited By ~ 1

Author(s):

Ricardo D’Oliveira Albanus ◽

Yasuhiro Kyono ◽

John Hensley ◽

Arushi Varshney ◽

Peter Orchard ◽

...

Keyword(s):

Gene Expression ◽

Information Content ◽

Binding Sites ◽

Genome Organization ◽

Specific Protein ◽

Chromatin Accessibility ◽

Human Tissues ◽

Dna Interactions ◽

Cell State ◽

Chromatin Interactions

AbstractInteractions between transcription factors (TFs) and chromatin are fundamental to genome organization and regulation and, ultimately, cell state. Here, we use information theory to measure signatures of TF-chromatin interactions encoded in the patterns of the accessible genome, which we call chromatin information enrichment (CIE). We calculate CIE for hundreds of TF motifs across human tissues and identify two classes: low and high CIE. The 10-20% of TF motifs with high CIE associate with higher protein-DNA residence time, including different binding sites subclasses of the same TF, increased nucleosome phasing, specific protein domains, and the genetic control of both gene expression and chromatin accessibility. These results show that variations in the information content of chromatin architecture reflect functional biological variation, with implications for cell state dynamics and memory.

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Stable unmethylated DNA demarcates expressed genes and their cis-regulatory space in plant genomes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2010250117 ◽

2020 ◽

Vol 117 (38) ◽

pp. 23991-24000 ◽

Cited By ~ 2

Author(s):

Peter A. Crisp ◽

Alexandre P. Marand ◽

Jaclyn M. Noshay ◽

Peng Zhou ◽

Zefu Lu ◽

...

Keyword(s):

Dna Methylation ◽

Developmental Stages ◽

Chromatin Modification ◽

Leaf Tissue ◽

Cell Types ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Functional Genes ◽

Specific Cell ◽

Chromatin Interactions

The genomic sequences of crops continue to be produced at a frenetic pace. It remains challenging to develop complete annotations of functional genes and regulatory elements in these genomes. Chromatin accessibility assays enable discovery of functional elements; however, to uncover the full portfolio of cis-elements would require profiling of many combinations of cell types, tissues, developmental stages, and environments. Here, we explore the potential to use DNA methylation profiles to develop more complete annotations. Using leaf tissue in maize, we define ∼100,000 unmethylated regions (UMRs) that account for 5.8% of the genome; 33,375 UMRs are found greater than 2 kb from genes. UMRs are highly stable in multiple vegetative tissues, and they capture the vast majority of accessible chromatin regions from leaf tissue. However, many UMRs are not accessible in leaf, and these represent regions with potential to become accessible in specific cell types or developmental stages. These UMRs often occur near genes that are expressed in other tissues and are enriched for binding sites of transcription factors. The leaf-inaccessible UMRs exhibit unique chromatin modification patterns and are enriched for chromatin interactions with nearby genes. The total UMR space in four additional monocots ranges from 80 to 120 megabases, which is remarkably similar considering the range in genome size of 271 megabases to 4.8 gigabases. In summary, based on the profile from a single tissue, DNA methylation signatures provide powerful filters to distill large genomes down to the small fraction of putative functional genes and regulatory elements.

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The Nuclear Lamina as an Organizer of Chromosome Architecture

Cells ◽

10.3390/cells8020136 ◽

2019 ◽

Vol 8 (2) ◽

pp. 136 ◽

Cited By ~ 21

Author(s):

Yuri Y. Shevelyov ◽

Sergey V. Ulianov

Keyword(s):

Gene Expression ◽

Interphase Nucleus ◽

Spatial Organization ◽

Nuclear Lamina ◽

Cell Types ◽

Embryonic Cells ◽

Chromosome Architecture ◽

Differentiated Cells ◽

Chromatin Interactions ◽

Associated Proteins

The nuclear lamina (NL) is a meshwork of lamins and lamin-associated proteins adjoining the inner side of the nuclear envelope. In early embryonic cells, the NL mainly suppresses background transcription, whereas, in differentiated cell types, its disruption affects gene expression more severely. Normally, the NL serves as a backbone for multiple chromatin anchoring sites, thus shaping the spatial organization of chromosomes in the interphase nucleus. However, upon cell senescence, aging, or in some types of terminally differentiated cells and lamin-associated diseases, the loss of NL-chromatin tethering causes drastic alterations in chromosome architecture. Here, we provide an overview of the recent advances in the field of NL-chromatin interactions, focusing on their impact on chromatin positioning, compaction, repression, and spatial organization.

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Activation-induced re-organization of chromatin in human T cells

10.1101/2020.06.08.135020 ◽

2020 ◽

Author(s):

Naiara G. Bediaga ◽

Hannah D. Coughlan ◽

Timothy M. Johanson ◽

Alexandra L. Garnham ◽

Gaetano Naselli ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

T Cell Activation ◽

Cell Activation ◽

Target Genes ◽

Nucleosome Occupancy ◽

Chromatin Accessibility ◽

Chromatin Architecture ◽

Chromatin Interactions ◽

Human T Cells

ABSTRACTRemodelling of chromatin architecture is known to regulate gene expression and has been well characterized in cell lineage development but less so in response to cell perturbation. Activation of T cells, which triggers extensive changes in transcriptional programs, serves as an instructive model to elucidate how changes in genome organization orchestrate gene expression in response to cell perturbation. To characterize coordinate changes at different levels of chromatin architecture, we analysed chromatin accessibility, chromosome conformation and gene expression after activation of human T cells. T cell activation led to widespread changes in chromatin interactions and accessibility that were mostly shared between CD4+ and CD8+ T cells. Differential chromatin interactions were associated with upregulation or downregulation of linked target genes. Moreover, activation was associated with the formation of shorter chromatin interactions, partitioning of topologically associating domains (TADs) and acquisition of new TAD boundaries characterized by higher nucleosome occupancy, and lower chromatin accessibility and gene expression. These findings render an integrated and multiscale characterization of activation-induced re-organization of chromatin architecture underlying gene transcription in human T cells.

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