An atlas of dynamic chromatin landscapes in mouse fetal development

AbstractThe Encyclopedia of DNA Elements (ENCODE) project has established a genomic resource for mammalian development, profiling a diverse panel of mouse tissues at 8 developmental stages from 10.5 days after conception until birth, including transcriptomes, methylomes and chromatin states. Here we systematically examined the state and accessibility of chromatin in the developing mouse fetus. In total we performed 1,128 chromatin immunoprecipitation with sequencing (ChIP–seq) assays for histone modifications and 132 assay for transposase-accessible chromatin using sequencing (ATAC–seq) assays for chromatin accessibility across 72 distinct tissue-stages. We used integrative analysis to develop a unified set of chromatin state annotations, infer the identities of dynamic enhancers and key transcriptional regulators, and characterize the relationship between chromatin state and accessibility during developmental gene regulation. We also leveraged these data to link enhancers to putative target genes and demonstrate tissue-specific enrichments of sequence variants associated with disease in humans. The mouse ENCODE data sets provide a compendium of resources for biomedical researchers and achieve, to our knowledge, the most comprehensive view of chromatin dynamics during mammalian fetal development to date.

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Systematic mapping of chromatin state landscapes during mouse development

10.1101/166652 ◽

2017 ◽

Cited By ~ 15

Author(s):

David U. Gorkin ◽

Iros Barozzi ◽

Yanxiao Zhang ◽

Ah Young Lee ◽

Bin Li ◽

...

Keyword(s):

Histone Modifications ◽

Target Genes ◽

Developmental Stages ◽

Developmental Time ◽

Chromatin State ◽

Mouse Development ◽

Disease Etiology ◽

Chromatin States ◽

Mouse Tissues ◽

Core Components

SUMMARYEmbryogenesis requires epigenetic information that allows each cell to respond appropriately to developmental cues. Histone modifications are core components of a cell’s epigenome, giving rise to chromatin states that modulate genome function. Here, we systematically profile histone modifications in a diverse panel of mouse tissues at 8 developmental stages from 10.5 days post conception until birth, performing a total of 1,128 ChIP-seq assays across 72 distinct tissue-stages. We combine these histone modification profiles into a unified set of chromatin state annotations, and track their activity across developmental time and space. Through integrative analysis we identify dynamic enhancers, reveal key transcriptional regulators, and characterize the role of chromatin-based repression in developmental gene regulation. We also leverage these data to link enhancers to putative target genes, revealing connections between coding and non-coding sequence variation in disease etiology. Our study provides a compendium of resources for biomedical researchers, and achieves the most comprehensive view of embryonic chromatin states to date.

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Spatiotemporal DNA Methylome Dynamics of the Developing Mammalian Fetus

10.1101/166744 ◽

2017 ◽

Cited By ~ 14

Author(s):

Yupeng He ◽

Manoj Hariharan ◽

David U. Gorkin ◽

Diane E. Dickel ◽

Chongyuan Luo ◽

...

Keyword(s):

Fetal Development ◽

Transcriptional Repression ◽

Essential Role ◽

Developmental Stages ◽

Genetic Diseases ◽

Regulatory Elements ◽

Early Embryogenesis ◽

Mammalian Development ◽

Genetic Studies ◽

Mouse Tissues

SummaryGenetic studies have revealed an essential role for cytosine DNA methylation in mammalian development. However, its spatiotemporal distribution in the developing embryo remains obscure. Here, we profiled the methylome landscapes of 12 mouse tissues/organs at 8 developmental stages spanning from early embryogenesis to birth. Indepth analysis of these spatiotemporal epigenome maps systematically delineated ~2 million methylation variant regions and uncovered widespread methylation dynamics at nearly one-half million tissue-specific enhancers, whose human counterparts were enriched for variants involved in genetic diseases. Strikingly, these predicted regulatory elements predominantly lose CG methylation during fetal development, whereas the trend is reversed after birth. Accumulation of non-CG methylation within gene bodies of key developmental transcription factors coincided with their transcriptional repression during later stages of fetal development. These spatiotemporal epigenomic maps provide a valuable resource for studying gene regulation during mammalian tissue/organ progression and for pinpointing regulatory elements involved in human developmental diseases.

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Annotation of chromatin states in 66 complete mouse epigenomes during development

Communications Biology ◽

10.1038/s42003-021-01756-4 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Arjan van der Velde ◽

Kaili Fan ◽

Junko Tsuji ◽

Jill E. Moore ◽

Michael J. Purcaro ◽

...

Keyword(s):

Target Genes ◽

Cell Types ◽

Developmental Trajectory ◽

Phase Iii ◽

Chromatin State ◽

Mammalian Development ◽

Chromatin States ◽

Transcription Start Sites ◽

Repressive Mark ◽

Distinct Cell

AbstractThe morphologically and functionally distinct cell types of a multicellular organism are maintained by their unique epigenomes and gene expression programs. Phase III of the ENCODE Project profiled 66 mouse epigenomes across twelve tissues at daily intervals from embryonic day 11.5 to birth. Applying the ChromHMM algorithm to these epigenomes, we annotated eighteen chromatin states with characteristics of promoters, enhancers, transcribed regions, repressed regions, and quiescent regions. Our integrative analyses delineate the tissue specificity and developmental trajectory of the loci in these chromatin states. Approximately 0.3% of each epigenome is assigned to a bivalent chromatin state, which harbors both active marks and the repressive mark H3K27me3. Highly evolutionarily conserved, these loci are enriched in silencers bound by polycomb repressive complex proteins, and the transcription start sites of their silenced target genes. This collection of chromatin state assignments provides a useful resource for studying mammalian development.

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

10.1101/2021.11.02.466869 ◽

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.

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Chromatin accessibility and regulatory vocabulary across indicine cattle tissues

Genome Biology ◽

10.1186/s13059-021-02489-7 ◽

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.

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Chromatin accessibility dynamics reveal novel functional enhancers in C. elegans

10.1101/088732 ◽

2016 ◽

Cited By ~ 2

Author(s):

Aaron C. Daugherty ◽

Robin Yeo ◽

Jason D. Buenrostro ◽

William J. Greenleaf ◽

Anshul Kundaje ◽

...

Keyword(s):

Transcription Factor ◽

Developmental Stages ◽

Model Organism ◽

High Sensitivity ◽

Chromatin Accessibility ◽

Chromatin Dynamics ◽

C Elegans ◽

Crucial Component ◽

Organismal Development

AbstractChromatin accessibility, a crucial component of genome regulation, has primarily been studied in homogeneous and simple systems, such as isolated cell populations or early-development models. Whether chromatin accessibility can be assessed in complex, dynamic systems in vivo with high sensitivity remains largely unexplored. In this study, we use ATAC-seq to identify chromatin accessibility changes in a whole animal, the model organism C. elegans, from embryogenesis to adulthood. Chromatin accessibility changes between developmental stages are highly reproducible, recapitulate histone modification changes, and reveal key regulatory aspects of the epigenomic landscape throughout organismal development. We find that over 5,000 distal non-coding regions exhibit dynamic changes in chromatin accessibility between developmental stages, and could thereby represent putative enhancers. When tested in vivo, several of these putative enhancers indeed drive novel cell-type-and temporal-specific patterns of expression. Finally, by integrating transcription factor binding motifs in a machine learning framework, we identify EOR-1 as a unique transcription factor that may regulate chromatin dynamics during development. Our study provides a unique resource for C. elegans, a system in which the prevalence and importance of enhancers remains poorly characterized, and demonstrates the power of using whole organism chromatin accessibility to identify novel regulatory regions in complex systems.

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Annotation of Chromatin States in 66 Complete Mouse Epigenomes During Development

10.1101/2020.07.23.218552 ◽

2020 ◽

Author(s):

Arjan van der Velde ◽

Kaili Fan ◽

Junko Tsuji ◽

Jill Moore ◽

Michael Purcaro ◽

...

Keyword(s):

Time Course ◽

Target Genes ◽

Cell Types ◽

Developmental Time ◽

Developmental Trajectory ◽

Phase Iii ◽

Chromatin State ◽

Mammalian Development ◽

Chromatin States ◽

Transcription Start Sites

ABSTRACTThe morphologically and functionally distinct cell types of a multicellular organism are maintained by epigenomes and gene expression programs. Phase III of the ENCODE Project profiled 66 mouse epigenomes across twelve tissues at daily intervals from embryonic day 10.5 to birth. Applying the ChromHMM algorithm to these epigenomes, we annotated eighteen chromatin states with characteristics of promoters, enhancers, transcribed regions, repressed regions, and quiescent regions throughout the developmental time course. Our integrative analyses delineate the tissue specificity and developmental trajectory of the loci in these chromatin states. Approximately 0.3% of each epigenome is assigned to a bivalent chromatin state, which harbors both active marks and the repressive mark H3K27me3. Highly evolutionarily conserved, these loci are enriched in silencers bound by Polycomb Repressive Complex proteins and the transcription start sites of their silenced target genes. This collection of chromatin state assignments provides a useful resource for studying mammalian development.

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Concentration dependent chromatin states induced by the bicoid morphogen gradient

eLife ◽

10.7554/elife.28275 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 35

Author(s):

Colleen E Hannon ◽

Shelby A Blythe ◽

Eric F Wieschaus

Keyword(s):

Large Scale ◽

Common Property ◽

Target Genes ◽

Positional Information ◽

Chromatin Accessibility ◽

Chromatin State ◽

Open Chromatin ◽

Genome Wide ◽

High Concentrations

In Drosophila, graded expression of the maternal transcription factor Bicoid (Bcd) provides positional information to activate target genes at different positions along the anterior-posterior axis. We have measured the genome-wide binding profile of Bcd using ChIP-seq in embryos expressing single, uniform levels of Bcd protein, and grouped Bcd-bound targets into four classes based on occupancy at different concentrations. By measuring the biochemical affinity of target enhancers in these classes in vitro and genome-wide chromatin accessibility by ATAC-seq, we found that the occupancy of target sequences by Bcd is not primarily determined by Bcd binding sites, but by chromatin context. Bcd drives an open chromatin state at a subset of its targets. Our data support a model where Bcd influences chromatin structure to gain access to concentration-sensitive targets at high concentrations, while concentration-insensitive targets are found in more accessible chromatin and are bound at low concentrations. This may be a common property of developmental transcription factors that must gain early access to their target enhancers while the chromatin state of the genome is being remodeled during large-scale transitions in the gene regulatory landscape.

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Chromatin state transition underlies the temporal changes in gene expression during cardiomyocyte maturation

10.1101/2021.12.28.474318 ◽

2021 ◽

Author(s):

Chia-Yeh Lin ◽

Yao-Ming Chang ◽

Hsin-Yi Tseng ◽

Yen-Ling Shih ◽

Hsiao-Hui Yeh ◽

...

Keyword(s):

Gene Expression ◽

Heart Development ◽

Gene Networks ◽

Developmental Plasticity ◽

Chromatin Accessibility ◽

Chromatin State ◽

State Transitions ◽

Chromatin Dynamics ◽

Cardiac Gene ◽

Postnatal Environment

Congenital heart disease (CHD) is often rooted in aberrant gene expression during heart development. As cells commit to a specific lineage during development, chromatin dynamics and developmental plasticity generally become more limited. However, it remains unclear how differentiated cardiomyocytes (CMs) undergo morphological and functional adaptations to the postnatal environment during the process of CM maturation. We sought to investigate the regulatory mechanisms that control postnatal cardiac gene networks. A time-series transcriptomic analysis of postnatal hearts revealed an integrated, time-ordered transcriptional network that regulates CM maturation. Remarkably, depletion of histone H2B ubiquitin ligase RNF20 after formation of the four-chamber heart disrupted these highly coordinated gene networks. As such, its ablation caused early-onset cardiomyopathy, a phenotype reminiscent of CHD. Furthermore, the dynamic modulation of chromatin accessibility by RNF20 during CM maturation was necessary for the operative binding of cardiac transcription factors that drive transcriptional gene networks. Together, our results reveal how epigenetic-mediated chromatin state transitions modulate time-ordered gene expression for CM maturation.

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Chromatin-directed proteomics-identified network of endogenous androgen receptor in prostate cancer cells

Oncogene ◽

10.1038/s41388-021-01887-2 ◽

2021 ◽

Author(s):

Kaisa-Mari Launonen ◽

Ville Paakinaho ◽

Gianluca Sigismondo ◽

Marjo Malinen ◽

Reijo Sironen ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Target Genes ◽

Epithelial Mesenchymal Transition ◽

Protein A ◽

Chorioallantoic Membrane ◽

Chromatin Accessibility ◽

Castration Resistant Prostate Cancer ◽

Novel Therapy ◽

Mesenchymal Transition

AbstractTreatment of prostate cancer confronts resistance to androgen receptor (AR)-targeted therapies. AR-associated coregulators and chromatin proteins hold a great potential for novel therapy targets. Here, we employed a powerful chromatin-directed proteomics approach termed ChIP-SICAP to uncover the composition of chromatin protein network, the chromatome, around endogenous AR in castration resistant prostate cancer (CRPC) cells. In addition to several expected AR coregulators, the chromatome contained many nuclear proteins not previously associated with the AR. In the context of androgen signaling in CRPC cells, we further investigated the role of a known AR-associated protein, a chromatin remodeler SMARCA4 and that of SIM2, a transcription factor without a previous association with AR. To understand their role in chromatin accessibility and AR target gene expression, we integrated data from ChIP-seq, RNA-seq, ATAC-seq and functional experiments. Despite the wide co-occurrence of SMARCA4 and AR on chromatin, depletion of SMARCA4 influenced chromatin accessibility and expression of a restricted set of AR target genes, especially those involved in cell morphogenetic changes in epithelial-mesenchymal transition. The depletion also inhibited the CRPC cell growth, validating SMARCA4’s functional role in CRPC cells. Although silencing of SIM2 reduced chromatin accessibility similarly, it affected the expression of a much larger group of androgen-regulated genes, including those involved in cellular responses to external stimuli and steroid hormone stimulus. The silencing also reduced proliferation of CRPC cells and tumor size in chick embryo chorioallantoic membrane assay, further emphasizing the importance of SIM2 in CRPC cells and pointing to the functional relevance of this potential prostate cancer biomarker in CRPC cells. Overall, the chromatome of AR identified in this work is an important resource for the field focusing on this important drug target.

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