scholarly journals Annotation of Chromatin States in 66 Complete Mouse Epigenomes During Development

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.

scholarly journals Annotation of chromatin states in 66 complete mouse epigenomes during development

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.

scholarly journals Systematic mapping of chromatin state landscapes during mouse development

2017 ◽  
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.

scholarly journals chromstaR: Tracking combinatorial chromatin state dynamics in space and time

2016 ◽  
Author(s):  
Aaron Taudt ◽  
Minh Anh Nguyen ◽  
Matthias Heinig ◽  
Frank Johannes ◽  
Maria Colomé-Tatché
Keyword(s):  
Temporal Dynamics ◽  
Cell Types ◽  
R Package ◽  
Developmental Time ◽  
Genomic Region ◽  
Chromatin State ◽  
Post Translational Modifications ◽  
Chromatin States ◽  
Genome Wide ◽  
Experimental Treatments

AbstractBackgroundPost-translational modifications of histone residue tails are an important component of genome regulation. It is becoming increasingly clear that the combinatorial presence and absence of various modifications define discrete chromatin states which determine the functional properties of a locus. An emerging experimental goal is to track changes in chromatin state maps across different conditions, such as experimental treatments, cell-types or developmental time points.ResultsHere we present chromstaR, an algorithm for the computational inference of combinatorial chromatin state dynamics across an arbitrary number of conditions. ChromstaR uses a multivariate Hidden Markov Model to determine the number of discrete combinatorial chromatin states using multiple ChIP-seq experiments as input and assigns every genomic region to a state based on the presence/absence of each modification in every condition. We demonstrate the advantages of chromstaR in the context of three common experimental data scenarios. First, we study how different histone modifications combine to form combinatorial chromatin states in a single tissue. Second, we infer genome-wide patterns of combinatorial state differences between two cell types or conditions. Finally, we study the dynamics of combinatorial chromatin states during tissue differentiation involving up to six differentiation points. Our findings reveal a striking sparcity in the combinatorial organization and temporal dynamics of chromatin state maps.ConclusionschromstaR is a versatile computational tool that facilitates a deeper biological understanding of chromatin organization and dynamics. The algorithm is implemented as an R-package and freely available from http://bioconductor.org/packages/chromstaR/.

scholarly journals Inhibition of mTOR during a postnatal critical sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss of TSC1

2020 ◽  
Author(s):  
Mayukh Choudhury ◽  
Clara A. Amegandjin ◽  
Vidya Jadhav ◽  
Josianne Nunes Carriço ◽  
Ariane Quintal ◽  
...  
Keyword(s):  
Social Behavior ◽  
Time Course ◽  
Cell Types ◽  
Developmental Time ◽  
Adult Mice ◽  
Mtorc1 Signaling ◽  
Pv Cell ◽  
Mechanistic Basis

ABSTRACTMutations in regulators of the Mechanistic Target Of Rapamycin Complex 1 (mTORC1), such as Tsc1/2, lead to neurodevelopmental disorders associated with autism, intellectual disabilities and epilepsy. Whereas the effects of mTORC1 signaling dysfunction within diverse cell types are likely critical for the onset of the diverse neurological symptoms associated with mutations in mTORC1 regulators, they are not well understood. In particular, the effects of mTORC1 dys-regulation in specific types of inhibitory interneurons are unclear.Here, we showed that Tsc1 haploinsufficiency in parvalbumin (PV)-positive GABAergic interneurons either in cortical organotypic cultures or in vivo caused a premature increase in their perisomatic innervations, followed by a striking loss in adult mice. This effects were accompanied by alterations of AMPK-dependent autophagy in pre-adolescent but not adult mice. PV cell-restricted Tsc1 mutant mice showed deficits in social behavior. Treatment with the mTOR inhibitor Rapamycin restricted to the third postnatal week was sufficient to permanently rescue deficits in both PV cell innervation and social behavior in adult conditional haploinsufficient mice. All together, these findings identify a novel role of Tsc1-mTORC1 signaling in the regulation of the developmental time course and maintenance of cortical PV cell connectivity and provide a mechanistic basis for the targeted rescue of autism-related behaviors in disorders associated with deregulated mTORC1 signaling.

scholarly journals Emergence of neuronal diversity during vertebrate brain development

2019 ◽  
Author(s):  
Bushra Raj ◽  
Jeffrey A. Farrell ◽  
Aaron McKenna ◽  
Jessica L. Leslie ◽  
Alexander F. Schier
Keyword(s):  
Brain Development ◽  
Single Cell ◽  
Time Course ◽  
Temporal Dynamics ◽  
Cell Types ◽  
Developmental Time ◽  
Neural Progenitors ◽  
Neuronal Diversity ◽  
Gene Markers ◽  
Vertebrate Brain

ABSTRACTNeurogenesis in the vertebrate brain comprises many steps ranging from the proliferation of progenitors to the differentiation and maturation of neurons. Although these processes are highly regulated, the landscape of transcriptional changes and progenitor identities underlying brain development are poorly characterized. Here, we describe the first developmental single-cell RNA-seq catalog of more than 200,000 zebrafish brain cells encompassing 12 stages from 12 hours post-fertilization to 15 days post-fertilization. We characterize known and novel gene markers for more than 800 clusters across these timepoints. Our results capture the temporal dynamics of multiple neurogenic waves from embryo to larva that expand neuronal diversity from ∼20 cell types at 12 hpf to ∼100 cell types at 15 dpf. We find that most embryonic neural progenitor states are transient and transcriptionally distinct from long-lasting neural progenitors of post-embryonic stages. Furthermore, we reconstruct cell specification trajectories for the retina and hypothalamus, and identify gene expression cascades and novel markers. Our analysis reveal that late-stage retinal neural progenitors transcriptionally overlap cell states observed in the embryo, while hypothalamic neural progenitors become progressively distinct with developmental time. These data provide the first comprehensive single-cell transcriptomic time course for vertebrate brain development and suggest distinct neurogenic regulatory paradigms between different stages and tissues.

scholarly journals An atlas of dynamic chromatin landscapes in mouse fetal development

Nature ◽  
2020 ◽  
Vol 583 (7818) ◽  
pp. 744-751 ◽  
Author(s):  
David U. Gorkin ◽  
Iros Barozzi ◽  
Yuan Zhao ◽  
Yanxiao Zhang ◽  
Hui Huang ◽  
...  
Keyword(s):  
Fetal Development ◽  
Target Genes ◽  
Developmental Stages ◽  
Chromatin Accessibility ◽  
Chromatin State ◽  
Mammalian Development ◽  
Mouse Fetus ◽  
Chromatin Dynamics ◽  
Mouse Tissues ◽  
Genomic Resource

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.

scholarly journals High-throughput single-cell transcriptomics reveals the female germline differentiation trajectory in Arabidopsis thaliana

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Zhimin Hou ◽  
Yanhui Liu ◽  
Man Zhang ◽  
Lihua Zhao ◽  
Xingyue Jin ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Single Cell ◽  
Cell Fate ◽  
Single Cells ◽  
Expression Patterns ◽  
Cell Types ◽  
Developmental Time ◽  
Developmental Trajectory ◽  
Germline Differentiation ◽  
Female Germline

AbstractFemale germline cells in flowering plants differentiate from somatic cells to produce specialized reproductive organs, called ovules, embedded deep inside the flowers. We investigated the molecular basis of this distinctive developmental program by performing single-cell RNA sequencing (scRNA-seq) of 16,872 single cells of Arabidopsis thaliana ovule primordia at three developmental time points during female germline differentiation. This allowed us to identify the characteristic expression patterns of the main cell types, including the female germline and its surrounding nucellus. We then reconstructed the continuous trajectory of female germline differentiation and observed dynamic waves of gene expression along the developmental trajectory. A focused analysis revealed transcriptional cascades and identified key transcriptional factors that showed distinct expression patterns along the germline differentiation trajectory. Our study provides a valuable reference dataset of the transcriptional process during female germline differentiation at single-cell resolution, shedding light on the mechanisms underlying germline cell fate determination.

scholarly journals Schizophrenia Risk Alleles Often Affect The Expression of Many Genes and Each Gene May Have a Different Effect On The Risk; A Mediation Analysis

2020 ◽  
Author(s):  
Xi Peng ◽  
Joel S. Bader ◽  
Dimitrios Avramopoulos
Keyword(s):  
Gene Expression ◽  
Mediation Analysis ◽  
Target Genes ◽  
Risk Allele ◽  
Association Studies ◽  
Cell Types ◽  
Developmental Time ◽  
Genome Wide Association Studies ◽  
Expression Change ◽  
Risk Alleles

ABSTRACTVariants identified by genome-wide association studies (GWAS) are often expression quantitative trait loci (eQTLs), suggesting they are proxies or are themselves regulatory. Across many datasets analyses show that variants often affect multiple genes. Lacking data on many tissue types, developmental time points and homogeneous cell types, the extent of this one-to-many relationship is underestimated. This raises questions on whether a disease eQTL target gene explains the genetic association or is a by-stander and puts into question the direction of expression effect of on the risk, since the many variant - regulated genes may have opposing effects, imperfectly balancing each other. We used two brain gene expression datasets (CommonMind and BrainSeq) for mediation analysis of schizophrenia-associated variants. We confirm that eQTL target genes often mediate risk but the direction in which expression affects risk is often different from that in which the risk allele changes expression. Of 38 mediator genes significant in both datasets 33 showed consistent mediation direction (Chi2 test P=6*10−6). One might expect that the expression would correlate with the risk allele in the same direction it correlates with disease. For 15 of these 33 (45%), however, the expression change associated with the risk allele was protective, suggesting the likely presence of other target genes with overriding effects. Our results identify specific risk mediating genes and suggest caution in interpreting the biological consequences of targeted modifications of gene expression, as not all eQTL targets may be relevant to disease while those that are, might have different than expected directions.

scholarly journals Multi-scale annotations of chromatin states in 127 human cell-types

2020 ◽  
Author(s):  
Yan Kai ◽  
Stephanos Tsoucas ◽  
Shengbao Suo ◽  
Guo-Cheng Yuan
Keyword(s):  
Human Cell ◽  
Biological Function ◽  
Cell Types ◽  
Chromatin State ◽  
Cell Type ◽  
Chromatin States ◽  
Multi Scale ◽  
Public Data ◽  
Domain State ◽  
Cell Type Specific

AbstractGenome-wide profiling of chromatin states has been widely used to characterize the biological function of non-coding genomic sequences in a cell-type specific manner. However, the systematic, comprehensive annotations of chromatin states from experimental data are challenging and require not just extensive biological knowledge but also sophisticated computational modeling. Previously we developed a hierarchical hidden Markov model, named diHMM, to systematically annotate chromatin states at multiple scales based on the combination of histone mark and chromatin regulator binding profiles. Here, we have improved the method by optimizing computational efficiency and using an ensemble-clustering approach to achieve a unified annotation by integrating information from cell-type-specific models. We then applied this improved method to generate a unified multi-scale chromatin state map in 127 human cell types, based on public data generated by the Epigenome Roadmap and ENCODE consortia. We found cell types with similar origin are typically associated with similar chromatin states, but cultured cell lines have distinct structures than primary cells. The contribution of enhancer elements to gene regulation is mediated by the broader context of domain-state organization. Distinct domain-state patterns are associated with various 3D chromatin structures. As such, we have demonstrated the utility of the multi-scale chromatin state map in characterizing the biological function of the human genome.

scholarly journals A Genomic Approach to Identify Novel Progesterone Receptor Regulated Pathways in the Uterus during Implantation

2002 ◽  
Vol 16 (12) ◽  
pp. 2853-2871 ◽  
Author(s):  
Yong-Pil Cheon ◽  
Quanxi Li ◽  
Xueping Xu ◽  
Francesco J. DeMayo ◽  
Indrani C. Bagchi ◽  
...  
Keyword(s):  
Gene Networks ◽  
Time Course ◽  
Target Genes ◽  
Reproductive Tract ◽  
Cell Types ◽  
Temporal Analysis ◽  
Pregnant Mouse ◽  
Initial Examination ◽  
Mouse Uterus ◽  
Pregnant Uterus

Abstract The cellular actions of steroid hormone progesterone (P) are mediated via its nuclear receptors, which regulate the expression of specific target genes. The identity of gene networks that are regulated by the P receptors (PRs) in the uterus at various stages of the reproductive cycle and pregnancy, however, remain largely unknown. In this study, we have used oligonucleotide microarrays to identify mRNAs whose expression in the pregnant mouse uterus is modulated by RU486, a well-characterized PR antagonist, which is also an effective inhibitor of implantation. We found that, in response to RU486, expression of mRNAs corresponding to 78 known genes was down-regulated at least 2-fold in the preimplantation mouse uterus. The PR regulation of several of these genes was ascertained by administering P to ovariectomized wild-type and PR knockout (PRKO) mice. Detailed spatio-temporal analysis of these genes in the pregnant uterus indicated that their expression in the epithelium and stroma could be correlated with the expression of PR in those cell types. Furthermore, time-course studies suggested that many of these genes are likely primary targets of PR regulation. We also identified 70 known genes that were up-regulated at least 2-fold in the pregnant uterus in response to RU486. Interestingly, initial examination of a number of RU486-inducible genes reveals that their uterine expression is also regulated by estrogen. The identification of several novel PR-regulated gene pathways in the reproductive tract is an important step toward understanding how P regulates the physiological events leading to implantation.

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