scholarly journals RT States: systematic annotation of the human genome using cell type-specific replication timing programs

2018 ◽  
Author(s):  
Axel Poulet ◽  
Ben Li ◽  
Tristan Dubos ◽  
Juan Carlos Rivera-Mulia ◽  
David M. Gilbert ◽  
...  
Keyword(s):  
Human Genome ◽  
Cell Fate ◽  
Developmental Stages ◽  
Replication Timing ◽  
Cell Types ◽  
Biological Properties ◽  
Biological Processes ◽  
Genomic Locus ◽  
Genome Wide ◽  
Fundamental Biological Process

ABSTRACTThe replication timing (RT) program has been linked to many key biological processes including cell fate commitment, 3D chromatin organization and transcription regulation. Significant technology progress now allows to characterize the RT program in the entire human genome in a high-throughput and high-resolution fashion. These experiments suggest that RT changes dynamically during development in coordination with gene activity. Since RT is such a fundamental biological process, we believe that an effective quantitative profile of the local RT program from a diverse set of cell types in various developmental stages and lineages can provide crucial biological insights for a genomic locus. In the present study, we explored recurrent and spatially coherent combinatorial profiles from 42 RT programs collected from multiple lineages at diverse differentiation states. We found that a Hidden Markov Model with 15 hidden states provide a good model to describe these genome-wide RT profiling data. Each of the hidden state represents a unique combination of RT profiles across different cell types which we refer to as “RT states”. To understand the biological properties of these RT states, we inspected their relationship with chromatin states, gene expression, functional annotation and 3D chromosomal organization. We found that the newly defined RT states possess interesting genome-wide functional properties that add complementary information to the existing annotation of the human genome.AUTHOR SUMMARYThe replication timing (RT) program is an important cellular mechanism and has been linked to many key biological processes including cell fate commitment, 3D chromatin organization and transcription regulation. Significant technology progress now allows us to characterize the RT program in the entire human genome. Results from these experiments suggest that RT changes dynamically across different developmental stages. Since RT is such a fundamental biological process, we believe that the local RT program from a diverse set of cell types in various developmental stages can provide crucial biological insights for a genomic locus. In the present study, we explored combinatorial profiles from 42 RT programs collected from multiple lineages at diverse differentiation states. We developed a statistical model consist of 15 “RT states” to describe these genome-wide RT profiling data. To understand the biological properties of these RT states, we inspected the relationship between RT states and other types of functional annotations of the genome. We found that the newly defined RT states possess interesting genome-wide functional properties that add complementary information to the existing annotation of the human genome.

scholarly journals RT States: systematic annotation of the human genome using cell type-specific replication timing programs

2018 ◽  
Vol 35 (13) ◽  
pp. 2167-2176
Author(s):  
Axel Poulet ◽  
Ben Li ◽  
Tristan Dubos ◽  
Juan Carlos Rivera-Mulia ◽  
David M Gilbert ◽  
...  
Keyword(s):  
Human Genome ◽  
Cell Fate ◽  
Developmental Stages ◽  
Replication Timing ◽  
Cell Types ◽  
Biological Properties ◽  
Supplementary Information ◽  
Genomic Locus ◽  
Genome Wide ◽  
Fundamental Biological Process

Abstract Motivation The replication timing (RT) program has been linked to many key biological processes including cell fate commitment, 3D chromatin organization and transcription regulation. Significant technology progress now allows to characterize the RT program in the entire human genome in a high-throughput and high-resolution fashion. These experiments suggest that RT changes dynamically during development in coordination with gene activity. Since RT is such a fundamental biological process, we believe that an effective quantitative profile of the local RT program from a diverse set of cell types in various developmental stages and lineages can provide crucial biological insights for a genomic locus. Results In this study, we explored recurrent and spatially coherent combinatorial profiles from 42 RT programs collected from multiple lineages at diverse differentiation states. We found that a Hidden Markov Model with 15 hidden states provide a good model to describe these genome-wide RT profiling data. Each of the hidden state represents a unique combination of RT profiles across different cell types which we refer to as ‘RT states’. To understand the biological properties of these RT states, we inspected their relationship with chromatin states, gene expression, functional annotation and 3D chromosomal organization. We found that the newly defined RT states possess interesting genome-wide functional properties that add complementary information to the existing annotation of the human genome. Availability and implementation R scripts for inferring HMM models and Perl scripts for further analysis are available https://github.com/PouletAxel/script_HMM_Replication_timing. Supplementary information Supplementary data are available at Bioinformatics online.

Identification and expression analysis of E2 ubiquitin-conjugating enzymes in cucumber

2021 ◽  
Author(s):  
Wei Lai ◽  
Zhaoyang Hu ◽  
Chuxia Zhu ◽  
Yingui Yang ◽  
Shiqiang Liu ◽  
...  
Keyword(s):  
Gene Family ◽  
Developmental Stages ◽  
Expression Patterns ◽  
Biological Processes ◽  
Protein Ubiquitination ◽  
Genome Wide ◽  
Conjugating Enzymes ◽  
Gene Structures ◽  
Ubiquitin Conjugating Enzymes ◽  
Genome Wide Survey

Protein ubiquitination is one of the most common modifications that can degrade or modify proteins in eukaryotic cells. The E2 ubiquitin-conjugating enzymes (UBCs) are involved in multiple biological processes of eukaryotes and their response to adverse stresses. Genome-wide survey of the UBC gene family has been performed in many plant species but not in cucumber (Cucumis sativus). In this study, a total of 38 UBC family genes (designated as CsUBC1–CsUBC38) were identified in cucumber. The phylogenetic analysis of UBC proteins from cucumber, Arabidopsis and maize indicated that these proteins could be divided into 15 groups. Most of the phylogenetically related CsUBC members had similar conserved motif patterns and gene structures. The CsUBC genes were unevenly distributed on seven chromosomes, and gene duplication analysis indicated that segmental duplication has played a significant role in the expansion of the cucumber UBC gene family. Promoter analysis of these genes resulted in the identification of many hormone-, stress- and development-related cis-elements. The CsUBC genes exhibited differential expression patterns in different tissues and developmental stages of fruit ripening. In addition, a total of 14 CsUBC genes were differentially expressed upon downy mildew (DM) infection compared with the control. Our results lay the foundation for further clarification of the roles of the CsUBC genes in the future.

scholarly journals Replication timing maintains the global epigenetic state in human cells

2019 ◽  
Author(s):  
Kyle N. Klein ◽  
Peiyao A. Zhao ◽  
Xiaowen Lyu ◽  
Daniel A. Bartlett ◽  
Amar Singh ◽  
...  
Keyword(s):  
Embryonic Stem ◽  
Cancer Cell Line ◽  
Replication Timing ◽  
Cell Types ◽  
Control Factor ◽  
Epigenetic State ◽  
Genome Wide ◽  
A Genome ◽  
A Cell ◽  
Early Replication

AbstractDNA is replicated in a defined temporal order termed the replication timing (RT) program. RT is spatially segregated in the nucleus with early/late replication corresponding to Hi-C A/B chromatin compartments, respectively. Early replication is also associated with active histone modifications and transcriptional permissiveness. However, the mechanistic interplay between RT, chromatin state, and genome compartmentalization is largely unknown. Here we report that RT is central to epigenome maintenance and compartmentalization in both human embryonic stem cells (hESCs) and cancer cell line HCT116. Knockout (KO) of the conserved RT control factor RIF1, rather than causing discrete RT switches as previously suspected, lead to dramatically increased cell to cell heterogeneity of RT genome wide, despite RIF1’s enrichment in late replicating chromatin. RIF1 KO hESCs have a nearly random RT program, unlike all prior RIF1 KO cells, including HCT116, which show localized alterations. Regions that retain RT, which are prevalent in HCT116 but rare in hESCs, consist of large H3K9me3 domains revealing two independent mechanisms of RT regulation that are used to different extents in different cell types. RIF1 KO results in a striking genome wide downregulation of H3K27ac peaks and enrichment of H3K9me3 at large domains that remain late replicating, while H3K27me3 and H3K4me3 are re-distributed genome wide in a cell type specific manner. These histone modification changes coincided with global reorganization of genome compartments, transcription changes and a genome wide strengthening of TAD structures. Inducible degradation of RIF1 revealed that disruption of RT is upstream of genome compartmentalization changes. Our findings demonstrate that disruption of RT leads to widespread epigenetic mis-regulation, supporting previously speculative models in which the timing of chromatin assembly at the replication fork plays a key role in maintaining the global epigenetic state, which in turn drives genome architecture.

scholarly journals Allele-specific control of replication timing and genome organization during development

2017 ◽  
Author(s):  
Juan Carlos Rivera-Mulia ◽  
Andrew Dimond ◽  
Daniel Vera ◽  
Claudia Trevilla-Garcia ◽  
Takayo Sasaki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Genome Organization ◽  
Replication Timing ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Parental Origin ◽  
F1 Hybrid ◽  
Primary Mouse ◽  
Allele Specific

AbstractDNA replication occurs in a defined temporal order known as the replication-timing (RT) program. RT is regulated during development in discrete chromosomal units, coordinated with transcriptional activity and 3D genome organization. Here, we derived distinct cell types from F1 hybrid musculus X castaneus mouse crosses and exploited the high single nucleotide polymorphism (SNP) density to characterize allelic differences in RT (Repli-seq), genome organization (Hi-C and promoter-capture Hi-C), gene expression (nuclear RNA-seq) and chromatin accessibility (ATAC-seq). We also presentHARP: a new computational tool for sorting SNPs in phased genomes to efficiently measure allele-specific genome-wide data. Analysis of 6 different hybrid mESC clones with different genomes (C57BL/6, 129/sv and CAST/Ei), parental configurations and gender revealed significant RT asynchrony between alleles across ~12 % of the autosomal genome linked to sub-species genomes but not to parental origin, growth conditions or gender. RT asynchrony in mESCs strongly correlated with changes in Hi-C compartments between alleles but not SNP density, gene expression, imprinting or chromatin accessibility. We then tracked mESC RT asynchronous regions during development by analyzing differentiated cell types including extraembryonic endoderm stem (XEN) cells, 4 male and female primary mouse embryonic fibroblasts (MEFs) and neural precursors (NPCs) differentiatedin vitrofrom mESCs with opposite parental configurations. Surprisingly, we found that RT asynchrony and allelic discordance in Hi-C compartments seen in mESCs was largely lost in all differentiated cell types, coordinated with a more uniform Hi-C compartment arrangement, suggesting that genome organization of homologues converges to similar folding patterns during cell fate commitment.

scholarly journals Sensory neuron lineage mapping and manipulation in the Drosophila olfactory system

2018 ◽  
Author(s):  
Phing Chian Chai ◽  
Steeve Cruchet ◽  
Leonore Wigger ◽  
Richard Benton
Keyword(s):  
Sensory Neuron ◽  
Olfactory System ◽  
Developmental Stages ◽  
Cell Types ◽  
Fate Map ◽  
Genome Wide ◽  
A Genome ◽  
Ets Family ◽  
Lineage Mapping ◽  
Olfactory Tissue

AbstractNervous systems exhibit myriad cell types, but understanding how this diversity arises is hampered by the difficulty to visualize and genetically-interrogate specific lineages, especially at early developmental stages prior to expression of unique molecular markers. Here, we use a genetic immortalization method to analyze the development of sensory neuron lineages in the Drosophila olfactory system, from their origin to terminal differentiation. We apply this approach to first define a fate map of all olfactory lineages and refine the model of temporal patterns of lineage divisions. Taking advantage of a selective marker for the lineage that gives rise to Or67d pheromone-sensing neurons and a genome-wide transcription factor RNAi screen, we identify the spatial and temporal requirements for Pointed, an ETS family member, in this developmental pathway. Transcriptomic analysis of wild-type and Pointed-depleted olfactory tissue reveals a universal requirement for this factor as a switch-like determinant of fates in these sensory lineages.

scholarly journals Specification of diverse cell types during early neurogenesis of the mouse cerebellum

2018 ◽  
Author(s):  
John W. Wizeman ◽  
Qiuxia Guo ◽  
Elliot Wilion ◽  
James Y.H. Li
Keyword(s):  
Cell Fate ◽  
Developmental Trajectories ◽  
Ventricular Zone ◽  
Cell Types ◽  
Genome Wide ◽  
Integral Role ◽  
Cerebellar Cell ◽  
Early Neurogenesis ◽  
And Function ◽  
Developing Cerebellum

SUMMARYWe applied single-cell RNA sequencing to profile genome-wide gene expression in about 9,400 individual cerebellar cells from the mouse embryo at embryonic day 13.5. Reiterative clustering identified the major cerebellar cell types and subpopulations of different lineages. Through pseudotemporal ordering to reconstruct developmental trajectories, we identified novel transcriptional programs controlling cell fate specification of populations arising from the ventricular zone and the anterior rhombic lip, two distinct germinal zones of the embryonic cerebellum. Together, our data revealed cell-specific markers for studying the cerebellum, important specification decisions, and a number of previously unknown subpopulations that may play an integral role in the formation and function of the cerebellum. Importantly, we identified a potential mechanism of vermis formation, which is affected by multiple congenital cerebellar defects. Our findings will facilitate new discovery by providing insights into the molecular and cell type diversity in the developing cerebellum.

scholarly journals Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

2020 ◽  
Author(s):  
◽  
Stephan Ripke ◽  
James TR Walters ◽  
Michael C O'Donovan
Keyword(s):  
Developmental Disorder ◽  
Association Studies ◽  
Cell Types ◽  
Genome Wide Association Studies ◽  
Biological Processes ◽  
Neuronal Function ◽  
Protein Coding ◽  
Risk Alleles ◽  
Genome Wide ◽  
Coding Variants

Schizophrenia is a psychiatric disorder whose pathophysiology is largely unknown. It has a heritability of 60-80%, much of which is attributable to common risk alleles, suggesting genome-wide association studies can inform our understanding of aetiology. Here, in 69,369 people with schizophrenia and 236,642 controls, we report common variant associations at 270 distinct loci. Using fine-mapping and functional genomic data, we prioritise 19 genes based on protein-coding or UTR variation, and 130 genes in total as likely to explain these associations. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in autism and developmental disorder. Associations were concentrated in genes expressed in CNS neurons, both excitatory and inhibitory, but not other tissues or cell types, and implicated fundamental processes related to neuronal function, particularly synaptic organisation, differentiation and transmission. We identify biological processes of pathophysiological relevance to schizophrenia, show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders, and provide a rich resource of priority genes and variants to advance mechanistic studies.

scholarly journals Comprehensive analysis of retinal development at single cell resolution identifies NFI factors as essential for mitotic exit and specification of late-born cells

2018 ◽  
Author(s):  
Brian S. Clark ◽  
Genevieve L. Stein-O’Brien ◽  
Fion Shiau ◽  
Gabrielle H. Cannon ◽  
Emily Davis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Cell Fate ◽  
Regulatory Networks ◽  
Developmental Stages ◽  
Cell Types ◽  
Developmental Competence ◽  
Cellular Heterogeneity ◽  
Retinal Cell ◽  
Control Of Gene Expression

SUMMARYPrecise temporal control of gene expression in neuronal progenitors is necessary for correct regulation of neurogenesis and cell fate specification. However, the extensive cellular heterogeneity of the developing CNS has posed a major obstacle to identifying the gene regulatory networks that control these processes. To address this, we used single cell RNA-sequencing to profile ten developmental stages encompassing the full course of retinal neurogenesis. This allowed us to comprehensively characterize changes in gene expression that occur during initiation of neurogenesis, changes in developmental competence, and specification and differentiation of each of the major retinal cell types. These data identify transitions in gene expression between early and late-stage retinal progenitors, as well as a classification of neurogenic progenitors. We identify here the NFI family of transcription factors (Nfia, Nfib, and Nfix) as genes with enriched expression within late RPCs, and show they are regulators of bipolar interneuron and Müller glia specification and the control of proliferative quiescence.

scholarly journals Replication Timing Networks: a novel class of gene regulatory networks

2017 ◽  
Author(s):  
Juan Carlos Rivera-Mulia ◽  
Sebo Kim ◽  
Haitham Gabr ◽  
Abhijit Chakraborty ◽  
Ferhat Ay ◽  
...  
Keyword(s):  
Cell Fate ◽  
Regulatory Networks ◽  
Embryonic Stem ◽  
Replication Timing ◽  
Cell Types ◽  
Bipartite Networks ◽  
Transcriptional Regulatory Networks ◽  
3D Genome ◽  
Regulatory Link ◽  
Indirect Relationship

AbstractDNA replication occurs in a defined temporal order known as the replication-timing (RT) program and is regulated during development, coordinated with 3D genome organization and transcriptional activity. However, transcription and RT are not sufficiently coordinated to predict each other, suggesting an indirect relationship. Here, we exploit genome-wide RT profiles from 15 human cell types and intermediate differentiation stages derived from human embryonic stem cells to construct different types of RT regulatory networks. First, we constructed networks based on the coordinated RT changes during cell fate commitment to create highly complex RT networks composed of thousands of interactions that form specific functional sub-network communities. We also constructed directional regulatory networks based on the order of RT changes within cell lineages and identified master regulators of differentiation pathways. Finally, we explored relationships between RT networks and transcriptional regulatory networks (TRNs), by combining them into more complex circuitries of composite and bipartite networks, revealing novel trans interactions between transcription factors and downstream RT changes that were validated with ChIP-seq data. Our findings suggest a regulatory link between the establishment of cell type specific TRNs and RT control during lineage specification.

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