Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Global Reorganization of Chromatin Architecture during Embronic Stem Cell Differentiation

ABSTRACT: The 3D organization of the genome is important for regulation of diverse nuclear processes ranging from transcription to DNA replication. Knowledge of the higher order chromatin structure is critical for understanding mechanisms of gene regulation by long-range control elements such as enhancers and insulators. We describe high resolution, genome-wide dynamic chromatin interaction maps in human embryonic stem cells (hESC) as they differentiate into four distinct embryonic cell lineages. Extensive reorganization of higher-order chromatin structure occurs during hESC differentiation. In this process, topological domains remain largely intact but inter-domain association patterns change dramatically, coincident with widespread changes in chromatin state and gene expression. Moreover, using proximity ligation sequencing to generate chromosome span haplotypes, widespread allele biased gene activities are detected. The allelic gene expression patterns can be correlated to epigenetic state at distal enhancers, supporting the role of these elements in regulating gene expression over a distance. Two biological replicates of Hi-C experiment and one replicate of CTCF ChIP-Seq experiment in embryonic stem cells and 4 other differentiated cell-types from H1 cell line. Re-analysis of data from GSE16256 in an allele specific manner is linked as supplementary data.

ORGANISM(S): Homo sapiens

SUBMITTER: Jesse Dixon

PROVIDER: E-GEOD-52457 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Chromatin architecture reorganization during stem cell differentiation.

Dixon Jesse R JR Jung Inkyung I Selvaraj Siddarth S Shen Yin Y Antosiewicz-Bourget Jessica E JE Lee Ah Young AY Ye Zhen Z Kim Audrey A Rajagopal Nisha N Xie Wei W Diao Yarui Y Liang Jing J Zhao Huimin H Lobanenkov Victor V VV Ecker Joseph R JR Thomson James A JA Ren Bing B

Nature 20150201 7539

Higher-order chromatin structure is emerging as an important regulator of gene expression. Although dynamic chromatin structures have been identified in the genome, the full scope of chromatin dynamics during mammalian development and lineage specification remains to be determined. By mapping genome-wide chromatin interactions in human embryonic stem (ES) cells and four human ES-cell-derived lineages, we uncover extensive chromatin reorganization during lineage specification. We observe that alt ...[more]

PMID: 25693564

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Project description:Glycosylation is an abundant post-translational modification of both intracellular and extracellular proteins [1]. The majority of glycans are classified as N-linked chains, where the carbohydrate moiety is attached to asparagine residues, or O-linked chains, most commonly linked to a serine or threonine. N-linked glycosylation is initiated by the oligosaccharyltransferase complex with only two paralogs of the catalytic subunit, whereas O-glycan initiation is more complex. There are several types of O-linked glycosylation, but among the most diverse is the mucin or GalNAc type (hereafter referred to as O-glycosylation). O-glycosylation is initiated by 20 evolutionarily conserved polypeptide GalNAc-transferases (GalNAc-Ts), which catalyze the first step in the O-glycosylation of proteins by adding GalNAc residues to threonine, serine, and tyrosine amino acids (Fig 1A). Each of the GalNAc-Ts are differentially expressed in various tissues and have both distinct and overlapping peptide substrate specificities [2-12]. Thus, the repertoire of GalNAc-Ts expressed in a given cell determines the subset and O-glycosite pattern of glycosylated proteins [13]. Substantial efforts have been made to characterize and predict the substrate specificities of GalNAc-Ts in vitro, but understanding of the in vivo specificities of the individual GalNAc-Ts or their biological functions is limited [13-15]. This lack of insight prevents an understanding of how site-specific O-linked glycosylation affects diseases, such as metabolic disorders, cardiovascular disease, and various malignancies, that have been associated with GalNAc-Ts through genome-wide association studies and other linkage studies [16-26]. Therefore, it is imperative that we establish how O-glycosylation at specific sites in proteins affects protein function. A major task in achieving this goal is to identify the non-redundant biological functions of site-specific O-glycosylation. We and others recently developed new strategies for identifying specific sites on proteins that undergo O-glycosylation in different cell types and tissues [27-31]. Characterization of the O-glycoproteomic landscape in isolated human cells and multiple human cell lines suggests that more than 80 % of all proteins that traffic through the secretory pathway are O-glycoproteins [28, 30]. Probing the non-redundant contributions of individual GalNAc-Ts in cells with and without specific GalNAc-Ts [32-34] has revealed broad substrate specificities for some of the individual isoforms, whereas others seem to have very restricted substrate specificities [33-35]. Assessing all of the mapped O-glycosylation sites to identify associations between O-glycosites and protein annotations, we recently found that O-glycans are over-represented close to tandem repeat regions, protease cleavage sites, within propeptides, and on a select group of protein domains [28, 30, 36]. Although such general associations between the location of O-glycans and protein functions may direct future investigations, the strategy does not define the function of site-specific glycosylation. Further progress in discovering and defining novel functions of site-specific glycosylation events requires direct quantitative analysis of potential biological responses induced by the loss of distinct GalNAc-T isoforms, and such biological responses are not easily observed in single cell culture systems. Instead, more complex model systems can be used to examine and dissect the molecular mechanisms underlying the important biological functions of site-specific glycosylation. We previously used an organotypic tissue model equipped with genetically engineered cells to decipher the function of elongated O-glycans [29]. In the present study, we use the model combined with quantitative O-glycoproteomics and phosphoproteomics to perform open-ended discovery of the biological functions of site-specific glycosylation governed by GalNAc-Ts (Fig 1B). With this combinatorial strategy, we demonstrate that loss of individual GalNAc-T isoforms has distinct phenotypic consequences through their effect on distinct biological pathways, suggesting specific roles during epithelial formation.

Dataset Information

Global Reorganization of Chromatin Architecture during Embronic Stem Cell Differentiation

Publications

Chromatin architecture reorganization during stem cell differentiation.

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