Dataset Information

Comprehensive characterization of neutrophil genome topology.

ABSTRACT: Neutrophils are responsible for the first line of defense against invading pathogens. Their nuclei are uniquely structured as multiple lobes that establish a highly constrained nuclear environment. Here we found that neutrophil differentiation was not associated with large-scale changes in the number and sizes of topologically associating domains (TADs). However, neutrophil genomes were enriched for long-range genomic interactions that spanned multiple TADs. Population-based simulation of spherical and toroid genomes revealed declining radii of gyration for neutrophil chromosomes. We found that neutrophil genomes were highly enriched for heterochromatic genomic interactions across vast genomic distances, a process named supercontraction. Supercontraction involved genomic regions located in the heterochromatic compartment in both progenitors and neutrophils or genomic regions that switched from the euchromatic to the heterochromatic compartment during neutrophil differentiation. Supercontraction was accompanied by the repositioning of centromeres, pericentromeres, and long interspersed nuclear elements (LINEs) to the neutrophil nuclear lamina. We found that Lamin B receptor expression was required to attach centromeric and pericentromeric repeats but not LINE-1 elements to the lamina. Differentiating neutrophils also repositioned ribosomal DNA and mininucleoli to the lamina-a process that was closely associated with sharply reduced ribosomal RNA expression. We propose that large-scale chromatin reorganization involving supercontraction and recruitment of heterochromatin and nucleoli to the nuclear lamina facilitates the folding of the neutrophil genome into a confined geometry imposed by a multilobed nuclear architecture.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC5322729 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Comprehensive characterization of neutrophil genome topology.

Zhu Yina Y Gong Ke K Denholtz Matthew M Chandra Vivek V Kamps Mark P MP Alber Frank F Murre Cornelis C

Genes & development 20170101 2

Neutrophils are responsible for the first line of defense against invading pathogens. Their nuclei are uniquely structured as multiple lobes that establish a highly constrained nuclear environment. Here we found that neutrophil differentiation was not associated with large-scale changes in the number and sizes of topologically associating domains (TADs). However, neutrophil genomes were enriched for long-range genomic interactions that spanned multiple TADs. Population-based simulation of spheri ...[more]

PMID: 28167501

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Project description:BackgroundMembrane proteins are key components in a large spectrum of diverse functions and thus account for the major proportion of the drug-targeted portion of the genome. From a structural perspective, the α-helical transmembrane proteins can be categorized into major groups based on the number of transmembrane helices and these groups are often associated with specific functions. When compared to the well-characterized seven-transmembrane containing proteins (7TM), other TM groups are less explored and in particular the 4TM group. In this study, we identify the complete 4TM complement from the latest release of the human genome and assess the 4TM structure group as a whole. We functionally characterize this dataset and evaluate the resulting groups and ubiquitous functions, and furthermore describe disease and drug target involvement.ResultsWe classified 373 proteins, which represents ~7 % of the human membrane proteome, and includes 69 more proteins than our previous estimate. We have characterized the 4TM dataset based on functional, structural, and/or evolutionary similarities. Proteins that are involved in transport activity constitute 37 % of the dataset, 23 % are receptor-related, and 13 % have enzymatic functions. Intriguingly, proteins involved in transport are more than double the 15 % of transporters in the entire human membrane proteome, which might suggest that the 4TM topological architecture is more favored for transporting molecules over other functions. Moreover, we found an interesting exception to the ubiquitous intracellular N- and C-termini localization that is found throughout the entire membrane proteome and 4TM dataset in the neurotransmitter gated ion channel families. Overall, we estimate that 58 % of the dataset has a known association to disease conditions with 19 % of the genes possibly involved in different types of cancer.ConclusionsWe provide here the most robust and updated classification of the 4TM complement of the human genome as a platform to further understand the characteristics of 4TM functions and to explore pharmacological opportunities.

Dataset Information

Comprehensive characterization of neutrophil genome topology.

Publications

Comprehensive characterization of neutrophil genome topology.

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