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J Cell Biol. 2018 Nov 5;217(11):4025-4048. doi: 10.1083/jcb.201807108. Epub 2018 Aug 28.

Mapping 3D genome organization relative to nuclear compartments using TSA-Seq as a cytological ruler.

Author information

1
Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL.
2
Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL.
3
Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA.
4
Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, Netherlands.
5
Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL.
6
Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL asbel@illinois.edu.
7
Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL.
8
Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL.

Abstract

While nuclear compartmentalization is an essential feature of three-dimensional genome organization, no genomic method exists for measuring chromosome distances to defined nuclear structures. In this study, we describe TSA-Seq, a new mapping method capable of providing a "cytological ruler" for estimating mean chromosomal distances from nuclear speckles genome-wide and for predicting several Mbp chromosome trajectories between nuclear compartments without sophisticated computational modeling. Ensemble-averaged results in K562 cells reveal a clear nuclear lamina to speckle axis correlated with a striking spatial gradient in genome activity. This gradient represents a convolution of multiple spatially separated nuclear domains including two types of transcription "hot zones." Transcription hot zones protruding furthest into the nuclear interior and positioning deterministically very close to nuclear speckles have higher numbers of total genes, the most highly expressed genes, housekeeping genes, genes with low transcriptional pausing, and super-enhancers. Our results demonstrate the capability of TSA-Seq for genome-wide mapping of nuclear structure and suggest a new model for spatial organization of transcription and gene expression.

PMID:
30154186
PMCID:
PMC6219710
DOI:
10.1083/jcb.201807108
[Indexed for MEDLINE]
Free PMC Article

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