, Volume 116, Issue 3, pp 285–306 | Cite as

Radial chromatin positioning is shaped by local gene density, not by gene expression

  • Katrin Küpper
  • Alexandra Kölbl
  • Dorothee Biener
  • Sandra Dittrich
  • Johann von Hase
  • Tobias Thormeyer
  • Heike Fiegler
  • Nigel P. Carter
  • Michael R. Speicher
  • Thomas Cremer
  • Marion Cremer
Research Article


G- and R-bands of metaphase chromosomes are characterized by profound differences in gene density, CG content, replication timing, and chromatin compaction. The preferential localization of gene-dense, transcriptionally active, and early replicating chromatin in the nuclear interior and of gene-poor, later replicating chromatin at the nuclear envelope has been demonstrated to be evolutionary-conserved in various cell types. Yet, the impact of different local chromatin features on the radial nuclear arrangement of chromatin is still not well understood. In particular, it is not known whether radial chromatin positioning is preferentially shaped by local gene density per se or by other related parameters such as replication timing or transcriptional activity. The interdependence of these distinct chromatin features on the linear deoxyribonucleic acid (DNA) sequence precludes a simple dissection of these parameters with respect to their importance for the reorganization of the linear DNA organization into the distinct radial chromatin arrangements observed in the nuclear space. To analyze this problem, we generated probe sets of pooled bacterial artificial chromosome (BAC) clones from HSA 11, 12, 18, and 19 representing R/G-band-assigned chromatin, segments with different gene density and gene loci with different expression levels. Using multicolor 3D flourescent in situ hybridization (FISH) and 3D image analysis, we determined their localization in the nucleus and their positions within or outside the corresponding chromosome territory (CT). For each BAC data on local gene density within 2- and 10-Mb windows, as well as GC (guanine and cytosine) content, replication timing and expression levels were determined. A correlation analysis of these parameters with nuclear positioning revealed regional gene density as the decisive parameter determining the radial positioning of chromatin in the nucleus in contrast to band assignment, replication timing, and transcriptional activity. We demonstrate a polarized distribution of gene-dense vs gene-poor chromatin within CTs with respect to the nuclear border. Whereas we confirm previous reports that a particular gene-dense and transcriptionally highly active region of about 2 Mb on 11p15.5 often loops out from the territory surface, gene-dense and highly expressed sequences were not generally found preferentially at the CT surface as previously suggested.


Bacterial Artificial Chromosome Bacterial Artificial Chromosome Clone Gene Density Replication Timing Chromosome Territory 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.







average relative distances to the nuclear border


chromosome territory


chromosome territory-interchromatin compartment


relative distance difference


(enhanced) Absolute 3D distances to surface


giemsa dark band


human fibroblasts


human (B- and T-) lymphocytes


homo sapiens chromosome


Multicolor fluorescence in situ hybridization


giemsa light (reverse) band


regions of increased gene expression



We gratefully acknowledge very helpful discussions and technical support from Christian Lanctôt, Stefan Müller, Heiner Albiez, and Boris Joffe from our group. We thank C. Cremer for supporting JvH from his funding. We are grateful to Thomas Ried, NCI, Bethesda, MD, for generously providing us BAC-DNA from clones of chromosomes 12, 18, and 19. This work was supported by the Wilhelm-Sanderstiftung (2001.079.2) to TC and MRS and by the EU (3D Genome, LSHG-CT-2003-503441) to TC. HF and NPC were supported by the Wellcome Trust.

Supplementary material

412_2007_98_MOESM1_ESM.doc (1.5 mb)
Figure S1 Gene-density of chromosomes 12, 18, and 19 (DOC 1 527 808 kb)
412_2007_98_MOESM2_ESM.doc (1.1 mb)
Figure S2 Influence of the pepsin treatment on the detektion of Ki67 in Hfb nuclei (DOC 1 111 040 kb)
412_2007_98_MOESM3_ESM.doc (202 kb)
Table 1–8 Overview of all BAC-pools and detailed description of BACs used in this study with the following information (DOC 206 848 kb)


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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Katrin Küpper
    • 1
  • Alexandra Kölbl
    • 1
  • Dorothee Biener
    • 1
  • Sandra Dittrich
    • 1
  • Johann von Hase
    • 2
  • Tobias Thormeyer
    • 1
  • Heike Fiegler
    • 3
  • Nigel P. Carter
    • 3
  • Michael R. Speicher
    • 4
  • Thomas Cremer
    • 1
  • Marion Cremer
    • 1
  1. 1.Department of Biology II, Anthropology and Human GeneticsLudwig Maximilians UniversityMunichGermany
  2. 2.Kirchhoff Institute for PhysicsUniversity of HeidelbergHeidelbergGermany
  3. 3.The Wellcome Trust Sanger Institute, Wellcome Trust Genome CampusCambridgeUK
  4. 4.Institute of Medical Biology and Human GeneticsMedical University of GrazGrazAustria

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