The Three-Dimensional Structure of Human Interphase Chromosomes Is Related to the Transcriptome Map

Abstract

The three-dimensional (3D) organization of the chromosomal fiber in the human interphase nucleus is an important but poorly understood aspect of gene regulation. Here we quantitatively analyze and compare the 3D structures of two types of genomic domains as defined by the human transcriptome map. While ridges are gene dense and show high expression levels, antiridges, on the other hand, are gene poor and carry genes that are expressed at low levels. We show that ridges are in general less condensed, more irregularly shaped, and located more closely to the nuclear center than antiridges. Six human cell lines that display different gene expression patterns and karyotypes share these structural parameters of chromatin. This shows that the chromatin structures of these two types of genomic domains are largely independent of tissue-specific variations in gene expression and differentiation state. Moreover, we show that there is remarkably little intermingling of chromatin from different parts of the same chromosome in a chromosome territory, neither from adjacent nor from distant parts. This suggests that the chromosomal fiber has a compact structure that sterically suppresses intermingling. Together, our results reveal novel general aspects of 3D chromosome architecture that are related to genome structure and function.

We thank the Sanger Institute and Eric Schoenmakers (University Nijmegen) for providing BACs. We thank Peter van Sluis (AMC) for his assistance with RNA quality control and Richard Volckmann for his assistance with the Affymetrix data. We acknowledge the Centre of Advanced Microscopy of the University of Amsterdam for technical support and Scientific Volume Imaging BV (Hilversum, The Netherlands) for assistance with 3D deconvolution.

This work was supported by the European Commission as part of the 3DGENOME program, contract LSHG-CT-2003-503441.