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Transcriptional regulation constrains the organization of genes on eukaryotic chromosomes

Edited by Aaron Klug, Medical Research Council, Cambridge, United Kingdom, and approved
August 21, 2008 (received for review July 1, 2008)
Sarath Chandra Janga*,, Julio Collado-Vides, and M. Madan Babu*,
*Laboratory of Molecular Biology, Medical Research Council, Hills Road, Cambridge CB2 0QH, United Kingdom; and

‡Programa de Genomica Computacional, Centro de Ciencias Genomicas, Universidad Nacional Autonoma de Mexico, Apartado Postal 565-A, Av

Universidad, Cuernavaca, Morelos, 62100 Mexico D.F., Mexico


Genetic material in eukaryotes is tightly packaged in a hierarchical manner into multiple linear chromosomes within the nucleus. Although it is known that eukaryotic transcriptional regulation is complex and requires an intricate coordination of several molecular events both in space and time, whether the complexity of this process constrains genome organization is still unknown. Here, we present evidence for the existence of a higher-order organization of genes across and within chromosomes that is constrained by transcriptional regulation. In particular, we reveal that the target genes (TGs) of transcription factors (TFs) for the yeast, Saccharomyces cerevisiae, are encoded in a highly ordered manner both across and within the 16 chromosomes. We show that (i) the TGs of a majority of TFs show a strong preference to be encoded on specific chromosomes, (ii) the TGs of a significant number of TFs display a strong preference (or avoidance) to be encoded in regions containing particular chromosomal landmarks such as telomeres and centromeres, and (iii) the TGs of most TFs are positionally clustered within a chromosome. Our results demonstrate that specific organization of genes that allowed for efficient control of transcription within the nuclear space has been selected during evolution. We anticipate that uncovering such higher-order organization of genes in other eukaryotes will provide insights into nuclear architecture, and will have implications in genetic engineering experiments, gene therapy, and understanding disease conditions that involve chromosomal aberrations.


†To whom correspondence may be addressed. E-mail: sarath{at}mrc-lmb.cam.ac.uk or madanm{at}mrc-lmb.cam.ac.uk

Author contributions: S.C.J. and M.M.B. designed research; S.C.J. and M.M.B. performed research; J.C.-V. contributed new reagents/analytic tools; S.C.J. and M.M.B. analyzed data; and S.C.J. and M.M.B. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0806317105/DCSupplemental.

Freely available online through the PNAS open access option.