Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells
- Jessica Zuina,1,
- Jesse R. Dixonb,c,d,1,
- Michael I. J. A. van der Reijdena,
- Zhen Yeb,e,
- Petros Kolovosa,
- Rutger W. W. Brouwerf,g,
- Mariëtte P. C. van de Corputa,
- Harmen J. G. van de Werkena,
- Tobias A. Knochh,i,
- Wilfred F. J. van IJckenf,
- Frank G. Grosvelda,j,
- Bing Renb,e,2, and
- Kerstin S. Wendta,2
- aDepartment of Cell Biology,
- iBiophysical Genomics, Department of Cell Biology,
- fCenter for Biomics,
- jCancer Genomics Center, Erasmus Medical Center, 3015 GE, Rotterdam, The Netherlands;
- bLaboratory of Gene Regulation, Ludwig Institute for Cancer Research, La Jolla, CA 92093;
- cMedical Scientist Training Program,
- dBiomedical Sciences Graduate Program,
- eDepartment of Cellular and Molecular Medicine, Institute of Genomic Medicine, Moores Cancer Center, San Diego School of Medicine, University of California, San Diego, La Jolla, CA 92093;
- gNetherlands Bioinformatics Centre, 6500 HB, Nijmegen, The Netherlands; and
- hGenome Organization and Function, Bioquant Centre/German Cancer Research Center, 69120 Heidelberg, Germany
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Edited* by Richard A. Young, Massachusetts Institute of Technology, Cambridge, MA, and approved October 31, 2013 (received for review September 20, 2013)
Significance
For the 2m DNA to fit into the tiny cell nucleus, it is wrapped around nucleosomes and folded into loops clustering together in domains. Genome function depends on this 3D-organization, especially on-going dynamic processes like transcription. Techniques studying the network of DNA contacts genome-wide have recently revealed this 3D architecture, but the protein factors behind this are not understood. We study two proteins that are known to help form DNA loops: cohesin and CTCC-binding factor (CTCF). Respective depletion and analysis of DNA contacts genome-wide show that CTCF is required to separate neighboring folding domains and keep cohesin in place, whereas cohesin is important for shaping the domains. Consistently, we observe different changes of gene expression.
Abstract
Recent studies of genome-wide chromatin interactions have revealed that the human genome is partitioned into many self-associating topological domains. The boundary sequences between domains are enriched for binding sites of CTCC-binding factor (CTCF) and the cohesin complex, implicating these two factors in the establishment or maintenance of topological domains. To determine the role of cohesin and CTCF in higher-order chromatin architecture in human cells, we depleted the cohesin complex or CTCF and examined the consequences of loss of these factors on higher-order chromatin organization, as well as the transcriptome. We observed a general loss of local chromatin interactions upon disruption of cohesin, but the topological domains remain intact. However, we found that depletion of CTCF not only reduced intradomain interactions but also increased interdomain interactions. Furthermore, distinct groups of genes become misregulated upon depletion of cohesin and CTCF. Taken together, these observations suggest that CTCF and cohesin contribute differentially to chromatin organization and gene regulation.
Footnotes
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↵1J.Z. and J.R.D. contributed equally to this work.
- ↵2To whom correspondence may be addressed. E-mail: biren{at}ucsd.edu or k.wendt{at}erasmusmc.nl.
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Author contributions: J.Z., J.R.D., F.G.G., B.R., and K.S.W. designed research; J.Z., J.R.D., M.I.J.A.v.d.R., Z.Y., M.P.C.v.d.C., W.F.J.v.I., and K.S.W. performed research; J.Z., J.R.D., Z.Y., P.K., R.W.W.B., H.J.G.v.d.W., T.A.K., and F.G.G. analyzed data; and J.Z., J.R.D., B.R., and K.S.W. wrote the paper.
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The authors declare no conflict of interest.
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↵*This Direct Submission article had a prearranged editor.
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Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. GSE44267).
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See Commentary on page 889.
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This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1317788111/-/DCSupplemental.
