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Human Molecular Genetics Advance Access originally published online on December 2, 2008
Human Molecular Genetics 2009 18(5):835-846; doi:10.1093/hmg/ddn409
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© 2008 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Systematic identification of cis-silenced genes by trans complementation

Jae Hyun Lee1, Branimir Bugarija1, Enrique J. Millan1, Noah M. Walton1, Jedidiah Gaetz1, Croydon J. Fernandes1, Wei-Hua Yu2, Nitzan Mekel-Bobrov1, Tammy W. Vallender1, Gregory E. Snyder1, Andy Peng Xiang2 and Bruce T. Lahn1,2,*

1 Department of Human Genetics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA 2 Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou 510080, P.R. China

* To whom correspondence should be addressed. Tel: +1 7738344393; Fax: +1 7737020271; Email: blahn{at}bsd.uchicago.edu

Received November 6, 2008; Accepted December 1, 2008

A gene’s transcriptional output is the combined product of two inputs: diffusible factors in the cellular milieu acting in trans, and chromatin state acting in cis. Here, we describe a strategy for dissecting the relative contribution of cis versus trans mechanisms to gene regulation. Referred to as trans complementation, it entails fusing two disparate cell types and searching for genes differentially expressed between the two genomes of fused cells. Any differential expression can be causally attributed to cis mechanisms because the two genomes of fused cells share a single homogenized milieu in trans. This assay uncovered a state of transcriptional competency that we termed ‘occluded’ whereby affected genes are silenced by cis-acting mechanisms in a manner that blocks them from responding to the trans-acting milieu of the cell. Importantly, occluded genes in a given cell type tend to include master triggers of alternative cell fates. Furthermore, the occluded state is maintained during cell division and is extraordinarily stable under a wide range of physiological conditions. These results support the model that the occlusion of lineage-inappropriate genes is a key mechanism of cell fate restriction. The identification of occluded genes by our assay provides a hitherto unavailable functional readout of chromatin state that is distinct from and complementary to gene expression status.


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J. H. Lee, J. Gaetz, B. Bugarija, C. J. Fernandes, G. E. Snyder, E. C. Bush, and B. T. Lahn
Chromatin analysis of occluded genes
Hum. Mol. Genet., July 15, 2009; 18(14): 2567 - 2574.
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