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Promoter-intrinsic and local chromatin features determine gene repression in lamina-associated domains

View ORCID ProfileChrist Leemans, Marloes van der Zwalm, View ORCID ProfileLaura Brueckner, View ORCID ProfileFederico Comoglio, View ORCID ProfileTom van Schaik, View ORCID ProfileLudo Pagie, Joris van Arensbergen, View ORCID ProfileBas van Steensel
doi: https://doi.org/10.1101/464081
Christ Leemans
Division of Gene Regulation and Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands
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Marloes van der Zwalm
Division of Gene Regulation and Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands
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Laura Brueckner
Division of Gene Regulation and Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands
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Federico Comoglio
Division of Gene Regulation and Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands
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Tom van Schaik
Division of Gene Regulation and Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands
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Ludo Pagie
Division of Gene Regulation and Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands
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Joris van Arensbergen
Division of Gene Regulation and Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands
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Bas van Steensel
Division of Gene Regulation and Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands
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  • For correspondence: b.v.steensel@nki.nl
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Abstract

It is largely unclear whether genes that are naturally embedded in lamina associated domains (LADs) are inactive due to their chromatin environment, or whether LADs are merely secondary to the lack of transcription. We show that hundreds of human promoters become active when moved from their native LAD position to a neutral context in the same cells, indicating that LADs form a repressive environment. Another set of promoters inside LADs is able to "escape" repression, although their transcription elongation is attenuated. By inserting reporters into thousands of genomic locations, we demonstrate that these escaper promoters are intrinsically less sensitive to LAD repression. This is not simply explained by promoter strength, but by the interplay between promoter sequence and local chromatin features that vary strongly across LADs. Enhancers also differ in their sensitivity to LAD chromatin. This work provides a general framework for the systematic understanding of gene regulation by repressive chromatin.

Highlights

  • Two promoter transplantation strategies elucidate the regulatory role of LAD chromatin

  • LADs are generally repressive, but also highly heterogeneous

  • LADs can impede both promoter activity and transcription elongation

  • Promoters vary intrinsically in their sensitivity to LAD repression

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted November 06, 2018.
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Promoter-intrinsic and local chromatin features determine gene repression in lamina-associated domains
Christ Leemans, Marloes van der Zwalm, Laura Brueckner, Federico Comoglio, Tom van Schaik, Ludo Pagie, Joris van Arensbergen, Bas van Steensel
bioRxiv 464081; doi: https://doi.org/10.1101/464081
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Promoter-intrinsic and local chromatin features determine gene repression in lamina-associated domains
Christ Leemans, Marloes van der Zwalm, Laura Brueckner, Federico Comoglio, Tom van Schaik, Ludo Pagie, Joris van Arensbergen, Bas van Steensel
bioRxiv 464081; doi: https://doi.org/10.1101/464081

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