A cis-regulatory lexicon of DNA motif combinations mediating cell-type-specific gene regulation

Laura K H Donohue; Margaret G Guo; Yang Zhao; Namyoung Jung; Rose T Bussat; Daniel S Kim; Poornima H Neela; Laura N Kellman; Omar S Garcia; Robin M Meyers; Russ B Altman; Paul A Khavari

doi:10.1016/j.xgen.2022.100191

A cis-regulatory lexicon of DNA motif combinations mediating cell-type-specific gene regulation

Cell Genom. 2022 Nov 9;2(11):100191. doi: 10.1016/j.xgen.2022.100191. Epub 2022 Oct 5.

Authors

Laura K H Donohue^{1

2

3

4}, Margaret G Guo^{1

5

4}, Yang Zhao^{1

3}, Namyoung Jung^{1

6}, Rose T Bussat^{1

7}, Daniel S Kim^{1

5}, Poornima H Neela^{1

8}, Laura N Kellman^{1

9}, Omar S Garcia¹, Robin M Meyers^{1

2}, Russ B Altman^{2

5

10}, Paul A Khavari^{1

9

11

12}

Affiliations

¹ Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
³ Synthego, Redwood City, CA, USA.
⁴ These authors contributed equally.
⁵ Stanford Program in Biomedical Informatics, Stanford University, Stanford, CA, USA.
⁶ Department of Life Science, Pohang University of Science and Technology, Pohang, Korea.
⁷ 23andMe, Inc., Sunnyvale, CA, USA.
⁸ Fauna Bio, Emeryville, CA, USA.
⁹ Stanford Program in Cancer Biology, Stanford University, Stanford, CA, USA.
¹⁰ Department of Bioengineering, Stanford University, Stanford, CA, USA.
¹¹ Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA, USA.
¹² Lead contact.

Abstract

Gene expression is controlled by transcription factors (TFs) that bind cognate DNA motif sequences in cis-regulatory elements (CREs). The combinations of DNA motifs acting within homeostasis and disease, however, are unclear. Gene expression, chromatin accessibility, TF footprinting, and H3K27ac-dependent DNA looping data were generated and a random-forest-based model was applied to identify 7,531 cell-type-specific cis-regulatory modules (CRMs) across 15 diploid human cell types. A co-enrichment framework within CRMs nominated 838 cell-type-specific, recurrent heterotypic DNA motif combinations (DMCs), which were functionally validated using massively parallel reporter assays. Cancer cells engaged DMCs linked to neoplasia-enabling processes operative in normal cells while also activating new DMCs only seen in the neoplastic state. This integrative approach identifies cell-type-specific cis-regulatory combinatorial DNA motifs in diverse normal and diseased human cells and represents a general framework for deciphering cis-regulatory sequence logic in gene regulation.

Abstract

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