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

Autor:	Donohue LKH; Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Synthego, Redwood City, CA, USA.; These authors contributed equally., Guo MG; Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Program in Biomedical Informatics, Stanford University, Stanford, CA, USA.; These authors contributed equally., Zhao Y; Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.; Synthego, Redwood City, CA, USA., Jung N; Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Life Science, Pohang University of Science and Technology, Pohang, Korea., Bussat RT; Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.; 23andMe, Inc., Sunnyvale, CA, USA., Kim DS; Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Program in Biomedical Informatics, Stanford University, Stanford, CA, USA., Neela PH; Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.; Fauna Bio, Emeryville, CA, USA., Kellman LN; Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Program in Cancer Biology, Stanford University, Stanford, CA, USA., Garcia OS; Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA., Meyers RM; Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Altman RB; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Program in Biomedical Informatics, Stanford University, Stanford, CA, USA.; Department of Bioengineering, Stanford University, Stanford, CA, USA., Khavari PA; Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Program in Cancer Biology, Stanford University, Stanford, CA, USA.; Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA, USA.; Lead contact.
Jazyk:	angličtina
Zdroj:	Cell genomics [Cell Genom] 2022 Nov 09; Vol. 2 (11). Date of Electronic Publication: 2022 Oct 05.
DOI:	10.1016/j.xgen.2022.100191
Abstrakt:	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. Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.
Databáze:	MEDLINE
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