Massively parallel characterization of transcriptional regulatory elements in three diverse human cell types.

Autor:	Agarwal V; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.; mRNA Center of Excellence, Sanofi Pasteur Inc., Waltham, MA 02451, USA., Inoue F; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA.; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan., Schubach M; Berlin Institute of Health of Health at Charité - Universitätsmedizin Berlin, 10178, Berlin, Germany., Martin BK; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Dash PM; Berlin Institute of Health of Health at Charité - Universitätsmedizin Berlin, 10178, Berlin, Germany., Zhang Z; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan., Sohota A; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA., Noble WS; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.; Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA., Yardimci GG; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.; Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.; Cancer Early Detection Advanced Research Center, Oregon Health and Science University, Portland, OR, USA., Kircher M; Berlin Institute of Health of Health at Charité - Universitätsmedizin Berlin, 10178, Berlin, Germany.; Institute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck, Lübeck, Germany., Shendure J; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.; Howard Hughes Medical Institute, Seattle, WA 98195, USA.; Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA 98195, USA.; Allen Center for Cell Lineage Tracing, University of Washington, Seattle, WA 98195, USA., Ahituv N; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Mar 06. Date of Electronic Publication: 2023 Mar 06.
DOI:	10.1101/2023.03.05.531189
Abstrakt:	The human genome contains millions of candidate cis -regulatory elements (CREs) with cell-type-specific activities that shape both health and myriad disease states. However, we lack a functional understanding of the sequence features that control the activity and cell-type-specific features of these CREs. Here, we used lentivirus-based massively parallel reporter assays (lentiMPRAs) to test the regulatory activity of over 680,000 sequences, representing a nearly comprehensive set of all annotated CREs among three cell types (HepG2, K562, and WTC11), finding 41.7% to be functional. By testing sequences in both orientations, we find promoters to have significant strand orientation effects. We also observe that their 200 nucleotide cores function as non-cell-type-specific 'on switches' providing similar expression levels to their associated gene. In contrast, enhancers have weaker orientation effects, but increased tissue-specific characteristics. Utilizing our lentiMPRA data, we develop sequence-based models to predict CRE function with high accuracy and delineate regulatory motifs. Testing an additional lentiMPRA library encompassing 60,000 CREs in all three cell types, we further identified factors that determine cell-type specificity. Collectively, our work provides an exhaustive catalog of functional CREs in three widely used cell lines, and showcases how large-scale functional measurements can be used to dissect regulatory grammar. Competing Interests: Competing interests. V.A. is an employee of Sanofi Pasteur Inc. J.S. is a scientific advisory board member, consultant and/or co-founder of Cajal Neuroscience, Guardant Health, Maze Therapeutics, Camp4 Therapeutics, Phase Genomics, Adaptive Biotechnologies, Scale Biosciences, Sixth Street Capital, and Pacific Biosciences. N.A. is the cofounder and on the scientific advisory board of Regel Therapeutics and receives funding from BioMarin Pharmaceutical Incorporated. All other authors declare no competing interests.
Databáze:	MEDLINE
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