A multiomics approach reveals RNA dynamics promote cellular sensitivity to DNA hypomethylation

Alex Y Ge; Abolfazl Arab; Raymond Dai; Albertas Navickas; Lisa Fish; Kristle Garcia; Hosseinali Asgharian; Jackson Goudreau; Sean Lee; Kathryn Keenan; Melissa B Pappalardi; Michael T McCabe; Laralynne Przybyla; Hani Goodarzi; Luke A Gilbert

doi:10.1038/s41598-024-77314-9

A multiomics approach reveals RNA dynamics promote cellular sensitivity to DNA hypomethylation

Sci Rep. 2024 Oct 29;14(1):25940. doi: 10.1038/s41598-024-77314-9.

Authors

Alex Y Ge^{1

2

3}, Abolfazl Arab^{4

2

3}, Raymond Dai^{4

2

3}, Albertas Navickas^{2

3

5

6}, Lisa Fish^{2

3

5

6}, Kristle Garcia^{2

3

5

6}, Hosseinali Asgharian^{2

3

5

6}, Jackson Goudreau^{4

2

3

5

6}, Sean Lee^{2

3

5

6}, Kathryn Keenan⁷, Melissa B Pappalardi⁷, Michael T McCabe⁷, Laralynne Przybyla^{5

8}, Hani Goodarzi^{9

10

11

12

13}, Luke A Gilbert^{14

15

16}

Affiliations

¹ School of Medicine, University of California, San Francisco, San Francisco, CA, 94158, USA.
² Department of Urology, University of California, San Francisco, San Francisco, CA, 94158, USA.
³ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94158, USA.
⁴ Arc Institute, Palo Alto, CA, 94304, USA.
⁵ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, 94158, USA.
⁶ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, 94158, USA.
⁷ Tumor Cell Targeting Research Unit, Research, GSK, Collegeville, PA, 19426, USA.
⁸ Laboratory for Genomics Research, San Francisco, CA, 94158, USA.
⁹ Arc Institute, Palo Alto, CA, 94304, USA. Hani@arcinstitute.org.
¹⁰ Department of Urology, University of California, San Francisco, San Francisco, CA, 94158, USA. Hani@arcinstitute.org.
¹¹ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94158, USA. Hani@arcinstitute.org.
¹² Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, 94158, USA. Hani@arcinstitute.org.
¹³ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, 94158, USA. Hani@arcinstitute.org.
¹⁴ Arc Institute, Palo Alto, CA, 94304, USA. Luke@arcinstitute.org.
¹⁵ Department of Urology, University of California, San Francisco, San Francisco, CA, 94158, USA. Luke@arcinstitute.org.
¹⁶ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94158, USA. Luke@arcinstitute.org.

Abstract

The search for new approaches in cancer therapy requires a mechanistic understanding of cancer vulnerabilities and anti-cancer drug mechanisms of action. Problematically, some effective therapeutics target cancer vulnerabilities that have poorly defined mechanisms of anti-cancer activity. One such drug is decitabine, a frontline therapeutic approved for the treatment of high-risk acute myeloid leukemia (AML). Decitabine is thought to kill cancer cells selectively via inhibition of DNA methyltransferase enzymes, but the genes and mechanisms involved remain unclear. Here, we apply an integrated multiomics and CRISPR functional genomics approach to identify genes and processes associated with response to decitabine in AML cells. Our integrated multiomics approach reveals RNA dynamics are key regulators of DNA hypomethylation induced cell death. Specifically, regulation of RNA decapping, splicing and RNA methylation emerge as important regulators of cellular response to decitabine.

Abstract

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