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ACKNOWLEDGMENTS
We thank B. G. Childs, J. F. Limzerwala, C. J. Sieben, R. Bram,
J. Elisseeff, and B. van de Sluis for helpful and stimulating
discussions and/or careful evaluation of the manuscript. We also
thank R. Velasco Fierro for valuable technical assistance. We
are grateful to C. Ross for his work on the identification of
super-enhancers and the genes they control, M. H. Hofker for
conceptual discussions, and R. Thaler for assistance in generating
heatmaps. Flow cytometry was performed by the Mayo Clinic
Microscopy and Cell Analysis Core, sequencing by Mayo ClinicMedical Genomics Facility Sequencing Core, and ChIP in the
Epigenomics Core of the Mayo Clinic Center for Cell Signaling in
Gastroenterology.Funding:This work was supported by grants
from Mayo Clinic’s Center for Biomedical Discovery, the Paul F. Glenn
Foundation for Medical Research, the Keck Foundation, the US
National Institutes of Health (grants R01 AG057493, P30 DK084567
and R01 AG056318), the Mayo Clinic Cancer Center, and the David F.
and Margaret T. Grohne Cancer Immunology and Immunotherapy
Program.Author contributions:J.M.v.D. conceived the project. I.S.
and J.M.v.D. designed most experiments. I.S. performed most
experiments. J.-H.L. and T.O. performed ChIP-related experiments,
and C.Z., I.S., and H.L. conducted super-enhancer–related studies.
C.Z. and I.S. performed bioinformatic analyses. I.S., C.C.S., I.C.,
E.J.v.D., and J.T.S. conducted knockdown experiments, and K.B.J.
coimmunoprecipitation experiments. N.H., J.G., M.H., and D.Y.L.
generated and validated transgenic strains. R.M.L. helped with
experimental design and data interpretation. D.F. and V.S.
designed and executed neutralizing antibody experiments in mice
with I.S. and helped with interpretation of immunosurveillance
data. All authors contributed to data acquisition, analysis and
interpretation. J.M.v.D. and I.S. wrote the paper and all authors
edited the manuscript. D.J.B. helped supervise and interpret
experiments pertaining to the physiological relevance of the PASP.
H.L. directed, supervised, and helped interpret all bioinformatics
analyses and J.M.v.D. directed and supervised all other aspects of
the study.Competing interests:J.M.v.D. is a cofounder of Unity
Biotechnology. J.M.v.D., D.J.B., and R.M.L. are coinventors on
patents licensed to or filed by Unity Biotechnology. I.S., H.L., and
J.M.v.D. are listed as inventors on provisional patent application
U.S. 63/224,177 filed by Mayo Clinic that encompasses aspects of
this publication. J.M.v.D., H.L., R.M.L., and D.J.B. are current Unity
Biotechnology shareholders. This research has been reviewed
by the Mayo Clinic Conflict of Interest Review Board and is being
conducted in compliance with Mayo Clinic conflict of interest
policies.Data and materials availability:ChIP-seq and RNA-seq
data sets have been deposited in the Gene Expression Omnibus
(GSE117278). Mouse strainsL-p21,L-KRASG12V,L-p16andp21floxed
mice are available from Mayo Clinic upon completion of a
material transfer agreement.SUPPLEMENTARY MATERIALS
science.org/doi/10.1126/science.abb3420
Figs. S1 to S20
Tables S1 to S9
MDAR Reproducibility Checklist23 February 2020; resubmitted 7 April 2021
Accepted 3 September 2021
10.1126/science.abb3420Sturmlechneret al.,Science 374 , eabb3420 (2021) 29 October 2021 15 of 15
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