RT Journal Article
SR Electronic
T1 Ultra high-throughput whole-genome methylation sequencing reveals trajectories in precancerous polyps to early colorectal adenocarcinoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.30.494076
DO 10.1101/2022.05.30.494076
A1 Hayan Lee
A1 Gat Krieger
A1 Tyson Clark
A1 Aziz Khan
A1 Casey Ryan Hanson
A1 Yizhou Zhu
A1 Nasim Bararpour
A1 Aaron M. Horning
A1 Edward D. Esplin
A1 Stephanie Nevins
A1 Annika K. Weimer
A1 Eti Meiri
A1 Shlomit Gilad
A1 Sima Benjamin
A1 Danit Lebanony
A1 Nika Iremadze
A1 Florian Oberstrass
A1 Ariel Jaimovich
A1 William Greenleaf
A1 James M. Ford
A1 Doron Lipson
A1 Zohar Shipony
A1 Michael P. Snyder
YR 2022
UL http://biorxiv.org/content/early/2022/05/30/2022.05.30.494076.abstract
AB Aberrant shifts in DNA methylation have long been regarded as an early marker for cancer onset and progression. To chart DNA methylation changes that occur during the transformation from normal healthy colon tissue to malignant colorectal cancer (CRC), we collected over 50 samples from 15 familial adenomatous polyposis (FAP) and non-FAP colorectal cancer patients, and generated 30-70x whole-genome methylation sequencing (WGMS) runs via the novel Ultima Genomics ultra high-throughput sequencing platform. We observed changes in DNA methylation that occur early in the malignant transformation process, in gene promoters and in distal regulatory elements. Among these changes are events of hyper-methylation which are associated with a bivalent “poised” chromatin state at promoters and are CRC-specific. Distal enhancers show nonlinear dynamics, lose methylation in the progression from normal mucosa to dysplastic polyps but regain methylation in the adenocarcinoma state. Enhancers that gain chromatin accessibility in the adenocarcinoma state and are enriched with HOX transcription factor binding sites, a marker of developmental genes. This work demonstrates the feasibility of generating large high quality WGMS data using the Ultima Genomics platform and provides the first detailed view of methylation dynamics during CRC formation and progression in a model case.Competing Interest StatementG.K, T.C., E.M., S.G., S.B., D.Lebanony., F.O, N.I., A.J., D.L. and Z.S. are employees and shareholders of Ultima Genomics. M.P.S. is a cofounder and scientific advisor for Personalis, Qbio, January.ai, Filtricine, Mirvie, Protos and an advisor for Genapsys.