The Circadian Clock Gene, Bmal1, Regulates Intestinal Stem Cell Signaling and Represses Tumor Initiation
Kyle Stokes, Malika Nunes, Chantelle Trombley, Danilo E. F. L. Flôres, Gang Wu, Zainab Taleb, Abedalrhman Alkhateeb, Suhrid Banskota, Chris Harris, Oliver P. Love, Waliul I. Khan, Luis Rueda, John B. Hogenesch, Phillip Karpowicz
Abstract
BACKGROUND & AIMS: model of colorectal cancer. METHODS: allele were assessed for tumorigenesis. Tumors and normal nontransformed tissue were characterized. Intestinal organoids were assessed for circadian transcription rhythms by RNA sequencing, and in vivo and organoid assays were used to test Bmal1-dependent proliferation and self-renewal. RESULTS: clock-disrupted tumors show high Yes-associated protein 1 (Hippo signaling) activity but show low Wnt (Wingless and Int-1) activity. Intestinal organoid assays show that loss of Bmal1 increases self-renewal in a Yes-associated protein 1-dependent manner. CONCLUSIONS: Bmal1 regulates intestinal stem cell pathways, including Hippo signaling, and the loss of circadian rhythms potentiates tumor initiation. Transcript profiling: GEO accession number: GSE157357.