The Circadian Clock Gene, Bmal1, Regulates Intestinal Stem Cell Signaling and Represses Tumor Initiation

Background & Aims: Circadian rhythms are daily physiological oscillations driven by the circadian clock: a 24-hour transcriptional timekeeper that regulates hormones, inflammation, and metabolism. Circadian rhythms are known to be important for health, but whether their loss contributes to c...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Circadian Rhythms Intestinal Stem Cells Colorectal Cancer Hippo Pathway Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/ab5c749e56d34683944b22691e2cbd1f
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ab5c749e56d34683944b22691e2cbd1f
record_format	dspace
spelling	oai:doaj.org-article:ab5c749e56d34683944b22691e2cbd1f2021-11-12T04:39:26ZThe Circadian Clock Gene, Bmal1, Regulates Intestinal Stem Cell Signaling and Represses Tumor Initiation2352-345X10.1016/j.jcmgh.2021.08.001https://doaj.org/article/ab5c749e56d34683944b22691e2cbd1f2021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001685https://doaj.org/toc/2352-345XBackground & Aims: Circadian rhythms are daily physiological oscillations driven by the circadian clock: a 24-hour transcriptional timekeeper that regulates hormones, inflammation, and metabolism. Circadian rhythms are known to be important for health, but whether their loss contributes to colorectal cancer is not known. We tested the nonredundant clock gene Bmal1 in intestinal homeostasis and tumorigenesis, using the Apcmin model of colorectal cancer. Methods: Bmal1 mutant, epithelium-conditional Bmal1 mutant, and photoperiod (day/night cycle) disrupted mice bearing the Apcmin 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: Loss of Bmal1 or circadian photoperiod increases tumor initiation. In the intestinal epithelium the clock regulates transcripts involved in regeneration and intestinal stem cell signaling. Tumors have no self-autonomous clock function and only weak clock function in vivo. Apcmin 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.Kyle StokesMalika NunesChantelle TrombleyDanilo E.F. L. FlôresGang WuZainab TalebAbedalrhman AlkhateebSuhrid BanskotaChris HarrisOliver P. LoveWaliul I. KhanLuis RuedaJohn B. HogeneschPhillip KarpowiczElsevierarticleCircadian RhythmsIntestinal Stem CellsColorectal CancerHippo PathwayDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 5, Pp 1847-1872.e0 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Circadian Rhythms Intestinal Stem Cells Colorectal Cancer Hippo Pathway Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Circadian Rhythms Intestinal Stem Cells Colorectal Cancer Hippo Pathway Diseases of the digestive system. Gastroenterology RC799-869 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 The Circadian Clock Gene, Bmal1, Regulates Intestinal Stem Cell Signaling and Represses Tumor Initiation
description	Background & Aims: Circadian rhythms are daily physiological oscillations driven by the circadian clock: a 24-hour transcriptional timekeeper that regulates hormones, inflammation, and metabolism. Circadian rhythms are known to be important for health, but whether their loss contributes to colorectal cancer is not known. We tested the nonredundant clock gene Bmal1 in intestinal homeostasis and tumorigenesis, using the Apcmin model of colorectal cancer. Methods: Bmal1 mutant, epithelium-conditional Bmal1 mutant, and photoperiod (day/night cycle) disrupted mice bearing the Apcmin 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: Loss of Bmal1 or circadian photoperiod increases tumor initiation. In the intestinal epithelium the clock regulates transcripts involved in regeneration and intestinal stem cell signaling. Tumors have no self-autonomous clock function and only weak clock function in vivo. Apcmin 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.
format	article
author	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
author_facet	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
author_sort	Kyle Stokes
title	The Circadian Clock Gene, Bmal1, Regulates Intestinal Stem Cell Signaling and Represses Tumor Initiation
title_short	The Circadian Clock Gene, Bmal1, Regulates Intestinal Stem Cell Signaling and Represses Tumor Initiation
title_full	The Circadian Clock Gene, Bmal1, Regulates Intestinal Stem Cell Signaling and Represses Tumor Initiation
title_fullStr	The Circadian Clock Gene, Bmal1, Regulates Intestinal Stem Cell Signaling and Represses Tumor Initiation
title_full_unstemmed	The Circadian Clock Gene, Bmal1, Regulates Intestinal Stem Cell Signaling and Represses Tumor Initiation
title_sort	circadian clock gene, bmal1, regulates intestinal stem cell signaling and represses tumor initiation
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/ab5c749e56d34683944b22691e2cbd1f
work_keys_str_mv	AT kylestokes thecircadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT malikanunes thecircadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT chantelletrombley thecircadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT daniloeflflores thecircadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT gangwu thecircadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT zainabtaleb thecircadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT abedalrhmanalkhateeb thecircadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT suhridbanskota thecircadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT chrisharris thecircadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT oliverplove thecircadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT waliulikhan thecircadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT luisrueda thecircadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT johnbhogenesch thecircadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT phillipkarpowicz thecircadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT kylestokes circadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT malikanunes circadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT chantelletrombley circadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT daniloeflflores circadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT gangwu circadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT zainabtaleb circadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT abedalrhmanalkhateeb circadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT suhridbanskota circadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT chrisharris circadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT oliverplove circadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT waliulikhan circadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT luisrueda circadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT johnbhogenesch circadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation AT phillipkarpowicz circadianclockgenebmal1regulatesintestinalstemcellsignalingandrepressestumorinitiation
_version_	1718431250506579968

The Circadian Clock Gene, Bmal1, Regulates Intestinal Stem Cell Signaling and Represses Tumor Initiation

Ejemplares similares