BACKGROUND AND AIMS: The intestine exhibits profound diurnal rhythms in function and morphology, in part due to changes in enterocyte proliferation. The regulatory mechanisms behind these rhythms remain largely unknown. We hypothesized that microRNAs are involved in mediating these rhythms, and studied the role of microRNAs specifically in modulating intestinal proliferation. METHODS: Diurnal rhythmicity of microRNAs in rat jejunum was analyzed by microarrays and validated by qPCR. Temporal expression of diurnally rhythmic mir-16 was further quantified in intestinal crypts, villi, and smooth muscle using laser capture microdissection and qPCR. Morphological changes in rat jejunum were assessed by histology and proliferation by immunostaining for bromodeoxyuridine. In IEC-6 cells stably overexpressing mir-16, proliferation was assessed by cell counting and MTS assay, cell cycle progression and apoptosis by flow cytometry, and cell cycle gene expression by qPCR and immunoblotting. RESULTS: mir-16 peaked 6 hours after light onset (HALO 6) with diurnal changes restricted to crypts. Crypt depth and villus height peaked at HALO 13-14 in antiphase to mir-16. Overexpression of mir-16 in IEC-6 cells suppressed specific G1/S regulators (cyclins D1-3, cyclin E1 and cyclin-dependent kinase 6) and produced G1 arrest. Protein expression of these genes exhibited diurnal rhythmicity in rat jejunum, peaking between HALO 11 and 17 in antiphase to mir-16. CONCLUSIONS: This is the first report of circadian rhythmicity of specific microRNAs in rat jejunum. Our data provide a link between anti-proliferative mir-16 and the intestinal proliferation rhythm and point to mir-16 as an important regulator of proliferation in jejunal crypts. This function may be essential to match proliferation and absorptive capacity with nutrient availability.
BACKGROUND AND AIMS: The intestine exhibits profound diurnal rhythms in function and morphology, in part due to changes in enterocyte proliferation. The regulatory mechanisms behind these rhythms remain largely unknown. We hypothesized that microRNAs are involved in mediating these rhythms, and studied the role of microRNAs specifically in modulating intestinal proliferation. METHODS: Diurnal rhythmicity of microRNAs in rat jejunum was analyzed by microarrays and validated by qPCR. Temporal expression of diurnally rhythmic mir-16 was further quantified in intestinal crypts, villi, and smooth muscle using laser capture microdissection and qPCR. Morphological changes in rat jejunum were assessed by histology and proliferation by immunostaining for bromodeoxyuridine. In IEC-6 cells stably overexpressing mir-16, proliferation was assessed by cell counting and MTS assay, cell cycle progression and apoptosis by flow cytometry, and cell cycle gene expression by qPCR and immunoblotting. RESULTS:mir-16 peaked 6 hours after light onset (HALO 6) with diurnal changes restricted to crypts. Crypt depth and villus height peaked at HALO 13-14 in antiphase to mir-16. Overexpression of mir-16 in IEC-6 cells suppressed specific G1/S regulators (cyclins D1-3, cyclin E1 and cyclin-dependent kinase 6) and produced G1 arrest. Protein expression of these genes exhibited diurnal rhythmicity in rat jejunum, peaking between HALO 11 and 17 in antiphase to mir-16. CONCLUSIONS: This is the first report of circadian rhythmicity of specific microRNAs in rat jejunum. Our data provide a link between anti-proliferative mir-16 and the intestinal proliferation rhythm and point to mir-16 as an important regulator of proliferation in jejunal crypts. This function may be essential to match proliferation and absorptive capacity with nutrient availability.
Authors: Daehyun Baek; Judit Villén; Chanseok Shin; Fernando D Camargo; Steven P Gygi; David P Bartel Journal: Nature Date: 2008-07-30 Impact factor: 49.962
Authors: Irena Ivanovska; Alexey S Ball; Robert L Diaz; Jill F Magnus; Miho Kibukawa; Janell M Schelter; Sumire V Kobayashi; Lee Lim; Julja Burchard; Aimee L Jackson; Peter S Linsley; Michele A Cleary Journal: Mol Cell Biol Date: 2008-01-22 Impact factor: 4.272
Authors: Lin Xia; Dexin Zhang; Rui Du; Yanglin Pan; Lina Zhao; Shiren Sun; Liu Hong; Jie Liu; Daiming Fan Journal: Int J Cancer Date: 2008-07-15 Impact factor: 7.396
Authors: Anita Balakrishnan; Adam T Stearns; Jan Rounds; Jennifer Irani; Michael Giuffrida; David B Rhoads; Stanley W Ashley; Ali Tavakkolizadeh Journal: Surgery Date: 2008-06 Impact factor: 3.982
Authors: Anita Balakrishnan; Adam T Stearns; David B Rhoads; Stanley W Ashley; Ali Tavakkolizadeh Journal: Surgery Date: 2008-05-09 Impact factor: 3.982
Authors: Andrea Ventura; Amanda G Young; Monte M Winslow; Laura Lintault; Alex Meissner; Stefan J Erkeland; Jamie Newman; Roderick T Bronson; Denise Crowley; James R Stone; Rudolf Jaenisch; Phillip A Sharp; Tyler Jacks Journal: Cell Date: 2008-03-07 Impact factor: 41.582
Authors: Anita Balakrishnan; Adam T Stearns; Peter J Park; Jonathan M Dreyfuss; Stanley W Ashley; David B Rhoads; Ali Tavakkolizadeh Journal: Ann Surg Date: 2012-04 Impact factor: 12.969
Authors: Christopher A Gaulke; Matthew Porter; Yan-Hong Han; Sumathi Sankaran-Walters; Irina Grishina; Michael D George; Angeline T Dang; Shou-Wei Ding; Guochun Jiang; Ian Korf; Satya Dandekar Journal: J Virol Date: 2014-03-26 Impact factor: 5.103
Authors: Erik Engelen; Roel C Janssens; Kazuhiro Yagita; Veronique A J Smits; Gijsbertus T J van der Horst; Filippo Tamanini Journal: PLoS One Date: 2013-02-13 Impact factor: 3.240
Authors: Xiangli Cui; Erin E Witalison; Alena P Chumanevich; Alexander A Chumanevich; Deepak Poudyal; Venkataraman Subramanian; Aaron J Schetter; Curtis C Harris; Paul R Thompson; Lorne J Hofseth Journal: PLoS One Date: 2013-01-07 Impact factor: 3.240
Authors: Neeta Adhikari; Weihua Guan; Brian Capaldo; Aaron J Mackey; Marjorie Carlson; Sundaram Ramakrishnan; Dinesha Walek; Manu Gupta; Adam Mitchell; Peter Eckman; Ranjit John; Euan Ashley; Paul J Barton; Jennifer L Hall Journal: PLoS One Date: 2014-07-17 Impact factor: 3.240