Nuclear Receptor Co-repressor Is Required to Maintain Proliferation of Normal Intestinal Epithelial Cells in Culture and Down-modulates the Expression of Pigment Epithelium-derived Factor

Stem cells of the gut epithelium constantly produce precursors that progressively undergo a succession of molecular changes resulting in growth arrest and commitment to a specific differentiation program. Few transcriptional repressors have been identified that maintain the normal intestinal epithelial cell (IEC) proliferation state. Herein, we show that the nuclear receptor co-repressor (NCoR1) is differentially expressed during the proliferation-to-differentiation IEC transition. Silencing of NCoR1 expression in proliferating cells of crypt origin resulted in a rapid growth arrest without associated cell death. A genechip profiling analysis identified several candidate genes to be up-regulated in NCoR1-deficient IEC. Pigment epithelium-derived factor (PEDF, also known as serpinf1), a suspected tumor suppressor gene that plays a key role in the inhibition of epithelial tissue growth, was significantly up-regulated in these cells. Chromatin immunoprecipitation experiments showed that the PEDF gene promoter was occupied by NCoR1 in proliferating epithelial cells. Multiple retinoid X receptor (RXR) heterodimers interacting sites of the PEDF promoter were confirmed to interact with RXR and retinoid acid receptor (RAR). Cotransfection assays showed that RXR and RAR were able to transactivate the PEDF promoter and that NCoR1 was repressing this effect. Finally, forced expression of PEDF in IEC resulted in a slower rate of proliferation. These observations suggest that NCoR1 expression is required to maintain IEC in a proliferative state and identify PEDF as a novel transcriptional target for NCoR1 repressive action. Stem cells of the gut epithelium constantly produce precursors that progressively undergo a succession of molecular changes resulting in growth arrest and commitment to a specific differentiation program. Few transcriptional repressors have been identified that maintain the normal intestinal epithelial cell (IEC) proliferation state. Herein, we show that the nuclear receptor co-repressor (NCoR1) is differentially expressed during the proliferation-to-differentiation IEC transition. Silencing of NCoR1 expression in proliferating cells of crypt origin resulted in a rapid growth arrest without associated cell death. A genechip profiling analysis identified several candidate genes to be up-regulated in NCoR1-deficient IEC. Pigment epithelium-derived factor (PEDF, also known as serpinf1), a suspected tumor suppressor gene that plays a key role in the inhibition of epithelial tissue growth, was significantly up-regulated in these cells. Chromatin immunoprecipitation experiments showed that the PEDF gene promoter was occupied by NCoR1 in proliferating epithelial cells. Multiple retinoid X receptor (RXR) heterodimers interacting sites of the PEDF promoter were confirmed to interact with RXR and retinoid acid receptor (RAR). Cotransfection assays showed that RXR and RAR were able to transactivate the PEDF promoter and that NCoR1 was repressing this effect. Finally, forced expression of PEDF in IEC resulted in a slower rate of proliferation. These observations suggest that NCoR1 expression is required to maintain IEC in a proliferative state and identify PEDF as a novel transcriptional target for NCoR1 repressive action. The intestinal epithelium consists of a cell monolayer organized in crypts and villi. This epithelium is under constant and rapid renewal, which is assured by constant division of the stem cells located at the base of the crypts (1Crosnier C. Stamataki D. Lewis J. Nat. Rev. Genet. 2006; 7: 349-359Crossref PubMed Scopus (571) Google Scholar). The descendant progenitor cells are progressively instructed to differentiate to exert their functional role during their journey along the villus compartment (2Menard D. Beaulieu J.F. Boudreau F. Perreault N. Rivard N. Vachon P.H. Unsicker K. Krieglstein K. Cell Signaling and Growth Factors in Development: From Molecules to Organogenesis. Wiley-VCH, 2006Google Scholar). The proliferation-to-differentiation transition of single progenitor cell is tightly regulated by morphogens, growth factors and hormones that impact on intracellular signaling pathways. Molecular alterations of specific components from these different classes of molecules are suspected to be important during the development of intestinal cancer (3van den Brink G.R. Offerhaus G.J. Cancer Cell. 2007; 11: 109-117Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). In vivo studies have demonstrated the role of steroid hormones and ligands during intestinal epithelial development and homeostasis (4Henning S.J. Annu. Rev. Physiol. 1985; 47: 231-245Crossref PubMed Google Scholar). For example, the thyroid hormone exerts a positive effect on gut mucosal maturation (5Hodin R.A. Chamberlain S.M. Upton M.P. Gastroenterology. 1992; 103: 1529-1536Abstract Full Text PDF PubMed Scopus (46) Google Scholar) and enterocyte differentiation (6Malo M.S. Zhang W. Alkhoury F. Pushpakaran P. Abedrapo M.A. Mozumder M. Fleming E. Siddique A. Henderson J.W. Hodin R.A. Mol. Endocrinol. 2004; 18: 1941-1962Crossref PubMed Scopus (33) Google Scholar, 7Hodin R.A. Shei A. Morin M. Meng S. Surgery. 1996; 120: 138-143Abstract Full Text PDF PubMed Scopus (27) Google Scholar). Members of the nuclear hormone receptor superfamily are activated by metabolically transformed lipids that are absorbed by intestinal epithelial cells (IEC) 4The abbreviations used are:IECintestinal epithelial cellsAP-1activator protein-1β2-micβ2-microglobulinChIPchromatin immunoprecipitationeGFPenhanced green fluorescence proteinHDAChistone deacetylaseNCoR1nuclear receptor co-repressorPEDFpigment epithelium-derived factorPPARperoxisome proliferator-activated receptorsPBGDporphobilinogen deaminaseqRT-PCRquantitative reverse-transcription polymerase chain reactionRARretinoid acid receptorRXRretinoid X receptorSMRTsilencing mediator of retinoid and thyroid receptorsEMSAelectrophoretic mobility shift assay. before interacting with their receptors and associated gene targets (8Chawla A. Repa J.J. Evans R.M. Mangelsdorf D.J. Science. 2001; 294: 1866-1870Crossref PubMed Scopus (1696) Google Scholar). Peroxisome proliferator-activated receptors (PPARs) are well-described examples of lipophilic ligand binding transcription factors that can influence intestinal epithelial proliferation, differentiation (9Varnat F. Heggeler B.B. Grisel P. Boucard N. Corthésy-Theulaz I. Wahli W. Desvergne B. Gastroenterology. 2006; 131: 538-553Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 10Gupta R.A. Sarraf P. Mueller E. Brockman J.A. Prusakiewicz J.J. Eng C. Willson T.M. DuBois R.N. J. Biol. Chem. 2003; 278: 22669-22677Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar), and inflammation (11Wu G.D. Gastroenterology. 2003; 124: 1538-1542Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). These nuclear receptors can repress gene transcription via the formation of a well defined co-repressor protein complex (12Lazar M.A. Nucl. Recept. Signal. 2003; 1: e001Crossref PubMed Google Scholar). One major player of that repression activity is the nuclear receptor co-repressor (NCoR1) that was originally identified for its potential to repress genes via physical interaction with the thyroid hormone receptor (13Hörlein A.J. Näär A.M. Heinzel T. Torchia J. Gloss B. Kurokawa R. Ryan A. Kamei Y. Söderström M. Glass C.K. Nature. 1995; 377: 397-404Crossref PubMed Scopus (1714) Google Scholar). However, there is now growing evidence that NCoR1 can repress transcription through interaction with several other classes of transcriptional activators including activator protein (AP)-1 and NF-κB (14Perissi V. Aggarwal A. Glass C.K. Rose D.W. Rosenfeld M.G. Cell. 2004; 116: 511-526Abstract Full Text Full Text PDF PubMed Scopus (454) Google Scholar, 15Lee S.K. Kim J.H. Lee Y.C. Cheong J. Lee J.W. J. Biol. Chem. 2000; 275: 12470-12474Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). One additional important class of nuclear receptors that are recruiting NCoR1 repressive action is the retinoid receptors (16Weston A.D. Blumberg B. Underhill T.M. J. Cell Biol. 2003; 161: 223-228Crossref PubMed Scopus (116) Google Scholar). These receptors are composed of either RAR-RXR heterodimers or RXR-RXR homodimers and can repress transcription in a ligand-independent manner. In absence of co-repressors, these receptors are involved in the differentiation of various epithelia (17Kubota H. Chiba H. Takakuwa Y. Osanai M. Tobioka H. Kohama G. Mori M. Sawada N. Exp. Cell Research. 2001; 263: 163-172Crossref PubMed Scopus (87) Google Scholar, 18Fisher G.J. Voorhees J.J. Faseb J. 1996; 10: 1002-1013Crossref PubMed Scopus (359) Google Scholar). intestinal epithelial cells activator protein-1 β2-microglobulin chromatin immunoprecipitation enhanced green fluorescence protein histone deacetylase nuclear receptor co-repressor pigment epithelium-derived factor peroxisome proliferator-activated receptors porphobilinogen deaminase quantitative reverse-transcription polymerase chain reaction retinoid acid receptor retinoid X receptor silencing mediator of retinoid and thyroid receptors electrophoretic mobility shift assay. Ncor1 gene deletion in mice resulted in an impairment of neural stem cell proliferation and spontaneous differentiation into astrocytes (19Hermanson O. Jepsen K. Rosenfeld M.G. Nature. 2002; 419: 934-939Crossref PubMed Scopus (263) Google Scholar). Other reports have recently suggested an antiproliferative role for NCoR1 in hepatocytes (20Feng X. Jiang Y. Meltzer P. Yen P.M. J. Biol. Chem. 2001; 276: 15066-15072Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar) and thyroid tumor cells (21Furuya F. Guigon C.J. Zhao L. Lu C. Hanover J.A. Cheng S.Y. Mol. Cell. Biol. 2007; 27: 6116-6126Crossref PubMed Scopus (32) Google Scholar). Thus, NCoR1 may influence cell proliferation by affecting different gene targets in specific cellular contexts. Because many NCoR1-interacting partners are crucial to the regulation of many IEC functions, we sought to evaluate the functional role of NCoR1 in this specific context. We provide here the evidence that NCoR1 nuclear expression is associated with proliferative and non-differentiated epithelial cells and that NCoR1 silencing by RNA interference causes cells to growth arrest. The pigment epithelial-derived factor (PEDF), a 50-kDa member of the serine protease inhibitor family, was further identified as a transcriptional target for NCoR1 repressive action during this process. Ectopic expression of PEDF in IEC reduced the proliferation rate, an observation that was consistent with the tumor suppressor properties of this regulator in epithelial tissues (22Doll J.A. Stellmach V.M. Bouck N.P. Bergh A.R. Lee C. Abramson L.P. Cornwell M.L. J. Nat. 2003; PubMed Scopus Google Scholar). cells were in with cells were in with and In the were with and were for cell were at in Cell proliferation assays were a in the of to for cell of activity was with of into the cell was by the in with the on mice from were and the at and with as F. S. M. G. Beaulieu J.F. Rivard N. Perreault N. Faseb J. 2007; PubMed Scopus Google Scholar). were under in for cell were at for were with and for either nuclear protein or RNA F. S. M. G. Beaulieu J.F. Rivard N. Perreault N. Faseb J. 2007; PubMed Scopus Google Scholar). RNA was from cells as F. S. M. G. Beaulieu J.F. Rivard N. Perreault N. Faseb J. 2007; PubMed Scopus Google Scholar). transcription were at for in the of of of and of Molecular were in a of with of the of polymerase and of specific was a Molecular as F. S. M. G. Beaulieu J.F. Rivard N. Perreault N. Faseb J. 2007; PubMed Scopus Google Scholar). were and the to the Molecular during was and as in the A of a was used for the for gene which was used to for the in the of the are Cell protein and and was with the to the of protein was by and a Molecular was as F. S. M. G. Beaulieu J.F. Rivard N. Perreault N. Faseb J. 2007; PubMed Scopus Google Scholar). NCoR1 and were from histone and were from different of were for NCoR1 to the or with as the The were into F. S. M. G. Beaulieu J.F. Rivard N. Perreault N. Faseb J. 2007; PubMed Scopus Google Scholar) the and to were and used for cell to expression The of PEDF was from RNA and into and sites of the The cell was used for with and the and as I. C. M. Boudreau F. Rivard N. C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). cells were with either an or PEDF in the of of cells were with for the analysis were from RNA of were with the via the of and as R. 2002; PubMed Scopus Google Scholar). for changes in were the on the were for or of expression of a of and a of fluorescence and NCoR1 cells. Chromatin immunoprecipitation assays were the from the and cells were with for at for Chromatin was with or with NCoR1 One of the was to the of used for immunoprecipitation was and before The were used for PEDF promoter and mobility shift assays were as F. A.M. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar, M.A. A. Mol. Biol. 2001; Google Scholar) with The were in a of of binding and of nuclear protein from cells or with and expression of and of for For the of or were and the binding were for at were on a at for for at and on a Molecular The used was a and The of of potential RXR binding sites the promoter of the PEDF gene The PEDF gene promoter was by from from The used from the to to the transcriptional The was in the of the was confirmed by cells were by to the at with of of expression of NCoR1 expression of the and a constant of well in the of of of The was with an of The and were the the was with were expressed as were the was defined as the of NCoR1 expression during epithelial cell of epithelial cells from the intestinal were progressively along the a F. S. M. G. Beaulieu J.F. Rivard N. Perreault N. Faseb J. 2007; PubMed Scopus Google Scholar) RNA was from these epithelial cell and NCoR1 gene were by in NCoR1 expression was along the in to the of the gene in the villus epithelial cell a specific of intestinal epithelial cell differentiation Because been that NCoR1 regulation of expression be on in other J. M.G. M.A. PubMed Scopus Google Scholar), we the NCoR1 protein of expression in intestinal epithelial cell that were progressively from the NCoR1 protein was in crypt IEC and in the epithelial The of NCoR1 protein expression with the of of the protein that are associated with cells M. P. D. M. C. Rivard N. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar) and the of the an inhibitor of IEC proliferation (9Varnat F. Heggeler B.B. Grisel P. Boucard N. Corthésy-Theulaz I. Wahli W. Desvergne B. Gastroenterology. 2006; 131: 538-553Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 10Gupta R.A. Sarraf P. Mueller E. Brockman J.A. Prusakiewicz J.J. Eng C. Willson T.M. DuBois R.N. J. Biol. Chem. 2003; 278: 22669-22677Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar) We to the of NCoR1 expression during the proliferation-to-differentiation transition of intestinal epithelial cells in The cell that into was been used as a of IEC differentiation F. Y. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus (75) Google Scholar, P.H. Beaulieu J.F. Gastroenterology. 1992; 103: Full Text PDF PubMed Scopus Google Scholar). in NCoR1 gene expression was during the proliferation-to-differentiation transition of cells in The gene was during this as been in the F. Y. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus (75) Google Scholar, P.H. Beaulieu J.F. Gastroenterology. 1992; 103: Full Text PDF PubMed Scopus Google Scholar). We the NCoR1 protein during cell growth arrest and and protein were at different cell and to NCoR1 protein significantly during the proliferation-to-differentiation transition of cells in a that was for NCoR1 protein and In protein was in cells these observations that NCoR1 protein expression was associated with non-differentiated protein is during the proliferation-to-differentiation transition of cells in RNA from cells at different of was used to of the and genes of cells were at different of were with histone and of cells were to with of was to for protein nuclear NCoR1 protein were and with the histone protein The functional NCoR1 protein expression and of cellular proliferation was The cell was further used been to to intestinal epithelial crypt cells A. J. J. Cell Biol. PubMed Scopus Google Scholar) and been used as a to normal and IEC proliferation. We sought to NCoR1 expression by an RNA interference In cell with an enhanced green fluorescence protein expression resulted in of However, of a into cells resulted in of positive cells the cell We that under the of a promoter that were to target the Ncor1 NCoR1 were to NCoR1 A was with from cell The NCoR1 protein was in cells with the as to cells with an an and other The silencing mediator of retinoid and thyroid receptors a member of NCoR1 X. M.A. Endocrinol. 2000; 11: Full Text Full Text PDF PubMed Scopus Google Scholar), was under these specific The specific was further to with NCoR1 cell were with either NCoR1 or of these cells resulted in cell of the NCoR1 In these cells progressively the of NCoR1 protein expression A was to the of NCoR1 impact on cell proliferation cell death. cells were with either or and into tissue inhibition of cell growth was for cells that for several with cells confirmed that NCoR1 expression was reduced in these cell during the in cell was and NCoR1 cells as by the or by of the specific D.W. A. C.K. M. Y. M. Nature. 1995; PubMed Scopus Google Scholar) of polymerase of NCoR1 cell proliferation. cells were with and and cells were at different of were at several during the and to analysis with the of NCoR1 and and were also used to for protein for of crucial cell as and was to identify changes at the protein in absence of NCoR1 the of the molecular changes during the silencing of NCoR1 expression and of crypt IEC proliferation, a gene expression profiling was cells were with NCoR1 or and RNA was The from the were used to for expression Ncor1 was This analysis identified gene targets to be by also known as or was to be in cells for NCoR1 This target was further of its and well role in cellular growth inhibition (22Doll J.A. Stellmach V.M. Bouck N.P. Bergh A.R. Lee C. Abramson L.P. Cornwell M.L. J. Nat. 2003; PubMed Scopus Google Scholar). RNA was at different cell and the of PEDF expression was by of PEDF was significantly in cell that were for NCoR1 as with In PEDF expression was significantly during the proliferation-to-differentiation transition of cells NCoR1 protein is well to be on the J. M.G. M.A. PubMed Scopus Google Scholar). The effect of the a inhibitor of the was on the of the NCoR1 protein in cells. The NCoR1 protein was in the of as with cells The gene that at F. Y. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus (75) Google Scholar, P.H. Beaulieu J.F. Gastroenterology. 1992; 103: Full Text PDF PubMed Scopus Google Scholar) was reduced in cells with In PEDF gene was significantly reduced under these the of gene along the intestinal was with RNA from of cells that were used to NCoR1 expression gene was significantly in the villus epithelial cell a that with the of NCoR1 protein expression further evaluate the PEDF gene be a target of NCoR1 transcriptional repressive experiments were cell chromatin was and with the NCoR1 of the PEDF promoter was on the chromatin NCoR1 with a specific located and in the PEDF of the promoter was to interact with a of the promoter under these NCoR1 can repress transcription in by specific transcription factors as nuclear further NCoR1 was able to repress the PEDF a analysis was of of the PEDF This analysis identified RXR binding We the of RXR and RAR to interact with these different potential binding sites of the PEDF was that to the interacting from cells or with and expression were used for the nuclear were major shift were for of the sites and in of The of complex was for sites and nuclear and were used in of these This complex was specific or were in the binding and of these These observations suggested that of sites be by heterodimers in We RXR and RAR NCoR1 transcriptional repression of the PEDF Cotransfection experiments with or expression a resulted in a of the PEDF The of a NCoR1 expression in the resulted in a of the or and a of the of the PEDF The effect of PEDF on IEC proliferation was cells were with either or and into tissue inhibition of cell growth was in cell that the with cells confirmed that was in these cell for NCoR1 in cell was and cells as by the NCoR1 is a crucial of a transcriptional complex well to exert transcriptional repression on genes in many different cellular (12Lazar M.A. Nucl. 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