SiDe Li

Histone lysine acetylation or methylation helps to regulate chromatin functions during gene transcription. Histone acetylation marks are typically recognized by proteins containing bromodomains, but recently, an alternative mechanism of acetyl-lysine binding was recognized in the tandem plant homeodomain (PHD) finger of human DPF3b, a protein that functions in gene activation. The three-dimensional solution structures of DPF3b bound to a lysine 14-acetylated histone H3 peptide have now been determined, offering mechanistic insight into the way the protein recognizes acetylation marks. The lysine residues of histone proteins can be acetylated or methylated, with important effects on gene expression. Until recently the protein modules that bind acetyl-lysine have been limited to bromodomains. However, the tandem plant homeodomain (PHD) finger of human DPF3b — which is involved in gene activation — has also been reported to bind to acetylated histones. Here, three-dimensional solution structures of DPF3b offer mechanistic insight into how this protein recognizes acetylation marks. Histone lysine acetylation and methylation have an important role during gene transcription in a chromatin context1,2. Knowledge concerning the types of protein modules that can interact with acetyl-lysine has so far been limited to bromodomains1. Recently, a tandem plant homeodomain (PHD) finger3 (PHD1–PHD2, or PHD12) of human DPF3b, which functions in association with the BAF chromatin remodelling complex to initiate gene transcription during heart and muscle development, was reported to bind histones H3 and H4 in an acetylation-sensitive manner4, making it the first alternative to bromodomains for acetyl-lysine binding5. Here we report the structural mechanism of acetylated histone binding by the double PHD fingers of DPF3b. Our three-dimensional solution structures and biochemical analysis of DPF3b highlight the molecular basis of the integrated tandem PHD finger, which acts as one functional unit in the sequence-specific recognition of lysine-14-acetylated histone H3 (H3K14ac). Whereas the interaction with H3 is promoted by acetylation at lysine 14, it is inhibited by methylation at lysine 4, and these opposing influences are important during transcriptional activation of the mouse DPF3b target genes Pitx2 and Jmjd1c. Binding of this tandem protein module to chromatin can thus be regulated by different histone modifications during the initiation of gene transcription.

The Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a transcriptional co-activator that plays a central role in adapted metabolic responses. PGC-1α is dynamically methylated and unmethylated at the residue K779 by the methyltransferase SET7/9 and the Lysine Specific Demethylase 1A (LSD1), respectively. Interactions of methylated PGC-1α[K779me] with the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, the Mediator members MED1 and MED17, and the NOP2/Sun RNA methytransferase 7 (NSUN7) reinforce transcription, and are concomitant with the m(5)C mark on enhancer RNAs (eRNAs). Consistently, loss of Set7/9 and NSun7 in liver cell model systems resulted in depletion of the PGC-1α target genes Pfkl, Sirt5, Idh3b, and Hmox2, which was accompanied by a decrease in the eRNAs levels associated with these loci. Enrichment of m(5)C within eRNA species coincides with metabolic stress of fasting in vivo. Collectively, these findings illustrate the complex epigenetic circuitry imposed by PGC-1α at the eRNA level to fine-tune energy metabolism.

Preadipocyte differentiation occurs during distinct periods of human development and is a key determinant of body mass. Transcriptional events underlying adipogenesis continue to emerge, but the link between chromatin remodeling of specific target loci and preadipocyte differentiation remains elusive. We have identified Krüppel-like factor-6 (KLF6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene Delta-like 1 (Dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation. Forced expression of KLF6 strongly inhibits Dlk1 expression in preadipocytes and NIH 3T3 cells in vivo, whereas down-regulation of KLF6 in 3T3-L1 cells by small interfering RNA prevents adipogenesis. Repression of Dlk1 requires HDAC3 deacetylase activity, which is recruited to the endogenous Dlk1 promoter where it interacts with KLF6. Our studies identify the interaction between HDAC3 and KLF6 as a potential mechanism underlying human adipogenesis, and highlight the role of KLF6 as a multifunctional transcriptional regulator capable of mediating adipocyte differentiation through gene repression. Preadipocyte differentiation occurs during distinct periods of human development and is a key determinant of body mass. Transcriptional events underlying adipogenesis continue to emerge, but the link between chromatin remodeling of specific target loci and preadipocyte differentiation remains elusive. We have identified Krüppel-like factor-6 (KLF6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene Delta-like 1 (Dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation. Forced expression of KLF6 strongly inhibits Dlk1 expression in preadipocytes and NIH 3T3 cells in vivo, whereas down-regulation of KLF6 in 3T3-L1 cells by small interfering RNA prevents adipogenesis. Repression of Dlk1 requires HDAC3 deacetylase activity, which is recruited to the endogenous Dlk1 promoter where it interacts with KLF6. Our studies identify the interaction between HDAC3 and KLF6 as a potential mechanism underlying human adipogenesis, and highlight the role of KLF6 as a multifunctional transcriptional regulator capable of mediating adipocyte differentiation through gene repression. Adipocyte differentiation requires coordinated expression of general and tissue-specific regulatory proteins in a defined sequence (1Rosen E.D. Spiegelman B.M. Annu. Rev. Cell Dev. Biol. 2000; 16: 145-171Crossref PubMed Scopus (1071) Google Scholar, 2Cowherd R.M. Lyle R.E. McGehee Jr., R.E. Semin. Cell Dev. Biol. 1999; 10: 3-10Crossref PubMed Scopus (242) Google Scholar). A critical regulator of adipogenesis is Dlk1, 1The abbreviations used are: Dlk1, Delta-like 1; KLF6, Krüppel-like factor 6; TSA, trichostatin A; shRNA, short hairpin ribonucleic acid; HDAC, histone deacetylase; ChIP, chromatin immunoprecipitation; siRNA, small interfering RNA; PPAR, peroxisome proliferator-activated receptor; PBS, phosphate-buffered saline; TEV, tobacco etch virus; Rb, retinoblastoma. also called preadipocyte factor-1, whose sustained expression prevents differentiation of 3T3-L1 preadipocytes into adipocytes (3Smas C.M. Sul H.S. Cell. 1993; 73: 725-734Abstract Full Text PDF PubMed Scopus (579) Google Scholar). Dlk1 encodes DLK1, a transmembrane epidermal growth factor repeat domain-containing protein highly expressed in preadipocytes and other cells (4Laborda J. Sausville E.A. Hoffman T. Notario V. J. Biol. Chem. 1993; 268: 3817-3820Abstract Full Text PDF PubMed Google Scholar). The abrupt down-regulation of Dlk1 following hormonal stimulation in preadipocytes is an early and necessary event in the phenotypic conversion to fat cells. Forced expression of Dlk1 prevents adipogenesis, whereas enforced down-regulation enhances adipocyte differentiation. Following the reduction in DLK1, rapid induction of adipogenic transcription factors, including SREBP1, C/EBPβ/γ then C/EBPα, and PPARγ2, leads to terminal differentiation of adipocytes, and expression of adipocyte proteins, including leptin and adipsin (1Rosen E.D. Spiegelman B.M. Annu. Rev. Cell Dev. Biol. 2000; 16: 145-171Crossref PubMed Scopus (1071) Google Scholar, 2Cowherd R.M. Lyle R.E. McGehee Jr., R.E. Semin. Cell Dev. Biol. 1999; 10: 3-10Crossref PubMed Scopus (242) Google Scholar). Our previous work (5Bieker J.J. J. Biol. Chem. 2001; 276: 34355-34358Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar) has explored the activity of a transcription factor, KLF6 (also known as Zf9 or CPBP), a ubiquitously expressed 283-amino acid Krüppel-like zinc finger protein and a member of a growing family of related transcriptional regulators. KLF6 contains an 82-amino acid C-terminal DNA-binding domain identical to other Krüppel-like factors, and a 201-amino acid N-terminal activation domain, whose only homology is to KLF7 in its N-terminal 41 amino acids (6Matsumoto N. Laub F. Aldabe R. Zhang W. Ramirez F. Yoshida T. Terada M. J. Biol. Chem. 1998; 273: 28229-28237Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). KLF6 was originally identified as a rapidly induced mRNA following activation of hepatic stellate cells, a mesenchymal liver cell, during liver injury (7Ratziu V. Lalazar A. Wong L. Dang Q. Collins C. Shaulian E. Jensen S. Friedman S.L. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9500-9505Crossref PubMed Scopus (238) Google Scholar). Most interestingly, stellate cells harbor many features of adipocytes, including the storage of lipids as vitamin A esters (retinoids), the production of leptin, and phenotypic plasticity in defined biologic contexts (8Friedman S.L. J. Biol. Chem. 2000; 275: 2247-2250Abstract Full Text Full Text PDF PubMed Scopus (1917) Google Scholar). Transcriptional targets of KLF6 include transforming growth factor-β1 and its receptors (9Kim Y. Ratziu V. Choi S.G. Lalazar A. Theiss G. Dang Q. Kim S.J. Friedman S.L. J. Biol. Chem. 1998; 273: 33750-33758Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar), urokinase-type plasminogen activator (10Kojima S. Hayashi S. Shimokado K. Suzuki Y. Shimada J. Crippa M.P. Friedman S.L. Blood. 2000; 95: 1309-1316PubMed Google Scholar), and the human immunodeficiency virus-long terminal repeat (11Suzuki T. Yamamoto T. Kurabayashi M. Nagai R. Yazaki Y. Horikoshi M. J. Biochem. (Tokyo). 1998; 124: 389-395Crossref PubMed Scopus (36) Google Scholar). Recently, we have established Krüppel-like factor 6 (KLF6) as a novel tumor suppressor gene frequently mutated in human prostate and colon cancers (12Narla G. Heath K.E. Reeves H.L. Li D. Giono L.E. Kimmelman A.C. Glucksman M.J. Narla J. Eng F.J. Chan A.M. Ferrari A.C. Martignetti J.A. Friedman S.L. Science. 2001; 294: 2563-2566Crossref PubMed Scopus (388) Google Scholar, 13Reeves H.L. Narla G. Ogunbiyi O. Haq A.I. Katz A. Benzeno S. Hod E. Harpaz N. Goldberg S. Tal-Kremer S. Eng F.J. Arthur M.J. Martignetti J.A. Friedman S.L. Gastroenterology. 2004; 126: 1090-1103Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). A key mechanism of tumor suppression by KLF6 is the transcriptional up-regulation of p21waf1,cdi a cyclin-dependent kinase inhibitor whose induction also accounts for the growth suppressive activity of the tumor suppressor p53 (12Narla G. Heath K.E. Reeves H.L. Li D. Giono L.E. Kimmelman A.C. Glucksman M.J. Narla J. Eng F.J. Chan A.M. Ferrari A.C. Martignetti J.A. Friedman S.L. Science. 2001; 294: 2563-2566Crossref PubMed Scopus (388) Google Scholar). Although many studies have described down-regulation of Dlk1 during adipocyte differentiation, the underlying mechanisms regulating this event have not been well characterized. The phenotype resemblance of hepatic stellate cells (the of to adipocytes to a potential role of KLF6 in adipogenesis, stellate activation in liver injury is also by KLF6 induction (7Ratziu V. Lalazar A. Wong L. Dang Q. Collins C. Shaulian E. Jensen S. Friedman S.L. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9500-9505Crossref PubMed Scopus (238) Google Scholar, S.L. J. Biol. Chem. 2000; 275: 2247-2250Abstract Full Text Full Text PDF PubMed Scopus (1917) Google Scholar). previous studies have the induction KLF6 during adipocyte differentiation, but its role in this has been Y. R. 1999; PubMed Scopus Google Scholar). Our a identified Dlk1 as a strongly mRNA following induction of KLF6 in not The of the was to Dlk1 is a transcriptional target of KLF6 to the mechanism of Dlk1 gene by KLF6. Our that KLF6 adipocyte differentiation by Dlk1 and this requires the deacetylase activity of expression was as described (7Ratziu V. Lalazar A. Wong L. Dang Q. Collins C. Shaulian E. Jensen S. Friedman S.L. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9500-9505Crossref PubMed Scopus (238) Google Scholar, S.L. J. Biol. Chem. 2000; 275: 2247-2250Abstract Full Text Full Text PDF PubMed Scopus (1917) Google Scholar). and W. F. M.J. W. E. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar) for and of The expression and and for the expression and for The expression was used to 3T3-L1 cells to a transcriptional 3T3-L1 following the of the into the expression was by with and The was then into the of The was by sequence Cell and differentiation of and Cell NIH and the 3T3-L1 cells in with and and NIH and cells in with and and induction of adipocyte differentiation, 3T3-L1 and 3T3 cells in the of the of in 1 and 1 was cells with in for in PBS, and with in for 3T3-L1 cells or cells in with of or with or as in the with the Dlk1 of in as a for cells with and The activity in of was the and a was to activity in the and of KLF6 in KLF6, 3T3-L1 cells with of of was as a cells with to the to for A for expression of KLF6 was established as described M. N. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), with was by the KLF6 into of A KLF6 was established by and into NIH 3T3 cells that expressed by with in the of induction of KLF6, cells with and to and of HDAC3 in 3T3-L1 the of HDAC3 into expression of 3T3-L1 cells the used following of the 3T3-L1 cells growth with and for to for and of 3T3-L1 cells. then for the induction of the HDAC3 target gene following with A and by with PBS, and RNA was to the of RNA was in with and to in and with for Dlk1 and with by to of cells induced to into adipocytes, as described and then RNA was and RNA was by of was of RNA with in the transcription to the The was in and of into for in an sequence was used as a gene for and was used as for KLF6 and Dlk1 and and and and as DNA-binding during of and of the by the of the was the as described in the sequence the which the of target a the of gene and is related to the of mRNA in the of was used to as the in for target and for was with the and expressed as was expressed as of the gene of with the to the was by the to the by the for the and target The of gene was its and with the of in of the and as and a The the Dlk1 promoter as and mutated with by 3T3-L1 preadipocytes used for DNA-binding with of 3T3-L1 for with 1 and with or A was for in the of KLF6 acids was expressed as a protein in and into by The was to for KLF6 in and of was with the in the of for 1 1 of was and the was for an The through a for and to for to with an a following the 3T3-L1 cells the of differentiation with for by and of the into to with of or and and of The and to the The was by for and proteins by for 1 was by and in the of and used as a for sequence the promoter to of transcriptional used to and cells with of cells with and for and The was for The was for 1 of or of with of or of The with of and in and to by as described a was or and with the and the and described in the 6 in and to a The in in and for 1 The was with or was used to by for an N-terminal was with HDAC3 in E. cells by expression L. K. S.L. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). in 1 and cells induced for and the by with to used for HDAC3 expressed its identical deacetylase activity was as described J. S.L. Science. PubMed Scopus Google Scholar) with of and then with for of human KLF6 in a in phosphate-buffered of with trichostatin A was for of the The was and to the of the N-terminal domain of histone then with of for The was with acid and acid was by with and by in and the of was to the of cells with KLF6 expression in as described cells following and as described of HDAC3 or protein a HDAC3 or with by with and into in of with of and of HDAC3 or then used in an by an as described a of by with protein then to and used in following of KLF6 with for with by the of of an acid of was to and for with a and by for 1 of the was and with 1 of of acid the histone was in a of of the used in the deacetylase to the or of specific protein in the used in the of and by proteins then and with HDAC3 and by the KLF6 used to KLF6 expression was as described R. R. Science. PubMed Scopus Google Scholar). the and into the of the 3T3-L1 with KLF6 of was with in into 3T3-L1 cells. cells with to the to for RNA of HDAC3 short RNA human and HDAC3 mRNA was as a the was 3T3-L1 cells the and specific short RNA acid following the Li J. M.J. Biochem. PubMed Scopus Google Scholar, L. J. L. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus (154) Google Scholar). KLF6 KLF6 and Dlk1 expression during differentiation of 3T3-L1 cells preadipocytes into adipocytes following stimulation with a defined hormonal that and (1Rosen E.D. Spiegelman B.M. Annu. Rev. Cell Dev. Biol. 2000; 16: 145-171Crossref PubMed Scopus (1071) Google Scholar, C.M. Sul H.S. Cell. 1993; 73: 725-734Abstract Full Text PDF PubMed Scopus (579) Google Scholar, C. M.J. E. J. J. 1999; PubMed Google Scholar) Following the of differentiation by hormonal KLF6 was induced in a with a induction following adipogenic stimulation by a sustained expression terminal differentiation, between and of KLF6 protein and was by an abrupt of Dlk1 mRNA as by by and then by KLF6 Dlk1, we Dlk1 mRNA in a 3T3 with KLF6 expression (12Narla G. Heath K.E. Reeves H.L. Li D. Giono L.E. Kimmelman A.C. Glucksman M.J. Narla J. Eng F.J. Chan A.M. Ferrari A.C. Martignetti J.A. Friedman S.L. Science. 2001; 294: 2563-2566Crossref PubMed Scopus (388) Google Scholar), and we protein in 3T3-L1 cells with expression of KLF6 following in and KLF6 Dlk1 expression in KLF6 NIH 3T3 cells and in 3T3-L1 preadipocytes with KLF6. a Transcriptional of Dlk1 as a potential target of KLF6 3T3-L1 preadipocytes and an to the of the Dlk1 promoter between and of the transcriptional a a to which KLF6 that the was by an to the of the a interaction between KLF6 and of the in the Dlk1 of KLF6 in and KLF6 adipocyte differentiation through of Dlk1, then expression of KLF6 to a of adipogenesis through sustained Dlk1 expression and expression of adipogenic this we the of KLF6 adipocyte differentiation of 3T3-L1 cells gene as well as gene expression not gene was by RNA the sequence in and of the KLF6 sequence gene of the the target KLF6 sequence cells with expression of endogenous KLF6 with the only with the We then the of down-regulation of KLF6 expression of Dlk1 and other adipogenic including C/EBPα, and following induction of adipocyte differentiation. in and the of Dlk1 to in cells in which KLF6 been with cells, whose Dlk1 during adipocyte differentiation. the expression of key adipogenic was in but not in cells the of differentiation terminal adipocytes, cells in the of differentiation with to fat in adipocytes in in which KLF6 been in a role of KLF6 in adipocyte differentiation through of The Repression of by KLF6 gene is with the activity of histone we the of Dlk1 by KLF6 was by the of the inhibitor M. S. N. Y. Acad. Sci. 1999; PubMed Scopus Google Scholar) of Dlk1, that activity is for Dlk1 by KLF6. The studies that activity was the transcriptional this we activity in this transcriptional KLF6 was of the and with and histone The activity, which was by by that KLF6 Dlk1 expression through of an interaction between KLF6 and 3T3-L1 cells to induced differentiation for and cells and as then a of the of endogenous HDAC3 with KLF6 in the 3T3-L1 cells, whereas or to a not that which has been to a role in adipogenesis L. V. R. J. K. S. J. Dev. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), is a for interaction with KLF6. HDAC3 as a of the identified and to and and but not S. A. C. D. Dev. 2001; PubMed Scopus Google Scholar). activity is a HDAC3 W. F. M.J. W. E. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). which Dlk1 by KLF6, we explored interaction with KLF6 by following into cells. this KLF6 with HDAC3 A and but not with or or not the of KLF6 for HDAC3 of KLF6 with which an HDAC3 interaction domain between amino acids and HDAC3 and KLF6 KLF6 protein an N-terminal was with HDAC3 in E. a expression S. 2001; PubMed Scopus Google Scholar). was used to the KLF6 protein with proteins, and the human KLF6 or HDAC3 to the with KLF6, HDAC3 to and the a between HDAC3 and KLF6. KLF6 to and the as a of expressed KLF6 to the The of the in was by the N-terminal with which the of the KLF6 by to the of HDAC3 and KLF6 is for that HDAC3 with KLF6 other or HDAC3 for HDAC3 is for the deacetylase activity with KLF6, we cells with KLF6 of specific of the including and with of the of by this we that HDAC3 is for the deacetylase activity with KLF6 of and not not deacetylase activity with KLF6. that HDAC3 is for the protein deacetylase activity with KLF6. the of HDAC3 to HDAC3 the an of and of HDAC3 by the of HDAC3 the used for KLF6 We also the of KLF6 following the of HDAC3 and a in KLF6 protein as by studies the of HDAC3 for deacetylase activity with KLF6. KLF6 also with other endogenous in 3T3-L1 cells, we in KLF6 is with in the of the and but not with and that of protein used between also with we the of of the in the 3T3-L1 as with only expression of HDAC3 with KLF6 of the studies in the of adipogenesis through its with HDAC3 L. V. R. J. K. S. J. Dev. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). the that activity with KLF6 is that also with we the of to of or activity with KLF6. of KLF6 cells was used to activity following the of of not activity with KLF6 that the activity with KLF6 is of HDAC3 the Repression of through that KLF6 in with HDAC3 to a Dlk1 not the of this to of the Dlk1 promoter during adipocyte differentiation. this we chromatin to that KLF6 HDAC3 to the endogenous Dlk1 promoter of chromatin KLF6 or HDAC3 was 3T3-L1 cells differentiation with Following of the and a to through of the Dlk1 promoter was by Our that the endogenous Dlk1 promoter was by but not KLF6, with following differentiation of 3T3-L1 cells A and the of HDAC3 to transcriptional of Dlk1, an was used to the induction of HDAC3 in 3T3-L1 cells. 3T3-L1 preadipocytes the and target stimulation of HDAC3 expression in by A to down-regulation of endogenous which was by of HDAC3 expression trichostatin A or HDAC3 we that HDAC3 is a of Dlk1 in of HDAC3 is by KLF6 to the Dlk1 we established a NIH 3T3 that cells with the KLF6 or the KLF6 expression of the activation domain and the DNA-binding in to to HDAC3 to the Dlk1 chromatin was a between KLF6 expression and HDAC3 to the endogenous Dlk1 identical the KLF6 to HDAC3 to the Dlk1 promoter that KLF6 the interaction of HDAC3 the Dlk1 the for KLF6 and HDAC3 to the Dlk1 during adipogenesis, chromatin was of 3T3-L1 cells or induction of adipogenesis. Although HDAC3 the endogenous Dlk1 to induction of adipogenesis, the promoter was following adipogenic induction KLF6 was also to its with the promoter was also adipogenesis. that that HDAC3 and KLF6 the Dlk1 but only in adipocytes and not Our a role for KLF6 in adipocyte differentiation. HDAC3 activity is recruited to the domain of KLF6, which to the Dlk1 promoter to to induction of key of adipocyte differentiation. of KLF6 mRNA or of KLF6 3T3-L1 differentiation, that KLF6 is not to preadipocytes into expression of KLF6 in the of a differentiation not adipogenesis in 3T3-L1 cells not Although and to differentiation of adipocytes, previous where transcriptional of a regulatory protein this A potential of KLF6 was by an Y. R. 1999; PubMed Scopus Google Scholar) in which was with adipogenesis following the induction of 3T3-L1 cells with adipogenic but its activity regulatory targets KLF6 a Transcriptional of and Adipocyte identify a novel transcriptional repressor of KLF6 in adipocyte differentiation, whereas previous studies have its role as a transcriptional activator in tumor suppression (12Narla G. Heath K.E. Reeves H.L. Li D. Giono L.E. Kimmelman A.C. Glucksman M.J. Narla J. Eng F.J. Chan A.M. Ferrari A.C. Martignetti J.A. Friedman S.L. Science. 2001; 294: 2563-2566Crossref PubMed Scopus (388) Google Scholar, C. Jr., J. Full Text Full Text PDF PubMed Scopus Google Scholar, A.C. Narla G. A. N. N. A. Martignetti J.A. Friedman S.L. Chan A.M. 2004; PubMed Scopus Google Scholar) and other biologic contexts (8Friedman S.L. J. Biol. Chem. 2000; 275: 2247-2250Abstract Full Text Full Text PDF PubMed Scopus (1917) Google Scholar, T. F. S. Shimada J. M. M.P. Ratziu V. C. Ramirez Friedman S. C. Blood. 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M.J. W. E. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, Chan Li J. J. Wong J. J. PubMed Scopus Google Scholar, O. Cell. Biol. 2001; PubMed Scopus Google Scholar, J. J. J. Wong J. J. 2000; PubMed Scopus Google Scholar, M. R.M. Dev. 2000; PubMed Google Scholar) or through to E. S. D. 2001; PubMed Scopus Google Scholar). that KLF6 with HDAC3 of or and and not The of in between KLF6 and HDAC3 that KLF6 of transcriptional of with that receptors that during adipocyte differentiation G. E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). HDAC3 is a for mechanisms that terminal differentiation of adipocytes, which is its interaction with KLF6. KLF6 of only a transcription HDAC3 in studies the of other and in this A and HDAC3 the only deacetylase activity recruited by KLF6 during adipogenesis, the of The of the interaction between HDAC3 and KLF6 is the of Dlk1, a gene encoding an epidermal growth transmembrane protein whose down-regulation is for adipocyte differentiation J. 2000; Google Scholar). HDAC3 has been recently a role in by with L. V. R. J. K. S. J. Dev. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). with previous studies by L. V. R. J. K. S. J. Dev. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), that HDAC3 to as a adipocyte differentiation through between KLF6 a of transcription factors, R. S. A. 2001; PubMed Scopus Google Scholar, 2001; 10: PubMed Scopus Google Scholar). studies that also a for differentiation of preadipocytes B.M. J. J. K. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, Lyle R.E. McGehee Jr., R.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. R. E. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). previous that KLF6 growth by transcriptional activation of a role for KLF6, with and differentiation the specific target gene and of the chromatin Our that KLF6 the of through transcriptional activation of specific cyclin-dependent kinase as p21waf1,cdi or of S. Narla G. J. Reeves H.L. J.A. J.A. D. Friedman S.L. 2004; PubMed Scopus Google Scholar) to and differentiation the of a that this to the transcriptional of Dlk1, that KLF6 adipocyte differentiation of through transcriptional activation of of adipocyte differentiation, and and that of KLF6 activity through in to the of of HDAC3 activity of the in many with is the that the of KLF6 to HDAC3 to the Dlk1 and histone of the Dlk1 that of KLF6 through as a mechanism for growth in We and for and and the of for in the We also and for