title: MLL histone methylases regulate expression of HDLR-SR-B1 in presence of estrogen and control plasma cholesterol in vivo.
abstract: High-density lipoprotein receptors scavenger receptor class B type I [HDLR-SR-B1 (SR-B1)] is a key player in reverse cholesterol transport and maintaining blood cholesterol. We demonstrated that human SR-B1 is transcriptionally activated by 17β-estradiol (E2) in HEPG2 and JAR cells. SR-B1 promoter contains multiple estrogen response elements (ERE half-sites) along with some Sp1 binding sites. Knockdown of estrogen receptor (ER)α and ERβ down-regulated E2-induced SR-B1 expression. ERs were bound to SR-B1 promoter EREs in an E2-dependent manner. Along with ERs, mixed-lineage leukemia (MLL) histone methylases, especially MLL1 and MLL2, play key roles in E2-mediated SR-B1 activation. MLL1 and MLL2 bind to SR-B1 promoter in an E2-dependent manner and control the assembly of transcription pre-initiation complex and RNA polymerase II (RNAPII) recruitment. ERs and MLLs play critical roles in determining the cholesterol uptake by steroidogenic tissues/cells, and their knockdown suppressed the E2-induced cholesterol uptake efficiencies of the cells. Intriguingly, MLL2 knockdown in mice resulted in a 33% increase in plasma cholesterol level and also reduced SR-B1 expression in mice liver, demonstrating its crucial functions in controlling plasma cholesterol in vivo.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, Texas 76019, USA.
authors.forename: Khairul I
authors.initials: KI
authors.lastname: Ansari
authors.forename: Sahba
authors.initials: S
authors.lastname: Kasiri
authors.forename: Imran
authors.initials: I
authors.lastname: Hussain
authors.forename: Samara A Morris
authors.initials: SA
authors.lastname: Bobzean
authors.forename: Linda I
authors.initials: LI
authors.lastname: Perrotti
authors.forename: Subhrangsu S
authors.initials: SS
authors.lastname: Mandal
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000097:blood*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004958:Estradiol / Q000502:physiology; D004967:Estrogens / Q000502:physiology*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D056945:Hep G2 Cells; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051788:Myeloid-Lymphoid Leukemia Protein / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D051122:Scavenger Receptors, Class B / Q000235:genetics* / Q000378:metabolism; D061785:Transcription Initiation, Genetic
chemical_list: D004268:DNA-Binding Proteins; D004967:Estrogens; C497422:KMT2A protein, human; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D011960:Receptors, Estrogen; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D051788:Myeloid-Lymphoid Leukemia Protein; D004958:Estradiol; D002784:Cholesterol; D049410:Luciferases, Renilla; D011495:Histone-Lysine N-Methyltransferase