MLL Histone Methylases Regulate Expression of HDLR-SR-B1 in Presence of Estrogen and Control Plasma Cholesterol in Vivo

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 27; no. 1; pp. 92 - 105
• Main Authors: Ansari, Khairul I, Kasiri, Sahba, Hussain, Imran, Bobzean, Samara A. Morris, Perrotti, Linda I, Mandal, Subhrangsu S
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.01.2013; Oxford University Press
• Subjects: Animals; Cholesterol - blood; DNA-Binding Proteins - physiology; Estradiol - physiology; Estrogens - physiology; Gene Expression Regulation; Gene Knockdown Techniques; Genes, Reporter; Hep G2 Cells; Histone-Lysine N-Methyltransferase; Humans; Luciferases, Renilla - biosynthesis; Luciferases, Renilla - genetics; Male; Mice; Mice, Nude; Myeloid-Lymphoid Leukemia Protein - physiology; Neoplasm Proteins - physiology; Oligonucleotides, Antisense - genetics; Original Research; Protein Binding; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Response Elements; Scavenger Receptors, Class B - genetics; Scavenger Receptors, Class B - metabolism; Transcription Initiation, Genetic
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2012-1147

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.