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Báo cáo khoa học: Mixed lineage leukemia histone methylases play critical roles in estrogen-mediated regulation of HOXC13

HOXC13, a homeobox-containing gene, is involved in hair development and human leukemia. The regulatory mechanism that drives HOXC13 expression is mostly unknown. Our studies have demonstrated that HOXC13 is transcriptionally activated by the steroid hormone estrogen (17b-estradiol; E2). | Mixed lineage leukemia histone methylases play critical roles in estrogen-mediated regulation of HOXC13 Khairul I. Ansari Sahba Kasiri Imran Hussain and Subhrangsu S. Mandal Department of Chemistry and Biochemistry The University of Texas at Arlington TX USA Keywords estrogen estrogen receptor HOXC13 gene regulation mixed lineage leukemia nuclear receptor Correspondence S. S. Mandal Department of Chemistry and Biochemistry The University of Texas at Arlington Arlington TX 76019 USA Fax 1 817 272 3808 Tel 1 817 272 3804 E-mail smandal@uta.edu Received 28 July 2009 revised 12 October 2009 accepted 20 October 2009 doi 10.1111 j.1742-4658.2009.07453.x HOXC13 a homeobox-containing gene is involved in hair development and human leukemia. The regulatory mechanism that drives HOXC13 expression is mostly unknown. Our studies have demonstrated that HOXC13 is transcriptionally activated by the steroid hormone estrogen 17b-estradiol E2 . The HOXC13 promoter contains several estrogen-response elements EREs including ERE1 and ERE2 which are close to the transcription start site and are associated with E2-mediated activation of HOXC13. Knockdown of the estrogen receptors ERs ERa and ERb suppressed E2-mediated activation of HOXC13. Similarly knockdown of mixed lineage leukemia histone methylase MLL 3 suppressed E2-induced activation of HOXC13. MLLs MLL1-MLL4 were bound to the HOXC13 promoter in an E2-dependent manner. Knockdown of either ERa or ERb affected the E2-dependent binding of MLLs MLL1-MLL4 into HOXC13 EREs suggesting critical roles of ERs in recruiting MLLs in the HOXC13 promoter. Overall our studies have demonstrated that HOXC13 is transcriptionally regulated by E2 and MLLs which in coordination with ERa and ERb play critical roles in this process. Although MLLs are known to regulate HOX genes the roles of MLLs in hormone-mediated regulation of HOX genes are unknown. Herein we have demonstrated that MLLs are critical players in E2-dependent regulation of the HOX gene. .