title: Mixed lineage leukaemia histone methylases 1 collaborate with ERα to regulate HOXA10 expression in AML.
abstract: HOXA10, a homeobox-containing gene involved in definitive haematopoiesis, which implicated in the pathogenesis of AML (acute myeloid leukaemia), has been studied extensively. But the regulatory mechanism that drives HOXA10 expression is still unclear. In the present paper, HOXA10 regulated by MLL1 (mixed lineage leukaemia histone methylase 1) with an epigenetic way has been demonstrated. The HOXA10 promoter contains several EREs (oestrogen response elements), including ERE1 and ERE2, which are close to the transcription start site, and are associated with E2-mediated activation of HOXA10. It has been shown that knockdown of the ERα (oestrogen receptor α) suppresses E2-mediated activation of HOXA10. Similarly, knockdown of MLL1 suppresses activation of HOXA10 and is bound to the ERE of HOXA10 promoter in an E2-dependent manner by forming complex with ERα. Knockdown of ERα affects the E2-dependent binding of MLL1 into HOXA10 EREs, suggesting critical roles of ERα in recruiting MLL on the HOXA10 promoter. More interestingly, the methylation status of histone protein H3K4 (H3 at lysine 4) with E2 is much higher than without E2 treatment in leukaemia cell. On the contrary, the methylation status of HOXA10 promoter with E2 treatment is much lower, which elevate the HOXA10 expression. Moreover, with ERα knockdown, the H3K4 methylation level is also decrease in myeloid cell. Overall, it has been clearly demonstrated that HOXA10 is transcriptionally regulated by MLL1, which, in coordination with ERα, plays a critical role in this process with epigenetic way and suggests a potential anti-E2 treatment of AML.
authors.affiliation: *Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yao
authors.affiliation: *Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Li-Chao
authors.initials: LC
authors.lastname: Fang
authors.affiliation: †Department of Hematology, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Zai-Lin
authors.initials: ZL
authors.lastname: Yang
authors.affiliation: *Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.affiliation: *Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: *Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Deng
authors.affiliation: *Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Junsong
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D018922:HL-60 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D006657:Histones; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; C069634:HOXA10 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D004958:Estradiol; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine