Publication Date:
2014-10-14
Description:
HOXA10, a homeobox-containing gene involved in definitive hematopoiesis, which implicated in the pathogenesis of acute myeloid leukemia, has been studied extensively. But the regulatory mechanism that drives HOXA10 expression is still unclear. In this paper, HOXA10 regulated by MLL1 with an epigenetic way has been demonstrated. The HOXA10 promoter contains several estrogen 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 suppresses E2-mediated activation of HOXA10. Similarly, knockdown of mixed lineage leukemia histone methylase 1(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 with E2 is much higher than without E2 treatment in leukemia 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.
Print ISSN:
0144-8463
Electronic ISSN:
1573-4935
Topics:
Biology
,
Chemistry and Pharmacology
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