Milne Thomas A, Briggs Scott D, Brock Hugh W, Martin Mary Ellen, Gibbs Denise, Allis C David, Hess Jay L
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Mol Cell. 2002 Nov;10(5):1107-17. doi: 10.1016/s1097-2765(02)00741-4.
MLL, the human homolog of Drosophila trithorax, maintains Hox gene expression in mammalian embryos and is rearranged in human leukemias resulting in Hox gene deregulation. How MLL or MLL fusion proteins regulate gene expression remains obscure. We show that MLL regulates target Hox gene expression through direct binding to promoter sequences. We further show that the MLL SET domain is a histone H3 lysine 4-specific methyltransferase whose activity is stimulated with acetylated H3 peptides. This methylase activity is associated with Hox gene activation and H3 (Lys4) methylation at cis-regulatory sequences in vivo. A leukemogenic MLL fusion protein that activates Hox expression had no effect on histone methylation, suggesting a distinct mechanism for gene regulation by MLL and MLL fusion proteins.
MLL是果蝇三体胸节蛋白的人类同源物，在哺乳动物胚胎中维持Hox基因的表达，并且在人类白血病中发生重排，导致Hox基因失调。MLL或MLL融合蛋白如何调节基因表达仍不清楚。我们发现MLL通过直接结合启动子序列来调节靶Hox基因的表达。我们进一步表明，MLL SET结构域是一种组蛋白H3赖氨酸4特异性甲基转移酶，其活性受到乙酰化H3肽的刺激。这种甲基化酶活性与体内顺式调控序列处的Hox基因激活和H3（赖氨酸4）甲基化相关。一种激活Hox表达的致白血病MLL融合蛋白对组蛋白甲基化没有影响，这表明MLL和MLL融合蛋白的基因调节机制不同。
