title: Histone H3K4 methyltransferase Mll1 regulates protein glycosylation and tunicamycin-induced apoptosis through transcriptional regulation.
abstract: Disrupting protein glycosylation induces ER (endoplasmic reticulum) stress, resulting in the activation of UPR (unfolded protein response) pathways. A key function of the UPR is to restore ER homeostasis, but prolonged or unsolved ER stress can lead to apoptosis. MLL1 (Mixed Lineage Leukemia 1, also named ALL-1 or HRX), a histone H3K4 methyltransferase in mammals, plays important roles in leukemogenesis, transcriptional regulation, cell cycle and development. Here, we find that Mll1 deficiency enhances UPR and apoptosis induced by the glycosylation inhibitor TM (tunicamycin). The abnormal regulation of the UPR appears to be caused by a defect in protein glycosylation. Furthermore, Mll1 directly binds to the promoters of H6pd, Galnt12 and Ugp2, which regulates H3K4 trimethylation and the subsequent expression of these genes. The knockdown of H6pd, Galnt12 or Ugp2 enhances TM-induced apoptosis in Mll1(+/+)MEF cells, whereas the ectopic expression of these proteins inhibits TM-induced apoptosis in Mll1(-/-) MEF cells. Together, our data suggest that the maturation of glycoproteins in the ER is subject to regulation at the epigenetic level by a histone methyltransferase whose abnormality can lead to cancer and developmental defects.
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Lingao
authors.initials: L
authors.lastname: Ju
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Jiadong
authors.initials: J
authors.lastname: Fan
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Liu
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhu
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China. Electronic address: wumin@whu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China. Electronic address: lilianyun@whu.edu.cn.
authors.forename: Lianyun
authors.initials: L
authors.lastname: Li
keywords: Apoptosis; Histone H3K4 methylation; Mll1; Protein glycosylation; Tunicamycin; UPR