Depletion of histone deacetylase 3 antagonizes PI3K-mediated overgrowth of Drosophila organs through the acetylation of histone H4 at lysine 16

被引:20
作者
Lv, Wen-Wen [1 ]
Wei, Hui-Min [1 ]
Wang, Da-Liang [1 ]
Ni, Jian-Quan [1 ]
Sun, Fang-Lin [1 ,2 ]
机构
[1] Tsinghua Univ, Sch Med, Inst Epigenet & Canc Res, Beijing 100084, Peoples R China
[2] Tongji Univ, Sch Life Sci, Shanghai 200438, Peoples R China
基金
美国国家科学基金会;
关键词
Drosophila; Histone deacetylase 3; Body size; H4K16; acetylation; PI3K signaling; CHROMATIN-STRUCTURE; CELL-PROLIFERATION; SIGNALING PATHWAY; INSULIN-RECEPTOR; COLON-CANCER; HDAC3; GENE; MELANOGASTER; COMPLEXES; GROWTH;
D O I
10.1242/jcs.106336
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Core histone modifications play an important role in chromatin remodeling and transcriptional regulation. Histone acetylation is one of the best-studied gene modifications and has been shown to be involved in numerous important biological processes. Herein, we demonstrated that the depletion of histone deacetylase 3 (Hdac3) in Drosophila melanogaster resulted in a reduction in body size. Further genetic studies showed that Hdac3 counteracted the organ overgrowth induced by overexpression of insulin receptor (InR), phosphoinositide 3-kinase (PI3K) or S6 kinase (S6K), and the growth regulation by Hdac3 was mediated through the deacetylation of histone H4 at lysine 16 (H4K16). Consistently, the alterations of H4K16 acetylation (H4K16ac) induced by the overexpression or depletion of males-absent-on-the-first (MOF), a histone acetyltransferase that specifically targets H4K16, resulted in changes in body size. Furthermore, we found that H4K16ac was modulated by PI3K signaling cascades. The activation of the PI3K pathway caused a reduction in H4K16ac, whereas the inactivation of the PI3K pathway resulted in an increase in H4K16ac. The increase in H4K16ac by the depletion of Hdac3 counteracted the PI3K-induced tissue overgrowth and PI3K-mediated alterations in the transcription profile. Overall, our studies indicated that Hdac3 served as an important regulator of the PI3K pathway and revealed a novel link between histone acetylation and growth control.
引用
收藏
页码:5369 / 5378
页数:10
相关论文
共 59 条
  • [1] Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila
    Akhtar, A
    Becker, PB
    [J]. MOLECULAR CELL, 2000, 5 (02) : 367 - 375
  • [2] Annunziato AT, 2000, GENE EXPRESSION, V9, P37
  • [3] Drosophila ecdysone receptor mutations reveal functional differences among receptor isoforms
    Bender, M
    Imam, FB
    Talbot, WS
    Ganetzky, B
    Hogness, DS
    [J]. CELL, 1997, 91 (06) : 777 - 788
  • [4] Gene activation by histone and factor acetyltransferases
    Berger, SL
    [J]. CURRENT OPINION IN CELL BIOLOGY, 1999, 11 (03) : 336 - 341
  • [5] Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control
    Bhaskara, Srividya
    Chyla, Brenda J.
    Amann, Joseph M.
    Knutson, Sarah K.
    Cortez, David
    Sun, Zu-Wen
    Hiebert, Scott W.
    [J]. MOLECULAR CELL, 2008, 30 (01) : 61 - 72
  • [6] Hdac3 Is Essential for the Maintenance of Chromatin Structure and Genome Stability
    Bhaskara, Srividya
    Knutson, Sarah K.
    Jiang, Guochun
    Chandrasekharan, Mahesh B.
    Wilson, Andrew J.
    Zheng, Siyuan
    Yenamandra, Ashwini
    Locke, Kimberly
    Yuan, Jia-ling
    Bonine-Summers, Alyssa R.
    Wells, Christina E.
    Kaiser, Jonathan F.
    Washington, M. Kay
    Zhao, Zhongming
    Wagner, Florence F.
    Sun, Zu-Wen
    Xia, Fen
    Holson, Edward B.
    Khabele, Dineo
    Hiebert, Scott W.
    [J]. CANCER CELL, 2010, 18 (05) : 436 - 447
  • [7] Drosophila's insulin/P13-kinase pathway coordinates cellular metabolism with nutritional conditions
    Britton, JS
    Lockwood, WK
    Li, L
    Cohen, SM
    Edgar, BA
    [J]. DEVELOPMENTAL CELL, 2002, 2 (02) : 239 - 249
  • [8] Histone deacetylase inhibitors as therapeutics for polyglutamine disorders
    Butler, Rachel
    Bates, Gillian P.
    [J]. NATURE REVIEWS NEUROSCIENCE, 2006, 7 (10) : 784 - 796
  • [9] The phosphoinositide 3-kinase pathway
    Cantley, LC
    [J]. SCIENCE, 2002, 296 (5573) : 1655 - 1657
  • [10] The Drosophila insulin receptor is required for normal growth
    Chen, C
    Jack, J
    Garofalo, RS
    [J]. ENDOCRINOLOGY, 1996, 137 (03) : 846 - 856