Trithorax, Hox, and TALE-class homeodomain proteins ensure cell survival through repression of the BH3-only gene egl-1

• Published in: Developmental biology Vol. 329; no. 2; pp. 374 - 385
• Main Authors: Potts, Malia B., Wang, David P., Cameron, Scott
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.05.2009
• Subjects: Apoptosis; Apoptosis - genetics; Caenorhabditis elegans Proteins - genetics; Cell Survival - physiology; egl-1; Electrophoretic Mobility Shift Assay; Homeodomain Proteins - genetics; Homeodomain Proteins - physiology; Hox; Humans; Leukemia; Meis; MLL; Motor Neurons - cytology; Mutagenesis, Site-Directed; Repressor Proteins - genetics; Transcription, Genetic; Trithorax; Hox; Trithorax; egl-1; Meis; Leukemia; MLL; Apoptosis
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2009.02.022

Mutations that aberrantly activate trithorax-group proteins, Hox transcription factors and TALE-class Hox cofactors promote leukemogenesis, but their target genes critical for leukemogenesis remain largely unknown. Through genetic analyses in C. elegans, we find that the trithorax-group gene lin-59 and the TALE-class Hox cofactor unc-62 are required for survival of the VC motor neurons. With the goal of providing a model for how aberrantly active Hox complexes might promote leukemia, we elucidate the mechanism through which these new inhibitors of programmed cell death act: lin-59 maintains transcription of the Hox gene lin-39, while unc-62 promotes nuclear localization of the TALE-class Hox cofactor ceh-20. A LIN-39/CEH-20 complex binds the promoter of the pro-apoptotic BH3-only gene egl-1, repressing its transcription and ensuring survival of the VC neurons. In the absence of this regulatory mechanism, egl-1 is transcribed and the VC neurons die. Furthermore, ectopic expression of the Hox gene lin-39, as occurs for human Hox genes in leukemia, is sufficient to block death of some cells. This work identifies BH3-only pro-apoptotic genes as targets of Hox-mediated repression and suggests that aberrant activation of Hox networks may promote leukemia in part by inhibiting apoptosis.