The programmed cell death pathway was first elucidated in C. elegans and is conserved among animals. The BH3-only gene
egl-1 initiates a genetic program that culminates in caspase activation and cellular suicide. Little is known about how cells reproducibly engage the PCD pathway and die or prevent pathway activation and survive. The mechanisms governing this life-or-death decision appear to be evolutionarily conserved and relevant to human disease. For example, the transcription factors
ces-1 and
ces-2 contribute to the ability of the NSM sisters and I2 neurons to correctly decide between PCD and survival by regulating
egl-1 transcription in the worm. In mammalian hematopoetic cells, their homologs Slug and HLF make the same critical decision through transcriptional regulation of the
egl-1 homolog Puma, and this process is critical to the transformed phenotype in specific human leukemias. Here, we demonstrate that the Hox cofactor and Meis/Prep homolog
unc-62 is a component of the survival decision in the six VC motor neurons of the ventral nerve cord. We created a transcriptional reporter for
egl-1 and screened essential transcription factors by RNAi to find genes necessary for the proper
egl-1 expression pattern. We found that
unc-62(RNAi) resulted in expression of the
egl-1 reporter in six cells in the central region of the ventral nerve cord, where
egl-1 is not normally expressed. Previous work from our laboratory and others has shown that the Hox gene
lin-39 and the Pbx/Extradenticle homolog
ceh-20 are required for survival of the six VC motor neurons; we suspected that
unc-62 might also be required for VC survival and that a Hox complex including UNC-62 might act by repressing transcription of
egl-1. Inactivation by RNAi or mutation of
lin-39,
ceh-20, or
unc-62 resulted in
egl-1 transcription and programmed cell death of six cells; lineage analysis confirmed that these were the VC neurons. Epistasis analysis showed that
lin-39,
ceh-20, and
unc-62 act upstream of
egl-1 to repress
egl-1 transcription in the VC neurons. Current experiments are aimed at determining whether repression is direct or indirect, and elucidating the nature of the repression complex. Our data show that Hox genes and cofactors can promote cell survival by repressing transcription of the BH3-only gene
egl-1. Human Hox, Pbx, and Meis genes are frequently affected by gain-of-function or neomorphic mutations in leukemias, where they have a causative role in promoting the disease. However, the relevant transcriptional targets are largely unknown. We hypothesize that the mammalian Hox genes and cofactors contribute to carcinogenesis by transcriptionally repressing BH3-only genes, promoting survival of premalignant cells.