Modulation of C. elegans transcription factor activity by HIM-8 and the related zinc finger ZIM proteins.

摘要

The C. elegans him-8 gene encodes a C2H2 zinc finger protein that binds to the pairing center of the X chromosome to mediate its synapsis and pairing in meiosis. HIM-8 belongs to a zinc finger protein family which also includes ZIM-1, ZIM-2 and ZIM-3. These ZIM proteins have analogous functions to HIM-8 in promoting pairing of specific autosomes in meiosis. Our lab recently has reported a novel role of HIM-8 in negatively regulating the Sox domain transcription factor EGL-13 encoded on the X chromosome. Mutation of him-8 suppresses the egg-laying and underlying vulval morphology defects of the egl-13 mutant with mutations in the Sox DNA binding domain. My data show that all ZIM proteins function similarly to HIM-8 in suppressing EGL-13 transcription factor. In addition, mutation of him-8 suppresses phenotypes caused by missense mutations in the DNA binding domain of other transcription factors, including the zinc finger protein SPTF-3, the PAX protein EGL-38, and the HOX protein LIN-39. Mutation of him-8 has no effect on null alleles of above transcription factors and non-null alleles of non-transcription factors including LIN-15, SUR-6, EGL-26 and UNC-37. These results suggest that HIM-8 and the related ZIM proteins have a broad ability in suppressing transcription factors encoded on multiple chromosomes; that the HIM-8/ZIMs suppression is specific to transcription factors with compromised DNA binding activity; and that the effects caused by HIM-8/ZIMs are global that occur in multiple tissues in the soma.;I further investigated the mechanism by which HIM-8/ZIMs suppresses the activities of the transcription factors. My data demonstrated that him-8 mutations increase the transcription of the targets of two transcription factors and that him-8 and zim-1 mutations result in increased H3K4 methylation level, indicating that the transcription level is increased and that the chromatin is modified to a more accessible status in him-8/zim-1 mutant. It is possible that him-8/zim-1 increases transcription level by mediating chromatin modification. dpy-30 RNAi did not clarify the role of DPY-30 in HIM-8 suppression, but it suggests that RNAi might be an additional mechanism of HIM-8 suppression.