We held Network Medicine Global COE Symposium on “Nuclear Signaling Network ∼Epigenetics and Development∼” at Main Conference Room, Tohoku University School of Medicine, 12 December 2008.
Report: Prof. Kazuhiko Igarashi (member of Network Medicine-GCOE).
How signals are integrated in nuclei at the levels of transcription factors and chromatin was the main theme of this symposium. Dr. Ikura reported that histone H2AX is acetylated and then polyubiquitinated in response to DNA damage. He further showed how enzymes and protein complexes are talk to each other to achieve these modifications, which, as a code, induces eviction of H2AX from damaged chromatin. Dr. Funayama showed how genome-wide chromatin structure changed during cellular senescence, one of the critical tumor suppressing mechanisms. Histone H1 is lost from chromatin and is replaced by HMGA2 protein during senescence, indicating that gross chromatin re-organization may achieve re-programming of gene expression during senescence. Dr. Shrif reported that Np95 protein, a member of SRA domain family, is involved in the maintenance of DNA methylation. Thus, Np95 is involved in the epigenetic memory. He further showed that hemi-methylated DNA (methylated on one of the two DNA strands) can be demethylated but still repressed by polycomb protein complex. There are many ways to silence gene activity. Dr. Harata talked about nuclear actin family protein, Arp60. Strikingly, upon knockdown of Arp60 in chicken DT40 cells, chromosome territory was disorganized, with concomitant de-repression of many genes. Nuclear architecture is constructed by specific proteins and significantly affects individual gene expression. Dr. Ikeda reported that her favorite transcription factor, Six1, directs development of olfactory epithelium by utilizing CBP as its coactivator. Six1 function was shown specific for the pioneer neuron formation. Dr. Motohashi reported that MafG, a dual transcription factor that can either repress or activate genes, is targeted to nuclear matrix. By using transgenic complementation assays in mice, the nuclear matrix targeting was shown critical for its biological function, thrombopoiesis. Thus, transcription factors do things beyond DNA binding and activation/repression.
Dr. Workman gave a special lecture on chromatin regulation. He first described that histone modifications (acetylation and methylation of H3 and H4) generates a dynamic signaling network during transcription elongation. Elongating RNA polymerase II recruits Set2, which methylates lysine 36 of histone H3 (H3K36Me). This modification is bound by histone deacetylation complex Rpd3S, resulting in deacetylation of H3 and H4. This combination of histone modifications achieves proper chromatin reassembly after transcription. Without this system (i.e., mutants), the yeast genome becomes very noisy with many meaningless transcripts generated. Dr. Workman also showed how Rpd3S recognized H3K36Me using its complex component Eaf3 and Rco1, each with bromo domain and PHD finger, respectively. His approach using both genetics and biochemistry of yeast has been extremely powerful in this field.
Issues covered in this symposium were very diverse. However, key concepts are emerging: nuclear proteins function in contexts of interacting, dense, and dynamic networks of protein. If we can identify a kind of hub molecules for cell proliferation, differentiation, and cancer, these will be prime targets for intervention.
