Interplay Of PHF6 And SUV39H1 Regulates RDNA Transcription

PHF6(Plant Homeodomain Finger Protein 6)was originally discovered in the research of Borjeson-Forssman-Lehmann syndrome and the mutation of PHF6 was the cause of BFLS.Later several investigations showed that some BFLS patients suffered from the T-cell leukaemia,and mutants of PHF6 also existed in some patients who only suffered from T-cell leukemia.These studies suggested mutation of PHF6 gene was probably associated with the genesis of leukemia.In fact,some research had identified several mutated genes encoding ribosomal proteins in T-cell leukemia,so it revealed that abnormal ribosome biogenesis may contribute to T-cell leukemia.During the ribosomes biogenesis,the first step is to recruit RNA polymerase I to rDNA locus and initiate the transcription of the pre-rRNA.It was confirmed PHF6 was able to be located in the nucleolus and could negatively regulate the transcription of rDNA,these results suggested that the regulation of rDNA transcription by PHF6 may play an important role in the occurrence and development of leukemia.Therefore,we wanted to explore more about the mechanism of the regulation of rDNA transcription by PHF6.In our study,we first proposed PHF6 could regulate rDNA transcription by affecting H3K9me3 level of the rDNA chromatin locus,and the process was dependent of histone-lysine N-methyltransferase SUV39H1.SUV39H1,involving in the formation of the heterochromatin and gene silencing,is specially responsible for tri-methylation modification of H3K9.Methylation of H3K9 is very conserved and served as the maker of the heterochromatin formation and transcription silencing.Here We found PHF6 could recruit histone-lysine N-methyltransferase SUV39H1 to rDNA locus to upregulate the H3K9me3 level by the methyltransferase activity of SUV39H1,and then led to the suppression of the rDNA transcription.Moreover,we found both PHDs of PHF6 were indispensable for the recruitment of SUV39H1 to rDNA locus by PHF6 and the regulation of rDNA transcription by PHF6.We selected two kinds of mutants of PHF6 in leukemia and discovered they lost the ability of suppressing rDNA transcription.And furthermore we proved that the dysregulation of rDNA transcription by these PHF6 mutants were caused by the impaired ability to recruit SUV39H1 to rDNA locus.Finally,we used the cell clones experiment and the implanted tumor model proved that knocking down PHF6 could promote the cell proliferation and the tumor growth by increasing rDNA transcription.In conclusion,we uncovered a novel mechanism of PHF6 regulating rDNA transcription,and found out the reason for the dysregulation of rDNA transcription by the two kinds of PHF6 mutants in leukemia,providing a new way for the diagnosis and treatment of mutated PHF6 related leukemia.