Identification of CHD7 _S as a novel splicing variant of CHD7 with functions similar and antagonistic to those of the full-length CHD7 _L

CHD7 is one of the nine members of the chromodomain helicase DNA-binding family of ATP-dependent chromatin remodeling enzymes. Mutations in CHD7 give rise to CHARGE syndrome, a human condition characterized by malformation of various organs. We have now identified a novel transcript of CHD7 that is generated by alternative splicing of exon 6. The protein encoded by this variant transcript (termed CHD7 _S) lacks one of the two chromodomains as well as the helicase/ATPase domain, DNA-binding domain and BRK domains of the full-length protein (CHD7 _L). CHD7 _S was found to localize specifically to the nucleolus in a manner dependent on a nucleolar localization signal. Over-expression of CHD7 _S, as well as that of CHD7 _L, resulted in an increase in 45S precursor rRNA production. Conversely, depletion of both CHD7 _S and CHD7 _L by RNA interference inhibited both 45S precursor rRNA production and cell proliferation to a greater extent than did depletion of CHD7 _L alone. Furthermore, we found that, like CHD7 _L, CHD7 _S binds to Sox2 in the nucleoplasm. Unexpectedly, however, whereas over-expression of CHD7 _L promoted Sox2-mediated transcriptional regulation, over-expression of CHD7 _S suppressed it. These results indicate that CHD7 _S functions cooperatively or antagonistically with CHD7 _L in the nucleolus and nucleoplasm, respectively.