Nizp1 zinc finger protein localization is determined by SCAN-domain inclusion regulated through alternative splicing

The NSD1 histone methyl transferase is involved in childhood acute myeloid leukemia and the outgrowth disorders Sotos and Weaver syndromes. NSD1 is a transcriptional co-repressor for the zinc finger protein Nizp1 (also abbreviated Zfp496 and Zkscan17). Nizp1 includes a SCAN-domain, a KRAB-domain, four C2H2 Krüppel related zinc fingers, and a C2HR transcriptional repression and protein interaction domain required for NSD1 interaction. In this study we have identified alternative splicing of the Nizp1 gene resulting in transcripts encoding Nizp1 protein isoforms with a short N-terminal deletion or a SCAN-domain deletion. The alternative Nizp1 transcripts are expressed in lower levels relative to the canonical Nizp1 transcript. The Nizp1 SCAN-domain mediates Nizp1 self-association but lacks intrinsic transcriptional activating or repressing capacity and has no influence on the transcriptional repression activity of Nizp1 in reporter assays. Sub-cellular localization analysis showed that a fraction of Nizp1 localizes to CBP nuclear bodies and that the SCAN-domain is required for the localization to nuclear bodies. The presented results show that alternative splicing is a functional mechanism to generate Nizp1 protein isoforms with different SCAN-domain compositions and accordingly different sub-cellular localizations.