Regulation of SETD2 stability by its intrinsically disordered regions maintains the fidelity of H3K36me3 deposition

The SET domain-containing protein SETD2 is the sole methyltransferase in mammals that can deposit the histone H3K36me3 mark. H3K36me3 is known to be involved in transcription elongation, pre-mRNA splicing, DNA methylation, and DNA damage repair. However, knowledge of the regulation of the SETD2 enzyme itself is limited. Here we show that the poorly characterized N-terminal region of SETD2 plays a determining role in regulating the stability of SETD2. This stretch of 1-1403 amino acid residues which contains disordered regions, is targeted for degradation by the proteasome. In addition, the SETD2 protein is aggregate-prone and forms insoluble inclusion bodies in nuclei especially upon proteasome inhibition. Removal of the N-terminal segment results in the stabilization of SETD2 and leads to a marked increase in global H3K36me3 which, uncharacteristically, can happen in an RNA Pol II-independent manner. The spurious H3K36me3 thus deposited displays a non-canonical distribution including reduced enrichment over gene bodies and exons. An increased SETD2 abundance leads to widespread changes in transcription and alternative splicing. Thus, the regulation of SETD2 levels through intrinsically disordered region-facilitated proteolysis is important to maintain the fidelity of transcription and splicing related processes.