The disordered regions of SETD2 govern H3K36me3 deposition by regulating its proteasome-mediated decay

SETD2 is the sole methyltransferase that tri-methylates histone H3 at lysine 36 in mammals. It has an extended N-terminal region which is absent in its yeast homolog Set2. The function of this poorly characterized region in regulating SETD2 stability has been reported. However, how this region regulates SETD2 half-life and the consequences of the cellular accumulation of SETD2 is unclear. Here we show that the SETD2 N-terminal region contains disordered regions and is targeted for degradation by the proteasome. The marked increase in global H3K36me3 that occurs on the removal of the N-terminal segment results in 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.