Nascent transcription profiling identifies H3K36 methylation as a custodian of the somatic transcriptome

In Drosophila wing imaginal discs, H3K36 methylation safeguards somatic transcriptome fidelity mainly in heterochromatin, where K36R in H3.2 derepresses repetitive loci far more than Set2 loss.

• Why it matters: Gene expression must suppress cryptic initiation, but it was unclear whether metazoans rely on Set2 or the K36 residue itself to prevent aberrant transcription.
• What they did: Using PRO-seq, RNA-seq, and chromatin profiling, the study compared effects of Set2 loss versus K36R substitutions in H3.2 and H3.3 on initiation and transcriptome fidelity.
• The result: Intragenic initiation was largely unresponsive to K36 methylation loss, while aberrant initiation concentrated in repetitive extragenic chromatin marked by H3K9me2/3 and H3K36me2 but depleted of H3K36me3, including piRNA clusters, germline-restricted genes, and LTR/LINE retrotransposons.