Epigenetic alterations that disrupt transcriptional control are a central feature of cancer, yet many of their consequences are difficult to detect with conventional expression analyses. The SETD2–H3K36 methylation axis is frequently perturbed in tumors, and loss of H3K36me3 has been linked to reduced transcriptional fidelity and aberrant initiation. Here, we present a data-driven, multi-omics framework to detect and characterize these hidden initiation events at high resolution. Using a histone gene replacement platform in Drosophila melanogaster, we generated precise H3K36 mutations (H3.2K36R and CRISPR-engineered H3.3K36R) and profiled nascent transcription in Set2/H3K36 mutant backgrounds with Precision Run-On Sequencing (PRO-seq). Our analyses identify aberrant transcription start site activity at both intragenic and extragenic regions in mutants relative to matched controls, consistent with widespread disruption of initiation control. To contextualize these signals mechanistically, we integrate PRO-seq with H4 acetylation Cut&Run to evaluate local chromatin states associated with cryptic initiation, and Poly-A RNA-seq to assess which initiation events produce stable transcripts. A major finding is that many cryptic initiation events coincide with transposon derepression, suggesting a coupling between epigenetic disruption and activation of repetitive elements. Overall, this work demonstrates how integrating complementary genomic modalities can reveal transcriptional dysregulation not captured by standard pipelines and provides an analytical blueprint directly relevant to cancer epigenomics and precision oncology.