The regulation of all chromatin-templated processes involves the selective recruitment of chromatin factors to facilitate DNA repair, replication, and transcription. Chromatin immunoprecipitation (ChIP) is a fundamental experimental method used to provide spatiotemporal evidence for the coordination of these chromatin-based events including the dynamic regulation of chromatin modifications at cis-regulatory elements. However, obtaining a global appreciation of all the factors that influence a specific chromatin event has remained challenging. Here, as a proof of concept we demonstrate the utility of coupling unbiased functional genomics with ChIP to identify the factors associated with active transcription. Specifically, we use CRISPR-ChIP to identify the major chromatin factors associated with recruitment of RNA Polymerase II (Pol II) and the catalysis of two evolutionarily conserved histone modifications: H3K4me3, present at the transcriptional start site and H3K79me2, present throughout the gene body of actively transcribed genes. With CRISPR-ChIP, we identify all the non-redundant COMPASS complex members required for H3K4me3 deposition, as well as the major components required for Pol II promoter recruitment and functional competency for productive transcription. Importantly, using CRISPR-ChIP in leukaemia cells driven by MLL translocations, we uncover a functional partitioning of H3K79 methylation into two distinct regulatory units: an oncogenic DOT1L complex, where the malignant driver directs the catalytic activity of DOT1L at MLL-fusion target genes and a separate endogenous DOT1L complex, where catalytic activity is directed by MLLT10 at actively expressed genes not controlled by the MLL-fusion protein. This functional demarcation has therapeutic implications and explains why Menin inhibition surprisingly controls methylation of H3K79 at a critical subset of genes that sustain MLL-fusion leukaemia. Overall, CRISPR-ChIP provides a powerful tool for the unbiased interrogation of the mechanisms underpinning chromatin regulation.