biostudies-literatureBurton AJNCI NIH HHSNIGMS NIH HHS520-527https://www.ebi.ac.uk/biostudies/studies/S-EPMC7331920biostudies-literatureUnknown12(6)Elucidating the physiological binding partners of histone post-translational modifications (hPTMs) is key to understanding fundamental epigenetic regulatory pathways. Determining such interactomes will enable the study of how perturbations of these interactions affect disease. Here we use a synthetic biology approach to set a series of hPTM-controlled photo-affinity traps in native chromatin. Using quantitative proteomics, the local interactomes of these chemically customized chromatin landscapes are determined. We show that the approach captures transiently interacting factors such as methyltransferases and demethylases, as well as previously reported and novel hPTM reader proteins. We also apply this in situ proteomics approach to a recently disclosed cancer-associated histone mutation, Nature chemistryIn situ chromatin interactomics using a chemical bait and trap approach.PMC7331920R01 GM086868P01 CA196539R37 GM086868F32 GM123659Burton AJMuir TWAllis CDHaugbro MBagert JDGates LAfalseIn situ chromatin interactomics using a chemical bait and trap approach.Elucidating the physiological binding partners of histone post-translational modifications (hPTMs) is key to understanding fundamental epigenetic regulatory pathways. Determining such interactomes will enable the study of how perturbations of these interactions affect disease. Here we use a synthetic biology approach to set a series of hPTM-controlled photo-affinity traps in native chromatin. Using quantitative proteomics, the local interactomes of these chemically customized chromatin landscapes are determined. We show that the approach captures transiently interacting factors such as methyltransferases and demethylases, as well as previously reported and novel hPTM reader proteins. We also apply this in situ proteomics approach to a recently disclosed cancer-associated histone mutation, 2020-01-01T00:00:00Z2020 Jun2026-04-16T13:40:33.157Z2022-02-10T13:13:14.183ZS-EPMC73319203247210310.1038/s41557-020-0474-8