DNA methylation is a significant component in proximal chromatin regulation and plays crucial roles in regulating gene expression and maintaining the repressive state of retrotransposon elements. However, accurate profiling of the proteomics which simultaneously identifies specific DNA sequences and their associated epigenetic modifications remains a challenge. Here, we report a strategy termed SelectID (selective profiling of epigenetic control at genome targets identified by dCas9), which introduces methylated DNA binding domain into dCas9-mediated proximity labeling system to enable in situ protein capture at repetitive elements with 5-methylcytosine (5mC) modifications. SelectID is demonstrated as feasible as dCas9-TurboID system at specific DNA methylation regions, such as the chromosome 9 satellite. Using SelectID, we successfully identify CHD4 as potential repressors of methylated long interspersed nuclear element-1 (LINE-1) retrotransposon through direct binding at the 5’ untranslated region (5’UTR) of young LINE-1 elements. Overall, our SelectID approach has opened up avenues for uncovering potential regulators of specific DNA regions with DNA methylation, which will greatly facilitate future studies on epigenetic regulation.
