High background in CUT&Tag data can occur due to a preference of Tn5 for accessible chromatin. The high-salt wash after pAG-Tn5 binding helps reduce signal at open chromatin, but some background may be present in the IgG control and when profiling repressive targets. To minimize background:
Use freshly harvested, native nuclei
Always include the IgG negative control for comparison
Confirm sample prep quality, as cell/nuclear lysis increases background. See the Sample Prep Section of this website for guidance on sample prep.