AbstractThe PLU‐1/JARID1B nuclear protein, which is expressed in a high proportion of breast cancers, but shows restricted expression elsewhere, belongs to the ARID family of proteins, known to play important roles in development, differentiation, transcriptional regulation and chromatin remodeling. PLU‐1/JARID1B is a strong transcriptional repressor, and here we show that the protein localizes in MAD bodies when cotransfected with class IIa histone deacetylases (HDACs) or N‐CoR. Direct binding to class I and class IIa HDACs is demonstrated, while the interaction with N‐CoR appears to be indirect. The domains involved in the HDAC4‐PLU‐1/JARID1B interaction were investigated in detail, and the data show that 2 PHD domains in PLU‐1/JARID1B, which are involved in transcriptional repression, are also crucial for binding to a domain in the 5′ region of HDAC4, overlapping the MEF‐2 binding region. Physiological relevance of this interaction in the mammary gland is suggested from the observation that HDAC4 and PLU‐1/JARID1B are coexpressed in the pregnant and involuting mouse mammary gland and are both silenced at lactation. Significantly, the expression of both proteins is seen in breast cancers. © 2007 Wiley‐Liss, Inc.