A SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylation

Nuclear receptor corepressors SMRT ( s ilencing m ediator of r etinoid and t hyroid receptors) and N‐CoR ( n uclear receptor cor epressor) recruit histone deacetylase (HDAC) activity to targeted regions of chromatin. These corepressors contain a closely spaced pair of SANT motifs whose sequence and organization is highly conserved. The N‐terminal SANT is a critical component of a d eacetylase a ctivation d omain (DAD) that binds and activates HDAC3. Here, we show that the second SANT motif functions as part of a h istone i nteraction d omain (HID). The HID enhances repression by increasing the affinity of the DAD‐HDAC3 enzyme for histone substrate. The two SANT motifs synergistically promote histone deacetylation and repression through unique functions. The HID contribution to repression is magnified by its ability to inhibit histone acetyltransferase enzyme activity. Remarkably, the SANT‐containing HID preferentially binds to unacetylated histone tails. This implies that the SMRT HID participates in interpreting the histone code in a feed‐forward mechanism that promotes and maintains histone deacetylation at genomic sites of SMRT recruitment.