Dichotomous engagement of HDAC3 activity governs inflammatory responses.

Abstract

Histone deacetylase 3 (HDAC3) is unique among the HDAC superfamily of chromatin modifiers that silence transcription through enzymatic modification of histones because interaction with nuclear receptor corepressors (NCoR1/2) is required for engagement of its catalytic activity1–3. However, loss of HDAC3 also represses transcription4–8. Here we report that, during lipopolysaccharide (LPS) activation of macrophages, recruitment of HDAC3 to ATF2-bound sites without NCoR1/2 non-canonically activates inflammatory gene expression. By contrast, HDAC3 deacetylase activity is selectively engaged at ATF3-bound sites that suppress toll-like receptor (TLR) signaling. Deletion of HDAC3 in macrophages safeguards mice from lethal exposure to LPS, but this protection is not conferred by genetic or pharmacological abolition of HDAC3 catalytic activity. Thus, HDAC3 is a dichotomous transcriptional activator and repressor whose non-canonical deacetylase-independent functions are vital for the innate immune system.