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 activity 1 – 3 . However, loss of HDAC3 also represses transcription 4 – 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.

HDAC3 regulates senescence and lineage specificity in non-small cell lung cancer

“…Mechanistically, HDAC3 has been shown to repress NF-kB activity by directly deacetylating p65 (15–17), although the engagement of this molecular mechanism in vivo has not been widely reported. Repression of NF-kB function by HDAC3 has been observed in macrophages (18), but has not been reported in the many other HDAC3-tissue specific knockouts. We have identified that in both KL and KP NSCLC cells, HDAC3 actively represses the NF-kB/p65 transcriptional program, resulting in repression of the tumor cell senescence program.…”

“…1a). In the absence of activating ligands, nuclear receptors interact on chromatin with NCoR and SMRT, which dampen gene expression 36,38,39 .…”

“…6 hours of Entinostat treatment induced acetylation of K310 on p65 as detected by western blot of protein lysates. Repression of NF-κB function by HDAC3 has been observed in macrophages (36), but has not been reported in the many other HDAC3-tissue specific knockouts. We have identified that in both KL and KP NSCLC cells, HDAC3 actively represses the p65 NF-κB transcriptional program, resulting in repression of the tumor cell SASP program.…”

“…Nuclear receptors function as signal-dependent transcription factors that integrate and deliver developmental, hormonal, environmental and nutrient cues to the genome, thereby acting as genetic switches of gene transcription [32][33][34][35] . In the classical model of nuclear receptor function, ligand binding elicits an allosteric change in the structure of the nuclear receptor, which facilitates differential recruitment of co-activators or co-repressors 36,37 Co-activators with HAT activity bind to ligand-bound nuclear receptors, whereas co-repressors bind ligand-free nuclear receptors to directly mediate gene repression or less commonly to indirectly mediate gene activation (FIG. 1a).…”

“…1a). In the absence of activating ligands, nuclear receptors interact on chromatin with NCoR and SMRT, which dampen gene expression 36,38,39 . HDAC3 is a stoichiometric component of both the NCoR 29,30 and the SMRT 31 co-repressor complexes.…”