Cationic polyamines such as spermidine and spermine are critical in all forms of life, as they regulate the function of biological macromolecules. Intracellular polyamine metabolism is regulated by reversible acetylation and dysregulated polyamine metabolism is associated with neoplastic diseases such as colon cancer, prostate cancer and neuroblastoma. Here we report that histone deacetylase 10 (HDAC10) is a robust polyamine deacetylase, using recombinant enzymes from Homo sapiens (human) and Danio rerio (zebrafish). The 2.85 Å-resolution crystal structure of zebrafish HDAC10 complexed with a transition-state analogue inhibitor reveals that a glutamate gatekeeper and a sterically constricted active site confer specificity for N8-acetylspermidine hydrolysis and disfavour acetyllysine hydrolysis. Both HDAC10 and spermidine are known to promote cellular survival through autophagy. Accordingly, this work sets a foundation for studying the chemical biology of autophagy through the structure-based design of inhibitors that may also serve as new leads for cancer chemotherapy.

The discovery of new histone modifications is unfolding at startling rates, however, the identification of effectors capable of interpreting these modifications has lagged behind. Here we report the YEATS domain as an effective reader of histone lysine crotonylation – an epigenetic signature associated with active transcription. We show that the Taf14 YEATS domain engages crotonyllysine via a unique π-π-π-stacking mechanism and that other YEATS domains have crotonyllysine binding activity.

Background:The six human SET1 family core complexes catalyze methylation of histone H3 lysine 4 (H3K4). Results: Different SET1 family core complexes catalyze different levels of H3K4 methylation. Conclusion: Product specificity of the SET1 family is correlated with evolutionary lineage. Significance: Core complex subunits differentially regulate the product specificity of different SET1 family members.

Highlights d Histone lysine crotonylation (Kcr) oscillates in the yeast metabolic cycle (YMC) d Deregulation of crotonyl-CoA metabolism results in YMC defects d Taf14, a histone Kcr reader, is needed for transcription oscillations in the YMC d Kcr reading by Taf14 reduces growth gene expression during nutrient limitation

Mixed Lineage Leukemia 1 (MLL1) protein is a member of the SET1 (or MLL) family of histone methyltransferases. In humans, this family consists of six members: MLL1-4, SETd1A, and SETd1B (1-8). The SET1 family catalyzes methylation of histone 3 lysine 4 (H3K4), 3 an epigenetic mark that is associated with active transcription (9 -12). The human SET1 family is composed of large proteins with several well characterized functional domains involved in chromatin binding and protein-protein interactions (13, 14) (Fig. 1A). Although some of these domains differ among family members, all share a C-terminal SET (suppressor of variegation, enhancer of Zeste, trithorax) domain that confers H3K4 methyltransferase activity (15). Like many chromatin-modifying enzymes, the SET1 family works as part of multiprotein complexes that contain binding partners involved in enzymatic regulation and gene targeting. Although the majority of isolated SET1 family SET domains catalyze weak H3K4 monomethylation (H3K4me1), enhanced methylation is observed in the context of a "core complex" (16). The minimal core complex required for enhanced methylation is composed of the SET1/MLL SET domain and a subcomplex called WRAD (WD-40 repeat protein 5 (WDR5), retinoblastoma-binding protein 5 (RbBP5), absent small homeotic 2-like (ASH2L), and dumpy-30 (DPY-30)) (17)(18)(19)(20). Interestingly, SET1 family core complexes preferentially catalyze different levels of H3K4 methylation in a manner that correlates with their evolutionary lineage (16). Whereas SETd1A/B core complexes catalyze mono-, di-, and trimethylation of H3K4 (H3K4me1, H3K4me2, and H3K4me3, respectively), the MLL1 and MLL4 (also known as MLL2) core complexes predominantly catalyze mono-and dimethylation (16). In contrast, MLL2 and MLL3 core complexes catalyze predominantly H3K4 monomethylation (16). In cells, different levels of H3K4 methylation are localized to distinct genomic regions and are associated with distinct functional outcomes (21-23). Assembly of the MLL1 core complex requires a direct interaction between MLL1 and WDR5, whereby WDR5 acts to stabilize the interaction between the MLL1 SET domain and the RbBP5/ASH2L heterodimer (18,24). The MLL1-WDR5 interaction occurs via the conserved Win (WDR5 interaction) * This work was supported, in whole or in part, by the National Institutes of Health Grant R01CA140522 (to M. S. C.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.