Chemical modifications of histones can mediate diverse DNA-templated processes including gene transcription 1 – 3 . Here, we provide evidence for a new class of histone posttranslational modification (PTM), serotonylation of glutamine, which occurs at position 5 (Q5ser) on histone H3 in serotonin (5-hydroxytryptamine, 5-HT) producing organisms. We demonstrate that tissue Transglutaminase 2 (TGM2) can serotonylate histone H3 tri-methylated lysine 4 (H3K4me3) marked nucleosomes resulting in the presence of combinatorial H3K4me3Q5ser in vivo . H3K4me3Q5ser displays a ubiquitous pattern of tissue expression in mammals, with enrichment observed in brain and gut, two organ systems responsible for the bulk of 5-HT production. Genome-wide analyses of human serotonergic neurons, developing mouse brain and cultured serotonergic cells indicate that the mark is enriched in euchromatin, is sensitive to cellular differentiation and correlates with permissive gene expression, phenomena that are linked to the mark’s potentiation of TFIID 4 – 6 interactions with H3K4me3. Cells ectopically expressing an H3 mutant that cannot be serotonylated display significantly altered expression of H3K4me3Q5ser target loci leading to deficits in differentiation. Taken together, these data identify a direct role for 5-HT, independent from its contributions to neurotransmission and cellular signaling, in the mediation of permissive gene expression.

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Recognition of histone covalent modifications by “reader” modules constitutes a major mechanism for epigenetic regulation. A recent upsurge of newly discovered histone lysine acylations, such as crotonylation (Kcr), butyrylation (Kbu), and propionylation (Kpr), greatly expands the coding potential of histone lysine modifications. Here we demonstrate that the histone acetylation-binding double PHD finger (DPF) domains of human MOZ (a.k.a. KAT6A) and DPF2 (a.k.a. BAF45d) accommodate a wide range of histone lysine acylations with the strongest preference for Kcr. Crystal structures of the DPF domain of MOZ in complex with H3K14cr, H3K14bu, and H3K14pr peptides reveal that these non-acetyl acylations are anchored in a hydrophobic “dead-end” pocket with selectivity for crotonylation arising from intimate encapsulation and amide-sensing hydrogen bonding network. Immunofluorescence and ChIP-qPCR show that MOZ and H3K14cr colocalize in a DPF-dependent manner. Our studies call attention to a new regulatory mechanism centered on histone crotonylation readout by DPF family members.

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Histone post-translational modifications (PTMs) and their recognition by histone readers exert crucial functions in eukaryotes. Despite extensive studies, conservation and diversity of histone PTM regulation between animals and plants remain less explored because of a lack of systematic knowledge of histone readers in plants. Based on a high-throughput surface plasmon resonance imaging (SPRi) platform, we report the lab-on-chip profiling of interactions between 204 putative reader domains and 11 types of histone peptides in Arabidopsis thaliana. Eleven reader hits were then chosen for histone combinatorial readout pattern profiling. Systematic analysis of histone PTM recognition in Arabidopsis thaliana reveals that plant and human histone readers share conservation in domain types and recognition mechanisms. The differences in particular histone mark recognition by transcription regulator EML1 and DNA damage repair factor MSH6 indicate plant-specific histone PTMs function in Arabidopsis thaliana acquired during evolution.

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Heterochromatin Protein 1 (HP1) recognizes histone H3 lysine 9 methylation (H3K9me) through its conserved chromodomain and maintains heterochromatin from fission yeast to mammals. However, in Arabidopsis, Like Heterochromatin Protein 1 (LHP1) recognizes and colocalizes genome-wide with H3K27me3, and is the functional homolog of Polycomb protein. This raises the question whether genuine HP1 homologs exist in plants. Here, we report on the discovery of ADCP1, a plant-specific triple tandem Agenet protein, as a multivalent H3K9me reader in Arabidopsis, and establish that ADCP1 is essential for heterochromatin formation and transposon silencing through modulating H3K9 and DNA methylation levels. Structural studies revealed the molecular basis underlying H3K9me-specific recognition by tandem Agenet of ADCP1. Similar to human HP1α and fly HP1a, ADCP1 mediates heterochromatin phase separation. Our results demonstrate that despite its distinct domain compositions, ADCP1 convergently evolves as an HP1-equivalent protein in plants to regulate heterochromatin formation.