Editors' ChoiceEpigenetics

Chromatin serotonylation limits differentiation

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Science Signaling  09 Apr 2019:
Vol. 12, Issue 576, eaau2218
DOI: 10.1126/scisignal.aau2218

Modification of histone H3 with the neurotransmitter serotonin impairs neuronal development.

Serotonin (5-HT) is a neurotransmitter that is also important for neuronal growth, survival, and differentiation. Recognition of 5-HT by its cognate receptor can activate well-defined signaling cascades; however, 5-HT can also be posttranslationally attached to target proteins in a process known as serotonylation. Mediated by transglutaminases (TGMs), serotonylation of cytoskeletal proteins and GTPases can alter cell signaling. Farrelly et al. found that the nuclear protein histone H3, but not H2A/B or H4, were also serotonylated. TGM2 serotonylated H3 at Gln5, a modification that was not prevented by adjacent trimethylation at Lys4. Antibodies specific for serotonylated histone H3 (H3Q4ser) or trimethylated serotonylated H3 (H3K5meQ4ser) identified only the dually modified form in multiple tissues and in both serotonergic and nonserotoninergic neurons as well as in nonneuronal cells. Deposition of this epigenetic modification at gene promoter sites was increased by differentiation of human pluripotent stem cells or RN46A-B14 immortalized neuronal cells into serotonergic neurons and correlated with altered gene expression. In differentiated RN46A-B14 cells, lentiviral expression of the H3 Q5A mutant, which cannot be serotonylated, reduced neurite length and the expression of genes involved in axonal guidance. Immunoprecipitation of nuclear extracts with synthetically modified and biotinylated H3 peptides showed that dual modification promoted the interaction of histone H3 with the transcription factor complex TFIID (TATA box binding–protein and its associated factors). These findings show that this type of posttranslational chromatin modification is important for gene expression and cellular differentiation, thereby extending our knowledge of the processes that are sensitive to serotonylation. Further studies are needed to determine whether or how serotonylation may influence other posttranslational epigenetic chromatin modifications or its effects in other cell types (see commentary by Cervantes and Sassone-Corsi).

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