PLX265700

GSE125159: Phosphorylation of the ancestral histone variant H3.3 amplifies stimulation-induced transcription

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

Complex organisms are able to rapidly induce select genes among thousands in response to diverse environmental cues. This occurs in the context of large genomes condensed with histone proteins into chromatin. The macrophage response to pathogen sensing, for example, rapidly engages highly conserved signaling pathways and transcription factors (TF) for coordination of inflammatory gene induction. Enriched integration of histone H3.3, the ancestral histone H3 variant, is a feature of inflammatory genes and, in general, dynamically regulated chromatin and transcription. However, little is known of how chromatin is regulated at rapidly induced genes and what features of H3.3, conserved from yeast to human, might enable rapid and high-level transcription. The amino-terminus of H3.3 contains a unique serine residue as compared with alanine residues found in canonical H3.1/2. We find that this H3.3-specific serine residue, H3.3S31, is phosphorylated (H3.3S31ph) in a stimulation-dependent manner along the gene-bodies of rapidly induced response genes in mouse macrophages responding to pathogen sensing. Further, this selective mark of stimulation-responsive genes directly engages histone methyltransferase (HMT) Setd2, a component of the active transcription machinery. Our structure-function studies reveal that a conserved positively charged cleft in Setd2 contacts H3.3S31ph and specifies preferential methylation of H3.3S31ph nucleosomes. We propose that features of H3.3, including H3.3S31ph, engage delegated mechanisms to afford selective and rapid transcription. SOURCE: Steven,Zvi,Josefowicz (sjosefowicz@gmail.com) - Josefowicz Lab Weill Cornell Medicine