Linker Histone H1.2 Cooperates with Cul4A and PAF1 to Drive H4K31 Ubiquitylation-Mediated Transactivation

• Histone H1.2 is a critical regulator of Cul4A-mediated H4K31 ubiquitylation
• H3K4me1/H3K4me3 and H3K79me1/H3K79me2 are dependent on H4K31 ubiquitylation
• H1.2 cooperates with Cul4A and PAF1 to activate developmental regulatory genes
• RNAPII Ser2 phosphorylation is needed to bring H1.2/Cul4A/PAF1 to target genes

SummaryIncreasing evidence suggests that linker histone H1 can influence distinct cellular processes by acting as a gene-specific regulator. However, the mechanistic basis underlying such H1 specificity and whether H1 acts in concert with other chromatin-altering activities remain unclear. Here, we show that one of the H1 subtypes, H1.2, stably interacts with Cul4A E3 ubiquitin ligase and PAF1 elongation complexes and that such interaction potentiates target gene transcription via induction of H4K31ubiquitylation, H3K4me3, and H3K79me2. H1.2, Cul4A, and PAF1 are functionally cooperative because their individual knockdown results in the loss of the corresponding histone marks and the deficiency of target gene transcription. H1.2 interacts with the serine 2-phosphorylated form of RNAPII, and we argue that it recruits the Cul4A and PAF1 complexes to target genes by bridging the interaction between the Cul4A and PAF1 complexes. These data define an expanded role for H1 in regulating gene transcription and illustrate its dependence on the elongation competence of RNAPII.

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