Histone Crosstalk between H3S10ph and H4K16ac Generates a Histone Code that Mediates Transcription Elongation

Abstract

The phosphorylation of the serine 10 at histone H3 has been shown to be important for transcriptional activation. Here, we report the molecular mechanism through which H3S10ph triggers transcript elongation of the FOSL1 gene. Serum stimulation induces the PIM1 kinase to phosphorylate the preacetylated histone H3 at the FOSL1 enhancer. The adaptor protein 14-3-3 binds the phosphorylated nucleosome and recruits the histone acetyltransferase MOF, which triggers the acetylation of histone H4 at lysine 16 (H4K16ac). This histone crosstalk generates the nucleosomal recognition code composed of H3K9acS10ph/H4K16ac determining a nucleosome platform for the bromodomain protein BRD4 binding. The recruitment of the positive transcription elongation factor b (P-TEFb) via BRD4 induces the release of the promoter-proximal paused RNA polymerase II and the increase of its processivity. Thus, the single phosphorylation H3S10ph at the FOSL1 enhancer triggers a cascade of events which activate transcriptional elongation.

Enforcing the pause: Transcription factor Sp3 limits productive elongation by RNA polymerase II

“…75 In this regard, phosphorylation of H3S10 and the recruitment of 14-3-3 has been reported to be part of a cascade of histone modifications and protein interactions to promote Brd4-dependent recruitment of P-TEFb. 76,77 Our data also support a role for PP1 and/or PP2A as the H3S10 phosphatase. 11,78-80 However, we found that while Sp3 inhibits H3S10 phosphorylation, Sp3 does not block P-TEFb recruitment, suggesting an alternative function for Sp3-regulated H3S10 phosphorylation.…”

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…Of note, the description of these histone posttranslational modifications above is not exhaustive as, for example, phosphorylation also occurs and impacts transcription. 21,22 …”

Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma

“…13 Similar to other bromodomain proteins, such as BRD2 and BRD3, BRD4 has also been shown to associate with chromatin via interaction with different histone acetylation marks, such as H4K5, H4K8, H4K12, H3K9, H3K14, H4K16, and H3K27. [13][14][15][16][17] Of these, BRD4 bound H3K27Ac sites have been associated with very high gene activity. 16 Emerging data links disruption of super-enhancers with inhibitory oncogene transcription that often exhibits high levels of BRD4 occupancy at nearby enhancer/ super-enhancer regions, such as c-Myc in haematopoietic malignancies.…”

“…[13][14][15][16][17] Of these, BRD4 bound H3K27Ac sites have been associated with very high gene activity. 16 Emerging data links disruption of super-enhancers with inhibitory oncogene transcription that often exhibits high levels of BRD4 occupancy at nearby enhancer/ super-enhancer regions, such as c-Myc in haematopoietic malignancies. 13 Interestingly, we and another group have found that pathologic c-Myc amplification is common in MCC.…”