Abstract
BackgroundH3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. However, it still remains largely uncharacterized how HIRA complex specifically recognizes and deposits H3.3 to the chromatin, such as promoters and enhancers.ResultsIn this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. While the HIRA subunit can enhance the binding affinity of UBN1 toward H3.3, Cabin1 subunit cannot. We also demonstrate that both Ala87 and Gly90 residues of H3.3 are required and sufficient for the specific recognition and binding by UBN1. ChIP-seq studies reveal that two independent HIRA complexes (UBN1-HIRA and UBN2-HIRA) can cooperatively deposit H3.3 to cis-regulatory regions, including active promoters and active enhancers in mouse embryonic stem (mES) cells. Importantly, disruption of histone chaperone activities of UBN1 and UBN2 by FID/AAA mutation results in the defect of H3.3 deposition at promoters of developmental genes involved in neural differentiation, and subsequently causes the failure of activation of these genes during neural differentiation of mES cells.ConclusionTogether, our results provide novel insights into the mechanism by which the HIRA complex specifically recognizes and deposits H3.3 at promoters and enhancers of developmental genes, which plays a critical role in neural differentiation of mES cells.
Highlights
H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation
To obtain a more straightforward functional implication, the 2560 upregulated genes during neural progenitor cell (NPC) differentiation was used as background control during DAVID analysis (Additional file 1: Figure S6D). These results indicated that the UBN1-HIRA and UBN2-HIRA complexes mediate H3.3 depositions at regulatory regions of genes involved in neural differentiation
We found that UBN1-HIRA and UBN2-HIRA complexes are responsible for H3.3 deposition at promoters, which is in agreement with the previous observation [12, 23]
Summary
H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. The 3D organization and dynamics of chromatin fibers play a central role in regulation of gene transcription and other biological processes involving DNA, such as DNA replication, repair, and recombination [1]. Histone variants are synthesized and incorporated into chromatin throughout the cell cycle [4]. Histone chaperones are essential in the regulation of histone dynamics, genome stability and cell identity [6]. The incorporation of histone variants may create architecturally distinct chromatin regions by regulating the structure and dynamics of chromatin fibers, which enables the chromatin to play diverse functions in chromatin-associated processes [7, 8]
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