Placing the HIRA Histone Chaperone Complex in the Chromatin Landscape

Abstract

Summary The HIRA chaperone complex, comprised of HIRA, UBN1 and CABIN1, collaborates with histone-binding protein ASF1a to incorporate histone variant H3.3 into chromatin in a DNA replication-independent manner. To better understand HIRA’s function and mechanism, we integrated HIRA, UBN1, ASF1a and histone H3.3 ChIP-seq and gene expression analyses. Most HIRA-binding sites co-localize with UBN1, ASF1a and H3.3 at active promoters and active and weak/poised enhancers. At promoters, binding of HIRA/UBN1/ASF1a correlates with the level of gene expression. HIRA is required for deposition of histone H3.3 at its binding sites. There are marked differences in nucleosome and co-regulator composition at different classes of HIRA-bound regulatory site. Underscoring this, we report novel physical interactions between the HIRA complex and transcription factors, a chromatin insulator and an ATP-dependent chromatin-remodelling complex. Our results map the distribution of the HIRA chaperone across the chromatin landscape and point to different interacting partners at functionally distinct regulatory sites.

O-linked N -acetylglucosamine transferase (OGT) interacts with the histone chaperone HIRA complex and regulates nucleosome assembly and cellular senescence

“…Therefore, these results support a model whereby OGT binds and modifies HIRA and promotes HIRA-mediated nucleosome assembly of H3.3-H4 and cellular senescence. Histone variant H3.3 is assembled into nucleosomes at distinct chromatin domains in a replication-independent process (11)(12)(13)(14)(15)(16)(17)(18). In addition, histone H3.3 is mutated in high-grade pediatric brain tumors, chondroblastoma, and giant cell tumors (56)(57)(58).…”

“…For instance, along with H4, canonical histone H3.1/H3.2 is deposited by the histone chaperone CAF-1 during S phase, whereas H3.3 is assembled into nucleosomes at pericentric and telomeric regions by DAXX/ATRX, and at genic regions by the HIRA complex (11)(12)(13)(14)(15)(16)(17)(18). In addition to histone chaperones, posttranslational modifications on newly synthesized histones impact nucleosome assembly, in part by regulating the interactions between histone chaperones and their histone cargo.…”

Transcription factor EKLF (KLF1) recruitment of the histone chaperone HIRA is essential for β-globin gene expression

“…However, EKLF recruitment is discriminatory: HIRA was selectively recruited to the β-promoter and not to the upstream HS2 and HS3 sites within the LCR. These data also provide an explanation for the selective enrichment of histone H3.3 at the promoter during erythroid differentiation (37), particularly because a large majority of HIRA binding sites are enriched for H3.3 (12). Depletion of HIRA decreases β-globin expression, and reduction of EKLF decreases HIRA recruitment.…”

“…Depletion of HIRA decreases β-globin expression, and reduction of EKLF decreases HIRA recruitment. Although a number of transcription factors have been shown to interact with HIRA (12,25,59), their ability to recruit it to a specific site had not been addressed. In this context, it is of interest that the EKLF zinc fingers are primarily responsible for its interaction with HIRA, because they are also critical for EKLF contact with histone H3 (37).…”

“…H3.3 deposition is mediated by distinct factors at specific genomic regions, with histone cell cycle regulation defective homolog A (HIRA) being involved in deposition of H3.3 at promoters and in the body of active genes (10)(11)(12). Further supporting these observations, the biochemical isolation and characterization of protein complexes containing preassembled histone H3.1 and H3.3 from human cells revealed that H3.1 associates with the chaperone chromatin assembly factor-1, whereas H3.3 is incorporated into chromatin by the HIRA chaperone complex consisting of HIRA, CABIN1, and UBN1 together with the histone-binding protein ASF1 (10,(13)(14)(15)(16)(17).…”