Di-n-butyl phthalate promotes the neural differentiation of mouse embryonic stem cells through neurogenic differentiation 1.

An understanding of the risk of gene deletion and mutation posed by endocrine-disrupting chemicals (EDCs) is necessary for the identification of etiological reagents for many human diseases. Therefore, the characterization of the genetic traits caused by developmental exposure to EDCs is an important research subject. A new regenerative approach using embryonic stem cells (ESCs) holds promise for the development of stem-cell-based therapies and the identification of novel therapeutic agents against human diseases. Here, we focused on the characterization of the genetic traits and alterations in pluripotency/stemness triggered by phthalate ester derivatives. Regarding their in vitro effects, we reported the abilities of ESCs regarding proliferation, cell-cycle control, and neural ectoderm differentiation. The expression of their stemness-related genes and their genetic changes toward neural differentiation were examined, which led to the observation that the tumor suppressor gene product p53/retinoblastoma protein 1 and its related cascades play critical functions in cell-cycle progression, cell death, and neural differentiation. In addition, the expression of neurogenic differentiation 1 was affected by exposure to di-n-butyl phthalate in the context of cell differentiation into neural lineages. The nervous system is one of the most sensitive tissues to exposure to phthalate ester derivatives. The present screening system provides a good tool for studying the mechanisms underlying the effects of EDCs on the developmental regulation of humans and rodents, especially on the neuronal development of ESCs.

Heterogeneity of Phase II Enzyme Ligands on Controlling the Progression of Human Gastric Cancer Organoids as Stem Cell Therapy Model.

Gastric cancer (GC) organoids are frequently used to examine cell proliferation and death as well as cancer development. Invasion/migration assay, xenotransplantation, and reactive oxygen species (ROS) production were used to examine the effects of antioxidant drugs, including perillaldehyde (PEA), cinnamaldehyde (CA), and sulforaphane (SFN), on GC. PEA and CA repressed the proliferation of human GC organoids, whereas SFN enhanced it. Caspase 3 activities were also repressed on treatment with PEA and CA. Furthermore, the tumor formation and invasive activities were repressed on treatment with PEA and CA, whereas they were enhanced on treatment with SFN. These results in three-dimensional (3D)-GC organoids showed the different cancer development of phase II enzyme ligands in 2D-GC cells. ROS production and the expression of TP53, nuclear factor erythroid 2-related factor (NRF2), and Jun dimerization protein 2 were also downregulated on treatment with PEA and CA, but not SFN. NRF2 knockdown reversed the effects of these antioxidant drugs on the invasive activities of the 3D-GC organoids. Moreover, ROS production was also inhibited by treatment with PEA and CA, but not SFN. Thus, NRF2 plays a key role in the differential effects of these antioxidant drugs on cancer progression in 3D-GC organoids. PEA and CA can potentially be new antitumorigenic therapeutics for GC.

Jdp2 is a spatiotemporal transcriptional activator of the AhR via the Nrf2 gene battery.

BACKGROUND: Crosstalk between the aryl hydrocarbon receptor (AhR) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling is called the "AhR-Nrf2 gene battery", which works synergistically in detoxification to support cell survival. Nrf2-dependent phase II gene promoters are controlled by coordinated recruitment of the AhR to adjacent dioxin responsive element (DRE) and Nrf2 recruitment to the antioxidative response element (ARE). The molecular interaction between AhR and Nrf2 members, and the regulation of each target, including phase I and II gene complexes, and their mediators are poorly understood. METHODS: Knockdown and forced expression of AhR-Nrf2 battery members were used to examine the molecular interactions between the AhR-Nrf2 axis and AhR promoter activation. Sequential immunoprecipitation, chromatin immunoprecipitation, and histology were used to identify each protein complex recruited to their respective cis-elements in the AhR promoter. Actin fiber distribution, cell spreading, and invasion were examined to identify functional differences in the AhR-Jdp2 axis between wild-type and Jdp2 knockout cells. The possible tumorigenic role of Jdp2 in the AhR-Nrf2 axis was examined in mutant Kras-Trp53-driven pancreatic tumors. RESULTS: Crosstalk between AhR and Nrf2 was evident at the transcriptional level. The AhR promoter was activated by phase I ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the AhR-Jdp2-Nrf2 axis in a time- and spatial transcription-dependent manner. Jdp2 was a bifunctional activator of DRE- and ARE-mediated transcription in response to TCDD. After TCDD exposure, Jdp2 activated the AhR promoter at the DRE and then moved to the ARE where it activated the promoter to increase reactive oxygen species (ROS)-mediated functions such as cell spreading and invasion in normal cells, and cancer regression in mutant Kras-Trp53-driven pancreatic tumor cells. CONCLUSIONS: Jdp2 plays a critical role in AhR promoter activation through the AhR-Jdp2-Nrf2 axis in a spatiotemporal manner. The AhR functions to maintain ROS balance and cell spreading, invasion, and cancer regression in a mouse model of mutant Kras-Trp53 pancreatic cancer. These findings provide new insights into the roles of Jdp2 in the homeostatic regulation of oxidative stress and in the antioxidation response in detoxification, inflammation, and cancer progression.

Independent Signaling of Hepatoma Derived Growth Factor and Tumor Necrosis Factor-Alpha in Human Gastric Cancer Organoids Infected by Helicobacter pylori.

We prepared three-dimensional (3-D) organoids of human stomach cancers and examined the correlation between the tumorigenicity and cytotoxicity of Helicobacter pylori (H. pylori). In addition, the effects of hepatoma-derived growth factor (HDGF) and tumor necrosis factor (TNFα) on the growth and invasion activity of H. pylori-infected gastric cancer organoids were examined. Cytotoxin-associated gene A (CagA)-green fluorescence protein (GFP)-labeled H. pylori was used to trace the infection in gastric organoids. The cytotoxicity of Cag encoded toxins from different species of H. pylori did not affect the proliferation of each H. pylori-infected cancer organoid. To clarify the role of HDGF and TNFα secreted from H. pylori-infected cancer organoids, we prepared recombinant HDGF and TNFα and measured the cytotoxicity and invasion of gastric cancer organoids. HDGF controlled the growth of each organoid in a species-specific manner of H. pylori, but TNFα decreased the cell viability in H. pylori-infected cancer organoids. Furthermore, HDGF controlled the invasion activity of H. pylori-infected cancer organoid in a species-dependent manner. However, TNFα decreased the invasion activities of most organoids. We found different signaling of cytotoxicity and invasion of human gastric organoids in response to HDGF and TNFα during infection by H. pylori. Recombinant HDGF and TNFα inhibited the development and invasion of H. pylori-infected gastric cancer differently. Thus, we propose that HDGF and TNFα are independent signals for development of H. pylori-infected gastric cancer. The signaling of growth factors in 3-D organoid culture systems is different from those in two-dimensional cancer cells.

Zinc binding of a Cys2His2-type zinc finger protein is enhanced by the interaction with DNA.

Zinc finger proteins specifically recognize DNA sequences and, therefore, play a crucial role in living organisms. In this study the Zn(II)-, and DNA-binding of 1MEY#, an artificial zinc finger protein consisting of three finger units was characterized by multiple methods. Fluorimetric, circular dichroism and isothermal calorimetric titrations were applied to determine the accurate stability constant of a zinc finger protein. Assuming that all three zinc finger subunits behave identically, the obtained thermodynamic data for the Zn(II) binding were ΔHbinding site = - (23.5 - 28.0) kcal/mol (depending on the applied protonation state of the cysteines) and logß'pH 7.4 = 12.2 ± 0.1, being similar to those of the CP1 consensus zinc finger peptide. The specific DNA binding of the protein can be characterized by logß'pH 7.4 = 8.20 ± 0.08, which is comparable to the affinity of the natural zinc finger proteins (Sp1, WT1, TFIIIA) toward DNA. This value is ~ 1.9 logß' unit higher than those determined for semi- or nonspecific DNA binding. Competitive circular dichroism and electrophoretic mobility shift measurements revealed that the conditional stability constant characteristic for Zn(II) binding of 1MEY# protein increased by 3.4 orders of magnitude in the presence of its target DNA sequence.

Stem Cell Biomarkers and Tumorigenesis in Gastric Cancer.

Stomach cancer has a high mortality, which is partially caused by an absence of suitable biomarkers to allow detection of the initiation stages of cancer progression. Thus, identification of critical biomarkers associated with gastric cancer (GC) is required to advance its clinical diagnoses and treatment. Recent studies using tracing models for lineage analysis of GC stem cells indicate that the cell fate decision of the gastric stem cells might be an important issue for stem cell plasticity. They include leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5+), Cholecystokinin receptor 2 (Cckr2+), and axis inhibition protein 2 (Axin2+) as the stem cell markers in the antrum, Trefoil Factor 2 (TFF2+), Mist1+ stem cells, and Troy+ chief cells in the corpus. By contrast, Estrogen receptor 1 (eR1), Leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1), SRY (sex determining region Y)-box 2 (Sox2), and B lymphoma Mo-MLV insertion region 1 homolog (Bmi1) are rich in both the antrum and corpus regions. These markers might help to identify the cell-lineage identity and analyze the plasticity of each stem cell population. Thus, identification of marker genes for the development of GC and its environment is critical for the clinical application of cancer stem cells in the prevention of stomach cancers.

ARHGAP1 Transported with Influenza Viral Genome Ensures Integrity of Viral Particle Surface through Efficient Budozone Formation.

Influenza viral particles are assembled at the plasma membrane concomitantly with Rab11a-mediated endocytic transport of viral ribonucleoprotein complexes (vRNPs). The mechanism of spatiotemporal regulation of viral budozone formation and its regulatory molecules on the endocytic vesicles remain unclear. Here, we performed a proximity-based proteomics approach for Rab11a and found that ARHGAP1, a Rho GTPase-activating protein, is transported through the Rab11a-mediated apical transport of vRNP. ARHGAP1 stabilized actin filaments in infected cells for the lateral clustering of hemagglutinin (HA) molecules, a viral surface membrane protein, to the budozone. Disruption of the HA clustering results in the production of virions with low HA content, and such virions were less resistant to protease and had enhanced antigenicity, presumably because reduced clustering of viral membrane proteins exposes hidden surfaces. Collectively, these results demonstrate that Rab11a-mediated endocytic transport of ARHGAP1 with vRNPs stimulates budozone formation to ensure the integrity of virion surface required for viral survival. IMPORTANCE The endocytic transport of the influenza viral genome triggers the clustering of viral membrane proteins at the plasma membrane to form the viral budozone. However, host factors that promote viral budozone formation in concert with viral genome transport have not been identified. Here, we found that ARHGAP1, a negative regulator of the Rho family protein, is transported with the viral genome and stabilizes actin filaments to promote budozone formation. We have shown that ARHGAP1-mediated efficient formation of viral budozone was crucial for the clustering of viral HA protein to the progeny viral particles. The clustering of HA proteins on the virions is responsible for the structural integrity of the viral particles, which promotes viral stability and viral immune evasion. This study highlights the molecular mechanism that works in concert with viral genome packaging to ensure the structural integrity of viral particles.

Dimethyl sulfoxide stimulates the AhR-Jdp2 axis to control ROS accumulation in mouse embryonic fibroblasts.

The aryl hydrocarbon receptor (AhR) is a ligand-binding protein that responds to environmental aromatic hydrocarbons and stimulates the transcription of downstream phase I enzyme-related genes by binding the cis element of dioxin-responsive elements (DREs)/xenobiotic-responsive elements. Dimethyl sulfoxide (DMSO) is a well-known organic solvent that is often used to dissolve phase I reagents in toxicology and oxidative stress research experiments. In the current study, we discovered that 0.1% DMSO significantly induced the activation of the AhR promoter via DREs and produced reactive oxygen species, which induced apoptosis in mouse embryonic fibroblasts (MEFs). Moreover, Jun dimerization protein 2 (Jdp2) was found to be required for activation of the AhR promoter in response to DMSO. Coimmunoprecipitation and chromatin immunoprecipitation studies demonstrated that the phase I-dependent transcription factors, AhR and the AhR nuclear translocator, and phase II-dependent transcription factors such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) integrated into DRE sites together with Jdp2 to form an activation complex to increase AhR promoter activity in response to DMSO in MEFs. Our findings provide evidence for the functional role of Jdp2 in controlling the AhR gene via Nrf2 and provide insights into how Jdp2 contributes to the regulation of ROS production and the cell spreading and apoptosis produced by the ligand DMSO in MEFs.

Translational models of 3-D organoids and cancer stem cells in gastric cancer research.

It is postulated as a general concept of cancer stem cells (CSCs) that they can produce cancer cells overtly and repopulate cancer progenitor cells indefinitely. The CSC niche is part of a specialized cancer microenvironment that is important to keep the phenotypes of CSCs. Stem cell- and induced pluripotent stem cell (iPSC)-derived organoids with genetic manipulation are beneficial to the investigation of the regulation of the microenvironment of CSCs. It would be useful to assess the efficiency of the cancer microenvironment on initiation and progression of cancers. To identify CSCs in cancer tissues, normal cell organoids and gastric cancer organoids from the cancerous areas, as well as iPSCs, were established several years ago. However, many questions remain about the extent to which these cultures recapitulate the development of the gastrointestinal tract and the mechanism of Helicobacter pylori-induced cancer progression. To clarify the fidelity of human organoid models, we have noted several key issues for the cultivation of, and differences between, normal and cancerous organoids. We developed precise culture conditions for gastric organoids in vitro to improve the accuracy of the generation of organoid models for therapeutic and medical applications. In addition, the current knowledge on gastrointestinal CSC research, including the topic of CSC markers, cancer cell reprogramming, and application to target cancer cell plasticity through niches, should be reinforced. We discuss the progression of cancers derived from human gastric organoids and the identification of CSCs.

Template activating factor-I epigenetically regulates the TERT transcription in human cancer cells.

Telomere, the terminus of linear chromosome in eukaryotes, is composed of specific repeat DNA which is mainly synthesized by a protein complex called telomerase. The maintenance of telomere DNA is important for unlimited proliferative capacity of cancer cells. The telomerase activity is controlled by the expression level of telomerase reverse transcriptase (TERT), a catalytic unit of telomerase, in some species including human. Therefore, to reveal the regulatory mechanisms of the transcription of TERT gene is important for understanding the tumor development. We found that template activating factor-I (TAF-I), a multifunctional nuclear protein, is involved in the transcriptional activation of TERT for the maintenance of telomere DNA in HeLa cells. TAF-I maintains the histone H3 modifications involved in transcriptional activation and hypomethylated cytosines in CpG dinucleotides around the transcription start site (TSS) in the TERT gene locus. Collectively, TAF-I is involved in the maintenance of telomere DNA through the regulation of TERT transcription, then consequently the occurrence and/or recurrence of cancer cells.

Therapeutic Strategies Targeting Tumor Suppressor Genes in Pancreatic Cancer.

The high mortality of pancreatic cancer is attributed to the insidious progression of this disease, which results in a delayed diagnosis and advanced disease stage at diagnosis. More than 35% of patients with pancreatic cancer are in stage III, whereas 50% are in stage IV at diagnosis. Thus, understanding the aggressive features of pancreatic cancer will contribute to the resolution of problems, such as its early recurrence, metastasis, and resistance to chemotherapy and radiotherapy. Therefore, new therapeutic strategies targeting tumor suppressor gene products may help prevent the progression of pancreatic cancer. In this review, we discuss several recent clinical trials of pancreatic cancer and recent studies reporting safe and effective treatment modalities for patients with advanced pancreatic cancer.

Deletion of Jdp2 enhances Slc7a11 expression in Atoh-1 positive cerebellum granule cell progenitors in vivo.

BACKGROUND: The cerebellum is the sensitive region of the brain to developmental abnormalities related to the effects of oxidative stresses. Abnormal cerebellar lobe formation, found in Jun dimerization protein 2 (Jdp2)-knockout (KO) mice, is related to increased antioxidant formation and a reduction in apoptotic cell death in granule cell progenitors (GCPs). Here, we aim that Jdp2 plays a critical role of cerebellar development which is affected by the ROS regulation and redox control. OBJECTIVE: Jdp2-promoter-Cre transgenic mouse displayed a positive signal in the cerebellum, especially within granule cells. Jdp2-KO mice exhibited impaired development of the cerebellum compared with wild-type (WT) mice. The antioxidation controlled gene, such as cystine-glutamate transporter Slc7a11, might be critical to regulate the redox homeostasis and the development of the cerebellum. METHODS: We generated the Jdp2-promoter-Cre mice and Jdp2-KO mice to examine the levels of Slc7a11, ROS levels and the expressions of antioxidation related genes were examined in the mouse cerebellum using the immunohistochemistry. RESULTS: The cerebellum of Jdp2-KO mice displayed expression of the cystine-glutamate transporter Slc7a11, within the internal granule layer at postnatal day 6; in contrast, the WT cerebellum mainly displayed Sla7a11 expression in the external granule layer. Moreover, development of the cerebellar lobes in Jdp2-KO mice was altered compared with WT mice. Expression of Slc7a11, Nrf2, and p21Cip1 was higher in the cerebellum of Jdp2-KO mice than in WT mice. CONCLUSION: Jdp2 is a critical regulator of Slc7a11 transporter during the antioxidation response, which might control the growth, apoptosis, and differentiation of GCPs in the cerebellar lobes. These observations are consistent with our previous study in vitro.

o-Quinone methide with overcrowded olefin component as a dehydridation catalyst under aerobic photoirradiation conditions.

An o-quinone methide (o-QM) featuring an overcrowded olefinic framework is introduced, which exhibits dehydridation activity owing to its enhanced zwitterionic character, particularly through photoexcitation. The characteristics of this o-QM enable the operation of dehydridative catalysis in the oxidation of benzylic secondary alcohols under aerobic photoirradiation conditions. An experimental analysis and density functional theory calculations provide mechanistic insights; the ground-state zwitterionic intermediate abstracts a hydride and proton simultaneously, and the active oxygen species facilitate catalyst regeneration.

Author Correction: Jdp2-deficient granule cell progenitors in the cerebellum are resistant to ROS-mediated apoptosis through xCT/Slc7a11 activation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Jdp2-deficient granule cell progenitors in the cerebellum are resistant to ROS-mediated apoptosis through xCT/Slc7a11 activation.

The Jun dimerization protein 2 (Jdp2) is expressed predominantly in granule cell progenitors (GCPs) in the cerebellum, as was shown in Jdp2-promoter-Cre transgenic mice. Cerebellum of Jdp2-knockout (KO) mice contains lower number of Atoh-1 positive GCPs than WT. Primary cultures of GCPs from Jdp2-KO mice at postnatal day 5 were more resistant to apoptosis than GCPs from wild-type mice. In Jdp2-KO GCPs, the levels of both the glutamate‒cystine exchanger Sc7a11 and glutathione were increased; by contrast, the activity of reactive oxygen species (ROS) was decreased; these changes confer resistance to ROS-mediated apoptosis. In the absence of Jdp2, a complex of the cyclin-dependent kinase inhibitor 1 (p21Cip1) and Nrf2 bound to antioxidant response elements of the Slc7a11 promoter and provide redox control to block ROS-mediated apoptosis. These findings suggest that an interplay between Jdp2, Nrf2, and p21Cip1 regulates the GCP apoptosis, which is one of critical events for normal development of the cerebellum.

Involvement of CTCF in transcription regulation of EGR1 at early G1 phase as an architecture factor.

Early growth response 1 (EGR1) is a transcription factor and regulates cellular processes such as proliferation, differentiation, and apoptosis. The expression of EGR1 is rapidly induced in response to several stimuli, and it activates the expression of downstream target genes involved in signaling cascades. EGR1 gene is also known to be transcribed in early G1 phase. However, the regulation of EGR1 transcription in early G1 phase is not clarified well. Here we found that CCCTC-binding factor (CTCF), a chromatin binding protein, is required to transcribe EGR1 gene at the onset of early G1 phase. We found that CTCF mediated the formation of higher-order chromatin structures among CTCF binding sites located in the EGR1 locus. Disruption of the CTCF-dependent higher-order chromatin structure using nuclease-dead Cas9 (dCas9)-mediated interference reduced the EGR1 transcription in early G1 phase. Collectively, we propose that CTCF has functional roles for the temporal expression of EGR1 in early G1 phase through regulation of higher-order chromatin structure organization.

Chemical Approach to Biological Safety: Molecular-Level Control of an Integrated Zinc Finger Nuclease.

Application of artificial nucleases (ANs) in genome editing is still hindered by their cytotoxicity related to off-target cleavages. This problem can be targeted by regulation of the nuclease domain. Here, we provide an experimental survey of computationally designed integrated zinc finger nucleases, constructed by linking the inactivated catalytic centre and the allosteric activator sequence of the colicin E7 nuclease domain to the two opposite termini of a zinc finger array. DNA specificity and metal binding were confirmed by electrophoretic mobility shift assays, synchrotron radiation circular dichroism spectroscopy, and nano-electrospray ionisation mass spectrometry. In situ intramolecular activation of the nuclease domain was observed, resulting in specific cleavage of DNA with moderate activity. This study represents a new approach to AN design through integrated nucleases consisting of three (regulator, DNA-binding, and nuclease) units, rather than simple chimera. The optimisation of such ANs could lead to safe gene editing enzymes.

Assembly and remodeling of viral DNA and RNA replicons regulated by cellular molecular chaperones.

A variety of cellular reactions mediated by interactions among proteins and nucleic acids requires a series of proteins called molecular chaperones. The viral genome encodes relatively few kinds of viral proteins and, therefore, host-derived cellular factors are required for virus proliferation. Here we discuss those cellular proteins known as molecular chaperones, which are essential for the assembly of functional viral DNA/RNA replicons. The function of these molecular chaperones in the cellular context is also discussed.

Reprogramming Antagonizes the Oncogenicity of HOXA13-Long Noncoding RNA HOTTIP Axis in Gastric Cancer Cells.

Reprogramming of cancer cells into induced pluripotent stem cells (iPSCs) is a compelling idea for inhibiting oncogenesis, especially through modulation of homeobox proteins in this reprogramming process. We examined the role of various long noncoding RNAs (lncRNAs)-homeobox protein HOXA13 axis on the switching of the oncogenic function of bone morphogenetic protein 7 (BMP7), which is significantly lost in the gastric cancer cell derived iPS-like cells (iPSLCs). BMP7 promoter activation occurred through the corecruitment of HOXA13, mixed-lineage leukemia 1 lysine N-methyltransferase, WD repeat-containing protein 5, and lncRNA HoxA transcript at the distal tip (HOTTIP) to commit the epigenetic changes to the trimethylation of lysine 4 on histone H3 in cancer cells. By contrast, HOXA13 inhibited BMP7 expression in iPSLCs via the corecruitment of HOXA13, enhancer of zeste homolog 2, Jumonji and AT rich interactive domain 2, and lncRNA HoxA transcript antisense RNA (HOTAIR) to various cis-element of the BMP7 promoter. Knockdown experiments demonstrated that HOTTIP contributed positively, but HOTAIR regulated negatively to HOXA13-mediated BMP7 expression in cancer cells and iPSLCs, respectively. These findings indicate that the recruitment of HOXA13-HOTTIP and HOXA13-HOTAIR to different sites in the BMP7 promoter is crucial for the oncogenic fate of human gastric cells. Reprogramming with octamer-binding protein 4 and Jun dimerization protein 2 can inhibit tumorigenesis by switching off BMP7. Stem Cells 2017;35:2115-2128.

Histone H1 chaperone activity of TAF-I is regulated by its subtype-dependent intramolecular interaction.

Linker histone H1 is involved in the regulation of gene activity through the maintenance of higher-order chromatin structure. Previously, we have shown that template activating factor-I (TAF-I or protein SET) is involved in linker histone H1 dynamics as a histone H1 chaperone. In human and murine cells, two TAF-I subtypes exist, namely TAF-Iα and TAF-Iß. TAF-I has a highly acidic amino acid cluster in its C-terminal region and forms homo- or heterodimers through its dimerization domain. Both dimer formation and the C-terminal region of TAF-I are essential for the histone chaperone activity. TAF-Iα exhibits less histone chaperone activity compared with TAF-Iß even though TAF-Iα and ß differ only in their N-terminal regions. However, it is unclear how subtype-specific TAF-I activities are regulated. Here, we have shown that the N-terminal region of TAF-Iα autoinhibits its histone chaperone activity via intramolecular interaction with its C-terminal region. When the interaction between the N- and C-terminal regions of TAF-Iα is disrupted, TAF-Iα shows a histone chaperone activity similar to that of TAF-Iß. Taken together, these results provide mechanistic insights into the concept that fine tuning of TAF-I histone H1 chaperone activity relies on the subtype compositions of the TAF-I dimer.