H2A.Z is a highly conserved histone variant in all species. The chromatin deposition of H2A.Z is specifically catalyzed by the yeast chromatin remodeling complex SWR1 and its mammalian counterpart SRCAP. However, the mechanism by which H2A.Z is preferentially recognized by non-histone proteins remains elusive. Here we identified Anp32e, a novel higher eukaryote-specific histone chaperone for H2A.Z. Anp32e preferentially associates with H2A.Z-H2B dimers rather than H2A-H2B dimers in vitro and in vivo and dissociates non-nucleosomal aggregates formed by DNA and H2A-H2B. We determined the crystal structure of the Anp32e chaperone domain (186-232) in complex with the H2A.Z-H2B dimer. In this structure, the region containing Anp32e residues 214-224, which is absent in other Anp32 family proteins, specifically interacts with the extended H2A.Z αC helix, which exhibits an unexpected conformational change. Genome-wide profiling of Anp32e revealed a remarkable co-occupancy between Anp32e and H2A.Z. Cells overexpressing Anp32e displayed a strong global H2A.Z loss at the +1 nucleosomes, whereas cells depleted of Anp32e displayed a moderate global H2A.Z increase at the +1 nucleosomes. This suggests that Anp32e may help to resolve the non-nucleosomal H2A.Z aggregates and also facilitate the removal of H2A.Z at the +1 nucleosomes, and the latter may help RNA polymerase II to pass the first nucleosomal barrier.

Histone variant H2A.Z, a universal mark of dynamic nucleosomes flanking gene promoters and enhancers, is incorporated into chromatin by SRCAP (SWR1), an ATP-dependent, multicomponent chromatin-remodeling complex. The YL1 (Swc2) subunit of SRCAP (SWR1) plays an essential role in H2A.Z recognition, but how it achieves this has been unclear. Here, we report the crystal structure of the H2A.Z-binding domain of Drosophila melanogaster YL1 (dYL1-Z) in complex with an H2A.Z-H2B dimer at 1.9-Å resolution. The dYL1-Z domain adopts a new whip-like structure that wraps over H2A.Z-H2B, and preferential recognition is largely conferred by three residues in loop 2, the hyperacidic patch and the extended αC helix of H2A.Z. Importantly, this domain is essential for deposition of budding yeast H2A.Z in vivo and SRCAP (SWR1)-catalyzed histone H2A.Z replacement in vitro. Our studies distinguish YL1-Z from known H2A.Z chaperones and suggest a hierarchical mechanism based on increasing binding affinity facilitating H2A.Z transfer from SRCAP (SWR1) to the nucleosome.

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Background: This study explored the effects of multi-component exercise training on the physical and cognitive function of the elderly with mild cognitive impairment (MCI). Methods: A total of 90 older adults with MCI were chosen from screened volunteers and randomly assigned into 2 groups (n=45), and 84 completed the 6-month follow-up. Participants in the control group received general community health instruction, while the multi-component exercise training performed on the other group. The multi-component exercise training performed on these participants was designed to suit Chinese elderly based on advice from the nursing specialist and sports medicine specialist after the preliminary experiment. The Chinese version Mini-Physical Performance Test (CM-PPT), the Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment (MoCA) scores were examined by repeated measures analysis of variance to evaluate the physical and cognitive function of adults with MCI before and at 3 and 6 months after the intervention. The follow-up data collectors were blinded to group allocation. P<0.05 was considered statistically significant. Results: (I) The average score of CM-PPT was increased from 11.36±2.69 to 11.88±2.40 and 12.83±2.19 in 3 and 6 months respectively after intervention, while control group was decreased from 10.79±2.73 to 10.24±2.62 in 3 months and 9.21±2.09 in 6 months. CM-PPT scores with the main intervention effect and the interaction between intervention and time were both statistically significant (P<0.05), indicating that the physical function of participants with MCI were improved after intervention. (II) The average score of MoCA was increased from 21.52±2.05 to 23.48±1.47 (3 months) and 25.19±1.29 (6 months) after intervention, while control group was decreased from 21.14.79±1.97 to 20.21±1.88 and 19.45±2.00 in 3 and 6 months. The score of MMSE showed the same trend with the score of MoCA. The MoCA score with main intervention effect and the MMSE and MoCA scores with the effect of time, the MMSE and MoCA scores with the interaction between the intervention and time were all statistically significant (P<0.05), showing that the cognitive function of participants with MCI was improved by the intervention. Conclusions: Multi-component exercise training could significantly improve physical function and cognitive function of the elderly with MCI.

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The characteristics of the electronic transition energy of Coumarin 120 (C120) and its H-bonded complexes in various solvents have been examined by time-dependent density functional theory (TDDFT) in combination with a polarizable continuum solvent model (PCM). Molecular structures of C120 and its H-bonded complexes are optimized with the B3LYP method in PCM solution, and the dihedral angle H14-N13-C7-H15 is dependent on solvent polarity and the type of H-bond. A linear correlation of the absorption maximum of C120 with the solvent polarity function is revealed with the PCM model for all solvents except DMSO. The experimental absorption maximum of C120 in nine solvents is well described by a PCM-TDDFT scheme augmented with explicit inclusion of a few H-bonded solvent molecules, and quantitative agreement between our calculated results and experimental measurements is obtained with an average error of less than 2 nm. H-bonding at three different sites shifts the absorption wavelength of C120 either to the blue or to the red, that is, a significant role is played by solvent molecules in the first solvation shell in determining the electronic transition energy of C120. The dependence on the H-bonding site and solvent polarity is examined by using the Kamlet-Taft equation for solvatochromism.

The SWR complex edits the histone composition of nucleosomes at promoters to facilitate transcription by replacing the two nucleosomal H2A-H2B (A-B) dimers with H2A.Z-H2B (Z-B) dimers. Swc5, a subunit of SWR, binds to A-B dimers, but its role in the histone replacement reaction was unclear. In this study, we showed that Swc5 uses a tandem DEF/Y motif within an intrinsically disordered region to engage the A-B dimer. A 2.37-Å X-ray crystal structure of the histone binding domain of Swc5 in complex with an A-B dimer showed that consecutive acidic residues and flanking hydrophobic residues of Swc5 form a cap over the histones, excluding histone–DNA interaction. Mutations in Swc5 DEF/Y inhibited the nucleosome editing function of SWR in vitro. Swc5 DEF/Y interacts with histones in vivo, and the extent of this interaction is dependent on the remodeling ATPase of SWR, supporting a model in which Swc5 acts as a wedge to promote A-B dimer eviction. Given that DEF/Y motifs are found in other evolutionary unrelated chromatin regulators, this work provides the molecular basis for a general strategy used repeatedly during eukaryotic evolution to mobilize histones in various genomic functions.

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