Alternative splicing and allosteric regulation modulate the chromatin binding of UHRF1.

UHRF1 is an important epigenetic regulator associated with apoptosis and tumour development. It is a multidomain protein that integrates readout of different histone modification states and DNA methylation with enzymatic histone ubiquitylation activity. Emerging evidence indicates that the chromatin-binding and enzymatic modules of UHRF1 do not act in isolation but interplay in a coordinated and regulated manner.

Exploring the Specificity, Synergy, and Durability of Auditory and Visual Computer Gameplay Transfer Effects in Healthy Older Adults.

Objectives: To determine whether auditory and visual computer games yield transfer effects that (a) are modality-specific to verbal memory (auditory stimulus presentation) and visual-processing tests, (b) affect working memory and processing speed, (c) are synergistic for combined game-type play, and (d) are durable.

Method: A Pilot Study (N = 44) assessed visual transfer effects in a two-group pre-post design. The Main Study (N = 151) employed a 2 (visual games: yes, no) × 2 (auditory games: yes, no) × 3 (test session: pretest, post-test, follow-up) design, allowing different training groups to act as active controls for each other.

When alpha meets beta, mast cells get hyper.

The evolutionary conservation of the catalytically inactive α-tryptase gene has remained a mystery. In this issue of , Le et al. (2019.

Conformational dynamics of the TTD-PHD histone reader module of the UHRF1 epigenetic regulator reveals multiple histone-binding states, allosteric regulation, and druggability.

UHRF1 is a key mediator of inheritance of epigenetic DNA methylation patterns during cell division and is a putative target for cancer therapy. Recent studies indicate that interdomain interactions critically influence UHRF1's chromatin-binding properties, including allosteric regulation of its histone binding. Here, using an integrative approach that combines small angle X-ray scattering, NMR spectroscopy, and molecular dynamics simulations, we characterized the dynamics of the tandem tudor domain-plant homeodomain (TTD-PHD) histone reader module, including its 20-residue interdomain linker.

Accessibility of different histone H3-binding domains of UHRF1 is allosterically regulated by phosphatidylinositol 5-phosphate.

UHRF1 is a multidomain protein crucially linking histone H3 modification states and DNA methylation. While the interaction properties of its specific domains are well characterized, little is known about the regulation of these functionalities. We show that UHRF1 exists in distinct active states, binding either unmodified H3 or the H3 lysine 9 trimethylation (H3K9me3) modification.

Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation.

Histone post-translational modifications regulate chromatin structure and function largely through interactions with effector proteins that often contain multiple histone-binding domains. While significant progress has been made characterizing individual effector domains, the role of paired domains and how they function in a combinatorial fashion within chromatin are poorly defined. Here we show that the linked tandem Tudor and plant homeodomain (PHD) of UHRF1 (ubiquitin-like PHD and RING finger domain-containing protein 1) operates as a functional unit in cells, providing a defined combinatorial readout of a heterochromatin signature within a single histone H3 tail that is essential for UHRF1-directed epigenetic inheritance of DNA methylation.

Divalent metal- and high mobility group N protein-dependent nucleosome stability and conformation.

High mobility group N proteins (HMGNs) bind specifically to the nucleosome core and act as chromatin unfolding and activating factors. Using an all-Xenopus system, we found that HMGN1 and HMGN2 binding to nucleosomes results in distinct ion-dependent conformation and stability. HMGN2 association with nucleosome core particle or nucleosomal array in the presence of divalent metal triggers a reversible transition to a species with much reduced electrophoretic mobility, consistent with a less compact state of the nucleosome.

DNA stretching and extreme kinking in the nucleosome core.

DNA stretching in chromatin may facilitate its compaction and influence site recognition by nuclear factors. In vivo, stretching has been estimated to occur at the equivalent of one to two base-pairs (bp) per nucleosome. We have determined the crystal structure of a nucleosome core particle containing 145 bp of DNA (NCP145).