The field of osteoarthritis (OA) biology is rapidly evolving and brilliant progress has been made this year as well. Landmark studies of OA biology published in 2021 and early 2022 were selected ...through PubMed search by personal opinion. These papers were classified by their molecular mechanisms, and it was largely divided into the intracellular signaling mechanisms and the inter-compartment interaction in chondrocyte homeostasis and OA progression. The intracellular signaling mechanisms involving OA progression included (1) Piezo1/transient receptor potential channels of the vanilloid subtype (TRPV) 4-mediated calcium signaling, (2) mechanical load–F-box and WD repeat domain containing 7 (FBXW7) in chondrocyte senescence, (3) mechanical loading-primary cilia-hedgehog signaling, (4) low grade inflammation by toll-like receptor (TLR)-CD14-lipopolysaccharide-binding protein (LBP) complex and inhibitor of NF-κB kinase (IKK) β–nuclear factor kappa B (NF-κB) signaling, (5) selenium pathway and reactive oxygen species (ROS) production, (6) G protein–coupled receptor (GPCR) and cyclic adenosine monophosphate (cAMP) signaling, (7) peroxisome proliferator-activated receptor α (PPARα)–acyl-CoA thioesterase 12 (ACOT12)-mediated de novo lipogenesis and (8) hypoxia–disruptor of telomeric silencing 1-like (DOT1L)–H3-lysine 79 (H3K79) methylation pathway. The studies on inter-compartment or intercellular interaction in OA progression included the following subjects; (1) the anabolic role of lubricin, glycoprotein from superficial zone cells, (2) osteoclast–chondrocyte interaction via exosomal miRNA and sphingosine 1-phosphate (S1P), (3) senescent fibroblast-like synoviocyte and chondrocyte interaction, (4) synovial macrophage and chondrocyte interaction through Flightless I, (5) αV integrin-mediated transforming growth factor beta (TGFβ) activation by mechanical loading, and (6) osteocytic TGFβ in subchondral bone thickening. Despite the disastrous Covid-19 pandemic, many outstanding studies have expanded the boundary of OA biology. They provide both critical insight into the pathophysiology as well as clues for the treatment of OA.
Elder Abuse in the COVID‐19 Era Han, S. Duke; Mosqueda, Laura
Journal of the American Geriatrics Society (JAGS),
July 2020, Letnik:
68, Številka:
7
Journal Article
We describe a Hi-C-based method, Micro-C, in which micrococcal nuclease is used instead of restriction enzymes to fragment chromatin, enabling nucleosome resolution chromosome folding maps. Analysis ...of Micro-C maps for budding yeast reveals abundant self-associating domains similar to those reported in other species, but not previously observed in yeast. These structures, far shorter than topologically associating domains in mammals, typically encompass one to five genes in yeast. Strong boundaries between self-associating domains occur at promoters of highly transcribed genes and regions of rapid histone turnover that are typically bound by the RSC chromatin-remodeling complex. Investigation of chromosome folding in mutants confirms roles for RSC, “gene looping” factor Ssu72, Mediator, H3K56 acetyltransferase Rtt109, and the N-terminal tail of H4 in folding of the yeast genome. This approach provides detailed structural maps of a eukaryotic genome, and our findings provide insights into the machinery underlying chromosome compaction.
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•Novel method for nucleosome-resolution analysis of chromosome folding•Self-associating domains in yeast are far shorter than those in mammals•Identification of several factors involved in chromosome folding•Evidence for a tri- or tetra-nucleosome motif in chromatin fibers
Mononucleosome resolution mapping of chromosome folding in yeast reveals self-associating domains similar to those found in other organisms. But they are far shorter, with domain size being scaled by gene number rather than linear distance.
Whereas folding of genomes at the large scale of epigenomic compartments and topologically associating domains (TADs) is now relatively well understood, how chromatin is folded at finer scales ...remains largely unexplored in mammals. Here, we overcome some limitations of conventional 3C-based methods by using high-resolution Micro-C to probe links between 3D genome organization and transcriptional regulation in mouse stem cells. Combinatorial binding of transcription factors, cofactors, and chromatin modifiers spatially segregates TAD regions into various finer-scale structures with distinct regulatory features including stripes, dots, and domains linking promoters-to-promoters (P-P) or enhancers-to-promoters (E-P) and bundle contacts between Polycomb regions. E-P stripes extending from the edge of domains predominantly link co-expressed loci, often in the absence of CTCF and cohesin occupancy. Acute inhibition of transcription disrupts these gene-related folding features without altering higher-order chromatin structures. Our study uncovers previously obscured finer-scale genome organization, establishing functional links between chromatin folding and gene regulation.
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•Micro-C resolves mammalian chromatin folding down to single nucleosomes•Nested structures are the prevalent folding feature within TADs•Transcription drives short-range interactions connecting enhancers and promoters•Only a subset of fine-scale structures appears to be CTCF- and cohesin-specific
Hsieh et al. describe chromatin folding at single-nucleosome resolution in mammalian cells using Micro-C, an enhanced chromosome conformation capture method. Micro-C uncovers genome-wide, fine-scale chromatin organizational features shaped by gene activity, transcriptional regulation, and gene silencing.
Over the past decade, 3C-related methods have provided remarkable insights into chromosome folding in vivo. To overcome the limited resolution of prior studies, we extend a recently developed Hi-C ...variant, Micro-C, to map chromosome architecture at nucleosome resolution in human ESCs and fibroblasts. Micro-C robustly captures known features of chromosome folding including compartment organization, topologically associating domains, and interactions between CTCF binding sites. In addition, Micro-C provides a detailed map of nucleosome positions and localizes contact domain boundaries with nucleosomal precision. Compared to Hi-C, Micro-C exhibits an order of magnitude greater dynamic range, allowing the identification of ∼20,000 additional loops in each cell type. Many newly identified peaks are localized along extrusion stripes and form transitive grids, consistent with their anchors being pause sites impeding cohesin-dependent loop extrusion. Our analyses comprise the highest-resolution maps of chromosome folding in human cells to date, providing a valuable resource for studies of chromosome organization.
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•Micro-C provides nucleosome resolution maps of chromosome folding•The resolution and signal-to-noise are significantly improved relative to Hi-C•Thousands of new loops are identified, suggesting weak pauses to loop extrusion•New loops suggest TADs represent heterogeneous collections of transient loops
Krietenstein et al. extend analyses of chromosome folding to nucleosome resolution in human cells. These ultra-deep Micro-C maps capture known features of chromosomes with improved signal-to-noise, identifying tens of thousands of new looping interactions. Newly identified loops reveal weak pause sites along cohesin extrusion tracks, providing insight into TAD structural heterogeneity.
Animal genomes are folded into loops and topologically associating domains (TADs) by CTCF and loop-extruding cohesins, but the live dynamics of loop formation and stability remain unknown. Here, we ...directly visualized chromatin looping at the
TAD in mouse embryonic stem cells using super-resolution live-cell imaging and quantified looping dynamics by Bayesian inference. Unexpectedly, the
loop was both rare and dynamic, with a looped fraction of approximately 3 to 6.5% and a median loop lifetime of approximately 10 to 30 minutes. Our results establish that the
TAD is highly dynamic, and about 92% of the time, cohesin-extruded loops exist within the TAD without bridging both CTCF boundaries. This suggests that single CTCF boundaries, rather than the fully CTCF-CTCF looped state, may be the primary regulators of functional interactions.
It remains unclear why acute depletion of CTCF (CCCTC-binding factor) and cohesin only marginally affects expression of most genes despite substantially perturbing three-dimensional (3D) genome ...folding at the level of domains and structural loops. To address this conundrum, we used high-resolution Micro-C and nascent transcript profiling in mouse embryonic stem cells. We find that enhancer-promoter (E-P) interactions are largely insensitive to acute (3-h) depletion of CTCF, cohesin or WAPL. YY1 has been proposed as a structural regulator of E-P loops, but acute YY1 depletion also had minimal effects on E-P loops, transcription and 3D genome folding. Strikingly, live-cell, single-molecule imaging revealed that cohesin depletion reduced transcription factor (TF) binding to chromatin. Thus, although CTCF, cohesin, WAPL or YY1 is not required for the short-term maintenance of most E-P interactions and gene expression, our results suggest that cohesin may facilitate TFs to search for and bind their targets more efficiently.
Merons which are topologically equivalent to one-half of skyrmions can exist only in pairs or groups in two-dimensional (2D) ferromagnetic (FM) systems. The recent discovery of meron lattice in ...chiral magnet Co
Zn
Mn
raises the immediate challenging question that whether a single meron pair, which is the most fundamental topological structure in any 2D meron systems, can be created and stabilized in a continuous FM film? Utilizing winding number conservation, we develop a new method to create and stabilize a single pair of merons in a continuous Py film by local vortex imprinting from a Co disk. By observing the created meron pair directly within a magnetic field, we determine its topological structure unambiguously and explore the topological effect in its creation and annihilation processes. Our work opens a pathway towards developing and controlling topological structures in general magnetic systems without the restriction of perpendicular anisotropy and Dzyaloshinskii-Moriya interaction.
Mammalian genomes are folded into topologically associating domains (TADs), consisting of chromatin loops anchored by CTCF and cohesin. Some loops are cell-type specific. Here we asked whether CTCF ...loops are established by a universal or locus-specific mechanism. Investigating the molecular determinants of CTCF clustering, we found that CTCF self-association in vitro is RNase sensitive and that an internal RNA-binding region (RBRi) mediates CTCF clustering and RNA interaction in vivo. Strikingly, deleting the RBRi impairs about half of all chromatin loops in mESCs and causes deregulation of gene expression. Disrupted loop formation correlates with diminished clustering and chromatin binding of RBRi mutant CTCF, which in turn results in a failure to halt cohesin-mediated extrusion. Thus, CTCF loops fall into at least two classes: RBRi-independent and RBRi-dependent loops. We speculate that evidence for RBRi-dependent loops may provide a molecular mechanism for establishing cell-specific CTCF loops, potentially regulated by RNA(s) or other RBRi-interacting partners.
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•An RNA-binding region (RBRi) in CTCF mediates self-association and clustering•Reorganization of TADs, loops, and stripes in ΔRBRi mutant cells•About half of all CTCF loops are disrupted in ΔRBRi mutant cells•CTCF loops fall into two classes: RBRi dependent and RBRi independent
CTCF is an architectural protein that mediates chromatin looping. Here, Hansen et al. demonstrate that an internal RNA-binding region (RBRi) in CTCF mediates CTCF clustering and that deletion of the RBRi causes disruption of about half of all chromatin loops in mouse embryonic stem cells.
Covalent histone modifications are highly conserved and play multiple roles in eukaryotic transcription regulation. Here, we mapped 26 histone modifications genome-wide in exponentially growing yeast ...and during a dramatic transcriptional reprogramming—the response to diamide stress. We extend prior studies showing that steady-state histone modification patterns reflect genomic processes, especially transcription, and display limited combinatorial complexity. Interestingly, during the stress response we document a modest increase in the combinatorial complexity of histone modification space, resulting from roughly 3% of all nucleosomes transiently populating rare histone modification states. Most of these rare histone states result from differences in the kinetics of histone modification that transiently uncouple highly correlated marks, with slow histone methylation changes often lagging behind the more rapid acetylation changes. Explicit analysis of modification dynamics uncovers ordered sequences of events in gene activation and repression. Together, our results provide a comprehensive view of chromatin dynamics during a massive transcriptional upheaval.
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•Comprehensive map of 26 histone marks during a transcriptional response in yeast•Stress does not alter global relationships between marks and transcription•Limited combinatorial complexity with transient modest increase during response•Ordered waves of histone modifications during transcriptional reprogramming
Weiner et al. carry out a thorough analysis of histone modification localization in budding yeast responding to stress. Histone modifications are highly correlated throughout the stress response, but a small number of nucleosomes enter unusual regions of 26-dimensional modification space during stress.
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