Disordered Regions of Condensate-promoting Proteins Have Distinct Molecular Signatures Associated with Cellular Function.

Disordered regions of proteins play crucial roles in cellular functions through diverse mechanisms. Some disordered regions function by promoting the formation of biomolecular condensates through dynamic multivalent interactions. While many have assumed that interactions among these condensate-promoting disordered regions are non-specific, recent studies have shown that distinct sequence compositions and patterning lead to specific condensate compositions associated with cellular function.

Tryptophan metabolite atlas uncovers organ, age, and sex-specific variations.

Although tryptophan (Trp) is the largest and most structurally complex amino acid, it is the least abundant in the proteome. Its distinct indole ring and high carbon content enable it to generate various biologically active metabolites such as serotonin, kynurenine (Kyn), and indole-3-pyruvate (I3P). Dysregulation of Trp metabolism has been implicated in diseases ranging from depression to cancer.

Genetically Labeled Premyelinating Oligodendrocytes: Bridging Oligodendrogenesis and Neuronal Activity.

To myelinate axons, oligodendrocyte precursor cells (OPCs) must stop dividing and differentiate into premyelinating oligodendrocytes (preOLs). PreOLs are thought to survey and begin ensheathing nearby axons, and their maturation is often stalled at human demyelinating lesions. Lack of genetic tools to visualize and manipulate preOLs has left this critical differentiation stage woefully understudied.

Modulation of the JAK2-STAT3 pathway promotes expansion and maturation of human iPSCs-derived myogenic progenitor cells.

Generation of induced pluripotent cells (hiPSCs)-derived skeletal muscle progenitor cells (SMPCs) holds great promise for regenerative medicine for skeletal muscle wasting diseases, as for example Duchenne Muscular Dystrophy (DMD). Multiple approaches, involving ectopic expression of key regulatory myogenic genes or small molecules cocktails, have been described by different groups to obtain SMPC towards cell-transplantation as a therapeutic approach to skeletal muscle diseases. However, hiPSCs-derived SMPC generated using transgene-free protocols are usually obtained in a low amount and resemble a more embryonal/fetal stage of differentiation.

Yin Yang 1 and guanine quadruplexes protect dopaminergic neurons from cellular stress via transmissive dormancy.

Neurons deploy diverse adaptive strategies to ensure survival and neurotransmission amid cellular stress. When these adaptive pathways are overwhelmed, functional impairment or neurodegeneration follows. Here we show that stressed neurons actively induce a state of transmissive dormancy as a protective measure.

Specific tRNAs promote mRNA decay by recruiting the CCR4-NOT complex to translating ribosomes.

The CCR4-NOT complex is a major regulator of eukaryotic messenger RNA (mRNA) stability. Slow decoding during translation promotes association of CCR4-NOT with ribosomes, accelerating mRNA degradation. We applied selective ribosome profiling to further investigate the determinants of CCR4-NOT recruitment to ribosomes in mammalian cells.

Coordinated translational control of multiple immune checkpoints by the integrated stress response pathway in lung cancer.

Unlabelled: The integrated stress response (ISR) is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. ISR activation potently induces Programmed Death Ligand 1 (PD-L1), leading to suppression of anti-tumor immunity. Here we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape.

Transcription regulation by biomolecular condensates.

Biomolecular condensates regulate transcription by dynamically compartmentalizing the transcription machinery. Classic models of transcription regulation focus on the recruitment and regulation of RNA polymerase II by the formation of complexes at the 1-10 nm length scale, which are driven by structured and stoichiometric interactions. These complexes are further organized into condensates at the 100-1,000 nm length scale, which are driven by dynamic multivalent interactions often involving domain-ligand pairs or intrinsically disordered regions.

Protocol for muscle fiber type and cross-sectional area analysis in cryosections of whole lower mouse hindlimbs.

We outline a protocol to visualize all mouse lower hindlimb skeletal muscles simultaneously. We describe procedures for orientating the whole lower hindlimb in gum tragacanth prior to freezing, simplifying the proceeding experimental steps, and enhancing the comprehensiveness of characterizations. We then detail steps for quantifying muscle fiber size and fiber type characteristics in a single cryosection using histochemistry and immunofluorescence.

Spatiotemporal coordination of actin regulators generates invasive protrusions in cell-cell fusion.

Invasive membrane protrusions play a central role in a variety of cellular processes. Unlike filopodia, invasive protrusions are mechanically stiff and propelled by branched actin polymerization. However, how branched actin filaments are organized to create finger-like invasive protrusions is unclear.

TASOR expression in naive embryonic stem cells safeguards their developmental potential.

The seamless transition through stages of pluripotency relies on a balance between transcription factor networks and epigenetic mechanisms. Here, we reveal the crucial role of the transgene activation suppressor (TASOR), a component of the human silencing hub (HUSH) complex, in maintaining cell viability during the transition from naive to primed pluripotency. TASOR loss in naive pluripotent stem cells (PSCs) triggers replication stress, disrupts H3K9me3 heterochromatin, and impairs silencing of LINE-1 (L1) transposable elements, with more severe effects in primed PSCs.

Branched actin polymerization drives invasive protrusion formation to promote myoblast fusion during skeletal muscle regeneration.

Skeletal muscle regeneration is a multistep process involving the activation, proliferation, differentiation, and fusion of muscle stem cells, known as satellite cells. The fusion of satellite cell-derived mononucleated muscle cells (SCMs) is indispensable for the generation of multinucleated, contractile myofibers during muscle repair. However, the molecular and cellular mechanisms underlying SCM fusion during muscle regeneration remain poorly understood.

Transcription factor KROX20 marks epithelial stem cell ancestors for hair follicle formation.

Epidermal stem cells control homeostasis and regeneration of skin and hair. In the hair follicle (HF) bulge of mammals, populations of slow-cycling stem cells regenerate the HF during cyclical rounds of anagen (growth), catagen (regression), and telogen (quiescence). Multipotent epidermal cells are also present in the HF above the bulge area, contributing to the formation and maintenance of sebaceous gland and upper and middle portions of the HF.

The Citron homology domain of MAP4Ks improves outcomes of traumatic brain injury.

JOURNAL/nrgr/04.03/01300535-202511000-00027/figure1/v/2024-12-20T164640Z/r/image-tiff The mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) signaling pathway plays a pivotal role in axonal regrowth and neuronal degeneration following insults. Whether targeting this pathway is beneficial to brain injury remains unclear.

Simple and highly specific targeting of resident microglia with adeno-associated virus.

Microglia, as the immune cells of the central nervous system (CNS), play dynamic roles in both healthy and diseased conditions. The ability to genetically target microglia using viruses is crucial for understanding their functions and advancing microglia-based treatments. We here show that resident microglia can be simply and specifically targeted using adeno-associated virus (AAV) vectors containing a 466-bp DNA fragment from the human () promoter.

Gene editing in common cardiovascular diseases.

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide, highlighting the high socioeconomic impact. Current treatment strategies like compound-based drugs or surgeries are often limited. On the one hand, systemic administration of substances is frequently associated with adverse side effects; on the other hand, they typically provide only short-time effects requiring daily intake.

Disorder-mediated interactions target proteins to specific condensates.

Selective compartmentalization of cellular contents is fundamental to the regulation of biochemistry. Although membrane-bound organelles control composition by using a semi-permeable barrier, biomolecular condensates rely on interactions among constituents to determine composition. Condensates are formed by dynamic multivalent interactions, often involving intrinsically disordered regions (IDRs) of proteins, yet whether distinct compositions can arise from these dynamic interactions is not known.

Protocol for muscle fiber type and cross-sectional area analysis in cryosections of whole lower mouse hindlimbs.

We outline a robust, simple, and cost-effective method to simultaneously visualize all mouse lower hindlimb skeletal muscles. We describe procedures for orientating the whole lower hindlimb in gum tragacanth prior to freezing, simplifying the proceeding experimental steps, and enhancing the clarity and comprehensiveness of characterizations. We then detail steps for quantifying muscle fiber size and fiber type characteristics in a single cryosection using immunofluorescence and histochemistry.

Mapping cellular interactions from spatially resolved transcriptomics data.

Cell-cell communication (CCC) is essential to how life forms and functions. However, accurate, high-throughput mapping of how expression of all genes in one cell affects expression of all genes in another cell is made possible only recently through the introduction of spatially resolved transcriptomics (SRT) technologies, especially those that achieve single-cell resolution. Nevertheless, substantial challenges remain to analyze such highly complex data properly.

Identification of FDA-approved drugs that induce heart regeneration in mammals.

Targeting Meis1 and Hoxb13 transcriptional activity could be a viable therapeutic strategy for heart regeneration. In this study, we performd an in silico screening to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the resolved crystal structure of Meis1 and Hoxb13 bound to DNA. Paromomycin (Paro) and neomycin (Neo) induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay and disruption of DNA binding by electromobility shift assay.

A molecular pathway for cancer cachexia-induced muscle atrophy revealed at single-nucleus resolution.

Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single-nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle.

An ultraconserved snoRNA-like element in long noncoding RNA promotes ribosome biogenesis and cell proliferation.

Cancer cells frequently upregulate ribosome production to support tumorigenesis. While small nucleolar RNAs (snoRNAs) are critical for ribosome biogenesis, the roles of other classes of noncoding RNAs in this process remain largely unknown. Here we performed CRISPRi screens to identify essential long noncoding RNAs (lncRNAs) in renal cell carcinoma (RCC) cells.