Cold Spring Harbor perspectives in biology最新文献

Human telomeric heterochromatin is unusual in that it does not show the enrichment of canonical repressive histone marks H3K9me3 or H4K20me3 seen in constitutive heterochromatin. Instead, human telomeres exhibit both facultative heterochromatin and euchromatin marks, consistent with their epigenetically regulated transcription into TERRA noncoding RNA. Additionally, telomeric DNA is out of phase with the DNA helical repeat and has no nucleosome positioning signal. Yet, human telomeric DNA forms a columnar structure of tightly stacked nucleosomes, alternating with open states, and regulated by histone tails and shelterin protein binding. We discuss the proposed mechanisms regulating human telomeric chromatin and the consequences that telomeric chromatin properties have on various cellular processes, such as telomere transcription, the regulation of shelterin binding, and the activation of the alternative lengthening of telomeres mechanism. Together, we summarize current evidence on the combination of hetero- and euchromatic properties of human telomeres that may help explain their crucial protective functions and plasticity to regulate telomere maintenance pathways and damage signaling.

Telomeric repeats recruit the shelterin complex to prevent activation of the double-strand break response at chromosome ends. Thousands of TTAGGG repeats are present at each chromosome end to ensure telomere function. This abundance of G-rich repeats comes with the propensity to generate unusual DNA structures. The telomere loop (t-loop) structure, generated by strand invasion of the 3' overhang in the internal repeats, contributes to telomere function. G4-DNA is promoted by the stretches of G-rich repeats in a single-stranded form and may affect telomere replication and elongation by telomerase. The intramolecular homology can lead to the formation of internal loops (i-loops) via intramolecular recombination at sites of telomeric damage, which can promote the excision of telomeric repeats as extrachromosomal circular DNA. Shelterin promotes t-loops, counteracting the accumulation of pathological structures either directly or via the recruitment of specialized helicases. Here, we will discuss the current evidence for the formation of unusual DNA structures at telomeres and possible implications for telomere function.

Excitation-contraction coupling (ECC) in skeletal muscle is mediated by mechanical coupling between the L-type voltage-dependent Ca²⁺ channel (Ca_V1.1) in the transverse tubules and the Ca²⁺ release channel (RYR1) in the sarcoplasmic reticulum (SR). However, ECC complexes are much more complicated than just these two ion channels. Triadic Ca²⁺ release units (CRUs) that mediate ECC in skeletal muscle are allosterically regulated complexes of ion channels, cytoplasmic modulators, SR transmembrane proteins, and lumenal Ca²⁺ buffers. While RYR1, Ca_V1.1α_1s, and Ca_V1.1β_1a, the SH3 and cysteine-rich domain protein (STAC3) and junctophilin (JPH1 and/or JPH2) are required for voltage-gated Ca²⁺ release, other auxiliary proteins modulate this process. In this review, we discuss what is known about the proteins in the triadic protein complex, their roles in ECC, and the mutations in the ECC proteins that give rise to skeletal muscle myopathies.

Telomeric repeat-containing RNA (TERRA) molecules are transcripts comprising extended stretches of telomeric G-rich repeats, which are generated from telomeres or intrachromosomal loci. TERRA production is an evolutionarily conserved process observed across all eukaryotic kingdoms. While originally thought to localize and function only at telomeres, it is now clear that TERRA is involved in numerous cellular pathways beyond telomere maintenance, including gene expression regulation and signaling of dysfunctional telomeres to the cytoplasm and the extracellular environment. In this work, we will review key aspects of TERRA biogenesis, regulation, and functional relevance and propose models to reconcile the multiple and sometimes contradictory functions ascribed to TERRA. Based on TERRA interaction with proteins involved in disparate cellular processes, we also suggest that the full spectrum of TERRA-associated functions is still far from being completely unveiled. We anticipate that further study of this complex and fascinating RNA will reveal additional surprises in the future.

Telomeres, the long nucleotide repeats, and protein complex at chromosome ends, are central to genomic integrity. Telomere length (TL) varies widely between populations due to germline genetics, environmental exposures, and other factors. Very short telomeres caused by pathogenic germline variants in telomere maintenance genes cause the telomere biology disorders, a spectrum of life-threatening conditions including bone marrow failure, liver and lung disease, cancer, and other complications. Cancer predisposition with long telomeres is caused by rare pathogenic germline variants in components of the shelterin telomere protection protein complex and associated primarily with elevated risk of melanoma, thyroid cancer, sarcoma, and lymphoproliferative malignancies. In the middle, studies of the general population at risk of common illnesses, such as cardiovascular disease and cancer, have found statistically significant differences in TL but uncertain clinical applicability. This work reviews connections between telomere biology and human disease focusing on similarities and differences across the phenotypic spectrum.

Acquired demyelinating diseases of the central nervous system (CNS) comprise inflammatory conditions, including multiple sclerosis (MS) and related diseases, as well as noninflammatory conditions caused by toxic, metabolic, infectious, traumatic, and neurodegenerative insults. Here, we review the spectrum of diseases producing acquired CNS demyelination before focusing on the prototypical example of MS, exploring the pathologic mechanisms leading to myelin injury in relapsing and progressive MS and summarizing the mechanisms and modulators of remyelination. We highlight the complex interplay between the immune system, oligodendrocytes and oligodendrocyte progenitor cells (OPCs), and other CNS glia cells such as microglia and astrocytes in the pathogenesis and clinical course of MS. Finally, we review emerging therapeutic strategies that exploit our growing understanding of disease mechanisms to limit progression and promote remyelination.

What drives the emergence of new species has fascinated biologists since Darwin. Reproductive barriers to gene flow are a key step in the formation of species, and recent advances have shed new light on how these are established. Genetic, genomic, and comparative techniques, together with improved theoretical frameworks, are increasing our understanding of the underlying mechanisms. They are also helping us forecast speciation and reveal the impact of human activity.

Telomere maintenance is crucial for preventing the linear eukaryotic chromosome ends from being mistaken for DNA double-strand breaks, thereby avoiding chromosome fusions and the loss of genetic material. Unlike most eukaryotes that use telomerase for telomere maintenance, Drosophila relies on retrotransposable elements-specifically HeT-A, TAHRE, and TART (collectively referred to as HTT)-which are regulated and precisely targeted to chromosome ends. Drosophila telomere protection is mediated by a set of fast-evolving proteins, termed terminin, which bind to chromosome termini without sequence specificity, balancing DNA damage response factors to avoid erroneous repair mechanisms. This unique telomere capping mechanism highlights an alternative evolutionary strategy to compensate for telomerase loss. The modulation of recombination and transcription at Drosophila telomeres offers insights into the diverse mechanisms of telomere maintenance. Recent studies at the population level have begun to reveal the architecture of telomere arrays, the diversity among the HTT subfamilies, and their relative frequencies, aiming to understand whether and how these elements have evolved to reach an equilibrium with the host and to resolve genetic conflicts. Further studies may shed light on the complex relationships between telomere transcription, recombination, and maintenance, underscoring the adaptive plasticity of telomeric complexes across eukaryotes.

Organ morphogenesis is multifaceted, multiscale, and fundamentally a robust process. Despite the complex and dynamic nature of embryonic development, organs are built with reproducible size, shape, and function, allowing them to support organismal growth and life. This striking reproducibility of tissue form exists because morphogenesis is not entirely hardwired. Instead, it is an emergent product of mechanochemical information flow, operating across spatial and temporal scales-from local cellular deformations to organ-scale form and function, and back. In this review, we address the mechanical basis of organ morphogenesis, as understood by observations and experiments in living embryos. To this end, we discuss how mechanical information controls the emergence of a highly conserved set of structural motifs that shape organ architectures across the animal kingdom: folds and loops, tubes and lumens, buds, branches, and networks. Moving forward, we advocate for a holistic conceptual framework for the study of organ morphogenesis, which rests on an interdisciplinary toolkit and brings the embryo center stage.