Results and Problems in Cell Differentiation最新文献

The cytoskeleton is conserved throughout the eukaryotic lineage and consists of a complex dynamic network mainly composed of three distinct polymers: microtubules (MTs), actin filaments, and intermediate filaments. MTs are polymers of α/β-tubulin heterodimers, playing a myriad of distinct cellular functions and are the main components of complex structures like the mitotic spindle, cilia, and centrioles. Post-translational modifications (PTMs) regulate the function and increase the complexity of the α/β-tubulin heterodimer pools. One of the PTMs that has been extensively studied is the acetylation of lysine 40 (K40) on α-tubulin, which specifically occurs inside the MT lumen.Acetylation plays a crucial role in controlling the stability and function of MTs, in response to signals from within and outside the cell. It impacts the cytoplasm's 3D arrangement and important cellular activities like intracellular transport, cell division, polarity, and migration. Recent research has also emphasized the significance of this PTM in regulating the mechanical properties of MTs and cellular sensing. The levels and activity of MT acetyltransferases and deacetylases are tightly regulated through various transcriptional, post-transcriptional, and post-translational mechanisms, including miRNAs, phosphorylation, protein-protein interactions, and regulated localization between the nucleus and cytoplasm. These regulatory processes involve components of diverse signaling pathways, and their deregulation has been implicated in numerous diseases, including neurological disorders, cancer, and cardiac conditions.

This chapter highlights the hallmarks of cardiac aging, distinguishing characteristics between cardiac aging and cardiac senescence. An overview of the molecular mechanisms underlying cardiac aging, with a particular focus on the role of reversible protein acetylation, emphasizes the role of sirtuins in regulating heart function and structure. The chapter explores how alterations in energy metabolism contribute to heart dysfunction, with a focus on the impact of mitochondrial dysfunction and phenomena of protein acetylation, along with the role of acetylase and deacetylase in an aging heart. Additionally, the chapter discusses the regulation of cardiomyocyte proliferation and the potential for enhancing cardiac regeneration. Finally, therapeutic strategies, including caloric restriction and HDAC inhibitors, microRNAs, stem cells, and other pharmacological agents are examined as potential approaches to slow or reverse the effects of cardiac aging.

Histone deacetylase inhibitors (HDACi) have gained attention for their potential therapeutic effects in various immune-related diseases and solid organ transplantation. This review focuses on the role of HDACs' expression in immune responses, especially of T and B cells, in organ transplant rejection. We examined the expression levels of HDACs in T and B cells across different immune states, providing insight into their regulatory functions during immune activation and tolerance. Through an analysis of in vitro, in vivo, and preclinical studies, we explored the effects of HDACi on immune modulation, highlighting their impact on T- and B-cell function in diseases other than cancer. Finally, we discussed the outcomes of HDACi treatment in various organ transplantation models, assessing their potential to mitigate rejection, promote tolerance, and improve graft survival. The review synthesizes current evidence, identifies knowledge gaps, and offers a comprehensive outlook on HDACi for clinical applications in organ transplantation.

Over the last three decades, we have witnessed great progress in uncovering the scope of reversible acetylation of non-histone proteins and understanding its mechanisms and functional consequences. In this review, we summarize the histone acetyltransferases (HATs)/deacetylases (HDACs) and their inhibitors, focusing on the role of reversible acetylation modification of non-histone proteins in tumor development while also exploring the application of HAT and HDAC inhibitors in cancer therapy.

Histone acetylation is an epigenetic modification responsible for changes in chromatin architecture, accessibility, and ultimately gene expression. At the onset of a new life, when the fully differentiated parental genomes fuse together to generate a new totipotent cell, the gametes' epigenetic program must be erased, and new ones are progressively installed. Together with other epigenetic modifications, histone acetylation participates in the early events of embryogenesis, undergoing dynamic changes that involve several amino acid residues on different histone proteins. By analyzing studies that followed these changes during the preimplantation development in different mammals, we identified critical windows of acetylation/deacetylation in relation to the oocyte-to-zygote transition, the activation of the embryonic genome, and the specification of cell lineages, all crucial events for early embryo development, the establishment of pluripotent embryonic tissue, and ultimately of a multicellular organism.Finally, this survey points out the possibility that while contributing to the necessary plasticity of the embryonic stem cells, the reversibility of histone acetylation/deacetylation patterns renders this mechanism prone to be hijacked by environmental conditions, such as maternal diet or pollutants, leading to the alterations of epigenetic marks that can be potentially transmitted to the daughter cells and up to adulthood.

Silent information regulator 1 (SIRT1), a conserved lysine deacetylase, is an important contributor to the function of macrophages, which are the scavengers of the innate immune system. Macrophages are part of the first line of defense against infection and key players in immunity due to their ability to survey tissue for infections or damage, release inflammatory cytokines, and clear pathogens. Macrophage function deteriorates with age and is a common indicator of immunosenescence. SIRT1 is known to influence multiple aspects of macrophage physiology, particularly proliferation, self-renewal, migration, the regulation of macrophage polarization, and the ability of macrophages to clear pathogens via phagocytosis and inflammasome signaling. Furthermore, mammalian SIRT1 and orthologous Sir2 in other organisms have well-defined roles in aging. Therefore, in this chapter, we discuss evidence that links SIRT1 to macrophage behavior and function, explore its role in inflammatory pathways linked to aging, and highlight key research questions in immunosenescence and the implications for epigenetic and non-epigenetic roles of SIRT1.

Bromodomain and PHD finger-containing protein 1 (BRPF1) is an essential epigenetic regulator and plays a key role in post-translational modification of histones. It is a chromatin reader that recognizes acetylated histones and interacts with the paralogous lysine acetyltransferases KAT6A and KAT6B to promote histone acetylation and related acylations, such as propionylation, at lysine 23 of histone H3, thereby influencing gene expression and regulating developmental programs. BRPF1 contributes to a variety of cellular processes such as cell cycle progression, cell proliferation, cell differentiation, and responses to cellular stresses, including DNA damage. Moreover, BRPF1 is implicated in hematopoiesis, embryonic development, skeletal development, neurodevelopment, neurogenesis, learning, and memory. BRPF1 gene knockout in mice leads to severe bone marrow failure, anemia, and eventual death in a few weeks after birth. This review provides a brief overview of BRPF1 and its contribution to the molecular structure and biological functions of KAT6A and KAT6B complexes. We will explore the emerging evidence linking BRPF1 dysfunction to human diseases, particularly cancer and abnormal neurodevelopment, to highlight promising therapeutic opportunities for treating associated pathology.

Lysine acetylation is a critical post-translational modification that regulates gene expression and cellular functions. The MYST family lysine acetyltransferases KAT6A (also known as MOZ and MYST3) and KAT6B (a.k.a. MORF and MYST4), in complex with the multivalent epigenetic regulator BRPF1, play key roles in hematopoietic and neural development. Dysregulation of these complexes is implicated in neurodevelopmental disorders, such as Genitopatellar and Say-Barber-Biesecker-Young-Simpson syndromes, as well as in various cancers, including leukemia and medulloblastoma. The evolutionary conservation of these complexes in Drosophila melanogaster and Caenorhabditis elegans underscores their fundamental biological significance. Understanding the structural and functional mechanisms of KAT6-BRPF1 complexes provides insight into their pathological roles and therapeutic potential.

Intercellular communication is indispensable across multicellular organisms, and any aberration in this process can give rise to significant anomalies in developmental and homeostatic processes. Thus, a comprehensive understanding of its mechanisms is imperative for addressing human health-related concerns. Recent advances have expanded our understanding of intercellular communication by elucidating additional signaling modalities alongside established mechanisms. Notably, cellular protrusion-mediated long-range communication, characterized by physical contact through thin and elongated cellular protrusions between cells involved in signal transmission and reception, has emerged as a significant intercellular signaling paradigm. This chapter delves into the exploration of a signaling cellular protrusion termed 'airinemes,' discovered in the zebrafish skin. It covers their identified signaling roles and the cellular and molecular mechanisms that underpin their functionality.

The retina transforms light into electrical signals, which are sent to the brain via the optic nerve to form our visual perception. This complex signal processing is performed by the retinal neuron and requires a significant amount of energy. Since neurons are unable to store energy, they must obtain glucose and oxygen from the bloodstream to produce energy to match metabolic needs. This process is called neurovascular coupling (NVC), and it is based on a precise mechanism that is not totally understood. The discovery of fine tubular processes termed tunnelling nanotubes (TNTs) set a new type of cell-to-cell communication. TNTs are extensions of the cellular membrane that allow the transfer of material between connected cells. Recently, they have been reported in the brain and retina of living mice, where they connect pericytes, which are vascular mural cells that regulate vessel diameter. Accordingly, these TNTs were termed interpericyte tunnelling nanotubes (IPTNTs), which showed a vital role in blood delivery and NVC. In this chapter, we review the involvement of TNTs in NVC and discuss their implications in retinal neurodegeneration.