Since their serendipitous discovery in nematodes, microRNAs (miRNAs) have emerged as key regulators of biological processes in animals. These small RNAs form complex networks that regulate cell ...differentiation, development and homeostasis. Deregulation of miRNA function is associated with an increasing number of human diseases, particularly cancer. Recent discoveries have expanded our understanding of the control of miRNA function. Here, we review the mechanisms that modulate miRNA activity, stability and cellular localization through alternative processing and maturation, sequence editing, post-translational modifications of Argonaute proteins, viral factors, transport from the cytoplasm and regulation of miRNA-target interactions. We conclude by discussing intriguing, unresolved research questions.
Neural development is accomplished by differentiation events leading to metabolic reprogramming. Glycosphingolipid metabolism is reprogrammed during neural development with a switch from globo‐ to ...ganglio‐series glycosphingolipid production. Failure to execute this glycosphingolipid switch leads to neurodevelopmental disorders in humans, indicating that glycosphingolipids are key players in this process. Nevertheless, both the molecular mechanisms that control the glycosphingolipid switch and its function in neurodevelopment are poorly understood. Here, we describe a self‐contained circuit that controls glycosphingolipid reprogramming and neural differentiation. We find that globo‐series glycosphingolipids repress the epigenetic regulator of neuronal gene expression AUTS2. AUTS2 in turn binds and activates the promoter of the first and rate‐limiting ganglioside‐producing enzyme GM3 synthase, thus fostering the synthesis of gangliosides. By this mechanism, the globo–AUTS2 axis controls glycosphingolipid reprogramming and neural gene expression during neural differentiation, which involves this circuit in neurodevelopment and its defects in neuropathology.
Synopsis
Schematic representation of glycosphingolipid reprogramming circuit in neural differentiation.
Globo‐series glycosphingolipids inhibit the production of ganglio‐series glycosphingolipids.
AUTS2 expression is repressed by globo‐series glycosphingolipids.
AUTS2 activates the promoter of the first and rate limiting enzyme involved in ganglio‐series glycosphingolipids production i.e., GM3 synthase by inducing histone acetylation.
The globo‐AUTS2 axis regulates the expression of neuronal genes during neural differentiation.
The decrease of globo‐series glycosphingolipids is required for AUTS2 induction and for stem cell differentiation to neural cells.
The switch from globo‐ to ganglio‐series glycophospholipids during neurodevelopment involves a self‐contained regulatory circuit controlling expression of both neuronal and ganglioside‐producing genes.
The strategies concerning modification of the complex immune pathological inflammatory environment during acute spinal cord injury remain oversimplified and superficial. Inspired by the acidic ...microenvironment at acute injury sites, a functional pH-responsive immunoregulation-assisted neural regeneration strategy was constructed. With the capability of directly responding to the acidic microenvironment at focal areas followed by triggered release of the IL-4 plasmid-loaded liposomes within a few hours to suppress the release of inflammatory cytokines and promote neural differentiation of mesenchymal stem cells in vitro, the microenvironment-responsive immunoregulatory electrospun fibers were implanted into acute spinal cord injury rats. Together with sustained release of nerve growth factor (NGF) achieved by microsol core-shell structure, the immunological fiber scaffolds were revealed to bring significantly shifted immune cells subtype to down-regulate the acute inflammation response, reduce scar tissue formation, promote angiogenesis as well as neural differentiation at the injury site, and enhance functional recovery in vivo. Overall, this strategy provided a delivery system through microenvironment-responsive immunological regulation effect so as to break through the current dilemma from the contradiction between immune response and nerve regeneration, providing an alternative for the treatment of acute spinal cord injury.
Type 1 regulatory T cells (Tr1 cells ) that produce interleukin 10 (IL-10) are instrumental in the prevention of tissue inflammation, autoimmunity and graft-versus-host disease. The transcription ...factor c-Maf is essential for the induction of IL-10 by Tr1 cells, but the molecular mechanisms that lead to the development of these cells remain unclear. Here we show that the ligand-activated transcription factor aryl hydrocarbon receptor (AhR), which was induced by IL-27, acted in synergy with c-Maf to promote the development of Tr1 cells. After T cell activation under Tr1-skewing conditions, the AhR bound to c-Maf and promoted transactivation of the Il10 and Il21 promoters, which resulted in the generation of Tr1 cells and the amelioration of experimental autoimmune encephalomyelitis. Manipulating AhR signaling could therefore be beneficial in the resolution of excessive inflammatory responses.
T follicular helper (TFH) cells play a crucial part in the development of humoral immunity by controlling the formation of, and the cellular reactions that occur in, germinal centres. Within these ...organized lymphoid tissue microstructures, B cells proliferate and somatically mutate to produce long-lived, high-affinity plasma cells and memory B cells. TFH cells exhibit unique molecular, cellular and tissue-dynamic features that are integral to their development and function but that are not necessarily compatible with the classical paradigm of effector CD4(+) T cell differentiation. Here, I discuss recent advances in TFH cell biology and their implications for our understanding of T cell differentiation and memory in humoral immunity from spatiotemporal and functional perspectives.
CD4(+) T helper (TH) cells regulate appropriate cellular and humoral immune responses to a wide range of pathogens and are central to the success of vaccines. However, their dysregulation can cause ...allergies and autoimmune diseases. The CD4(+) T cell population is characterized not only by a range of distinct cell subsets, such as TH1, TH2 and TH17 cells, regulatory T cells and T follicular helper cells--each with specific functions and gene expression programmes--but also by plasticity between the different TH cell subsets. In this Review, we discuss recent advances and emerging ideas about how microRNAs--small endogenously expressed oligonucleotides that modulate gene expression--are involved in the regulatory networks that determine TH cell fate decisions and that regulate their effector functions.
Among the many signalling lipids, endocannabinoids are increasingly recognized for their important roles in neuronal and glial development. Recent experimental evidence suggests that, during neuronal ...differentiation, endocannabinoid signalling undergoes a fundamental switch from the prenatal determination of cell fate to the homeostatic regulation of synaptic neurotransmission and bioenergetics in the mature nervous system. These studies also offer novel insights into neuropsychiatric disease mechanisms and contribute to the public debate about the benefits and the risks of cannabis use during pregnancy and in adolescence.
During chronic viral infection, CD8
T cells develop into three major phenotypically and functionally distinct subsets: Ly108
TCF-1
progenitors, Ly108
CX
CR1
terminally exhausted cells and the ...recently identified CX
CR1
cytotoxic effector cells. Nevertheless, how CX
CR1
effector cell differentiation is transcriptionally and epigenetically regulated remains elusive. Here, we identify distinct gene regulatory networks and epigenetic landscapes underpinning the formation of these subsets. Notably, our data demonstrate that CX
CR1
effector cells bear a striking similarity to short-lived effector cells during acute infection. Genetic deletion of Tbx21 significantly diminished formation of the CX
CR1
subset. Importantly, we further identify a previously unappreciated role for the transcription factor BATF in maintaining a permissive chromatin structure that allows the transition from TCF-1
progenitors to CX
CR1
effector cells. BATF directly bound to regulatory regions near Tbx21 and Klf2, modulating their enhancer accessibility to facilitate the transition. These mechanistic insights can potentially be harnessed to overcome T cell exhaustion during chronic infection and cancer.
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