Autophagy is an intracellular degradation pathway that recycles subcellular components to maintain metabolic homeostasis. NAD is an essential metabolite that participates in energy metabolism and serves as a substrate for a series of NAD+-consuming enzymes (NADases), including PARPs and SIRTs. Declining levels of autophagic activity and NAD represent features of cellular ageing, and consequently enhancing either significantly extends health/lifespan in animals and normalises metabolic activity in cells. Mechanistically, it has been shown that NADases can directly regulate autophagy and mitochondrial quality control. Conversely, autophagy has been shown to preserve NAD levels by modulating cellular stress. In this review we highlight the mechanisms underlying this bidirectional relationship between NAD and autophagy, and the potential therapeutic targets it provides for combatting age-related disease and promoting longevity.

Spatial omics facilitate an in-depth understanding of cell states and cell interactions. Recent work by Zhang et al. simultaneously seizes spatial epigenetic priming, differentiation, and gene regulation at nearly single-cell resolution by developing an epigenome-transcriptome comapping technology. This work displays how epigenetic features influence cell dynamics and transcriptional phenotypes at spatial and genome-wide levels.

Most mitochondrial proteins are synthesized in the cytosol and transported into mitochondria by protein translocases. Yet, mitochondria contain their own genome and gene expression system, which generates proteins that are inserted in the inner membrane by the oxidase assembly (OXA) insertase. OXA contributes to targeting proteins from both genetic origins. Recent data provides insights into how OXA cooperates with the mitochondrial ribosome during synthesis of mitochondrial-encoded proteins. A picture of OXA emerges in which it coordinates insertion of OXPHOS core subunits and their assembly into protein complexes but also participates in the biogenesis of select imported proteins. These functions position the OXA as a multifunctional protein insertase that facilitates protein transport, assembly, and stability at the inner membrane.

Regulated cell death occurs in many forms, including apoptosis, pyroptosis, necroptosis, and NETosis. Most obviously, the purpose of these pathways is to kill the cell. However, many cells need to complete a set of effector programs before they die, which we define as a cellular 'bucket list'. These effector programs are specific to the cell type, and mode and circumstances of death. For example, intestinal epithelial cells need to complete the process of extrusion before they die. Cells use regulatory mechanisms to temporarily prolong their life, including endosomal sorting complex required for transport (ESCRT)- and acid sphingomyelinase (ASM)-driven membrane repair. These allow cells to complete their bucket lists before they die.

Self-inflicted DNA strand breaks are canonically linked with cell death pathways and the establishment of genetic diversity in immune and germline cells. Moreover, this form of DNA damage is an established source of genome instability in cancer development. However, recent studies indicate that nonlethal self-inflicted DNA strand breaks play an indispensable but underappreciated role in a variety of cell processes, including differentiation and cancer therapy responses. Mechanistically, these physiological DNA breaks originate from the activation of nucleases, which are best characterized for inducing DNA fragmentation in apoptotic cell death. In this review, we outline the emerging biology of one critical nuclease, caspase-activated DNase (CAD), and how directed activation or deployment of this enzyme can lead to divergent cell fate outcomes.

RNA-binding proteins (RBPs) are essential regulators involved in the fate determination of diverse RNA species; however, emerging evidence indicates that a subset of RBPs may physically interact with chromatin and function at the transcriptional level. Here, we highlight the recently discovered mechanisms of chromatin-interacting RBPs (ChRBPs) in the regulation of chromatin/transcriptional activities.

Despite advances in uncovering vulnerabilities, identifying biomarkers, and developing more efficient treatments, cancer remains a threat because of its ability to progress while acquiring resistance to therapy. The circadian rhythm governs most of the cellular functions implicated in cancer progression, and its exploitation therefore opens new promising directions in the fight against metastasis. In this review we summarize the role of the circadian rhythm in tumor development and progression, with emphasis on the circadian rhythm-regulated elements that control the generation of circulating tumor cells (CTCs) and metastasis. We then present data on chronotherapy and discuss how circadian rhythm investigations may open new paths to more effective anticancer treatments.

Intestinal epithelial cells form the largest barrier in the body, separating us from the outside world. Here, we review recent findings that highlight the role of autophagy in the cell-intrinsic response of the epithelial cells to the harsh intestinal environment and how they shape host physiology.

Cohesin folds the genome in dynamic chromatin loops and holds the sister chromatids together. NIPBLScc2 is currently considered the cohesin loader, a role that may need reevaluation. NIPBL activates the cohesin ATPase, which is required for topological entrapment of sister DNAs and to fuel DNA loop extrusion, but is not required for chromatin association. Mechanistic dissection of these processes suggests that both NIPBL and the cohesin STAG subunit bind DNA. NIPBL also regulates conformational switches of the complex. Interactions of NIPBL with chromatin factors, including remodelers, replication proteins, and the transcriptional machinery, affect cohesin loading and distribution. Here, we discuss recent research addressing how NIPBL modulates cohesin activities and how its mutation causes a developmental disorder, Cornelia de Lange Syndrome (CdLS).

A recent report by Heath et al. reveals that obesity could impair cancer immunogenicity and foster a type I interferon (IFN-I)-deprived tumor microenvironment through saturated fatty acid-mediated stimulator of interferon genes (STING) inhibition.

'Canonical' journal clubs, which rely on a presenter guiding a group through the figures of a scientific article, do not fully realize their training potential. We provide a blueprint and resources for effectively leveraging journal clubs to meet specific training objectives and to further equity, diversity, inclusion, and belonging goals.

Since their discovery, members of the gasdermin (GSDM) family of proteins have been firmly established as executors of pyroptosis, with the N-terminal fragment of most GSDMs capable of forming pores in the plasma membrane. More recent findings suggest that some GSDMs can drive additional cell death pathways, such as apoptosis and necroptosis, through mechanisms independent of plasma membrane perforation. There is also emerging evidence that by associating with cellular compartments such as mitochondria, peroxisomes, endosomes, and the nucleus, GSDMs regulate cell death-independent aspects of cellular homeostasis. Here, we review the diversity of GSDM function across several cell types and explore how various cellular stresses can promote relocalization - and thus refunctionalization - of GSDMs.

Only in recent years have we begun to appreciate the involvement of fibroblasts in intestinal development, tissue homeostasis, and disease. These insights followed the advent of single-cell transcriptomics that allowed researchers to explore the heterogeneity of intestinal fibroblasts in unprecedented detail. Since researchers often defined cell types and their associated function based on the biological process they studied, there are a plethora of partially overlapping markers for different intestinal fibroblast populations. This ambiguity complicates putting different research findings into context. Here, we provide a census on the function and identity of intestinal fibroblasts in mouse and human. We propose a simplified framework consisting of three colonic and four small intestinal fibroblast populations to aid navigating the diversity of intestinal fibroblasts.

Increase in lineage infidelity and/or imbalance is frequently observed around the earliest stage of breast tumor initiation. In response to disruption of homeostasis, differentiated cells can partially lose their identity and gain cellular plasticity, a process involving epigenome landscape remodeling. This increase of cellular plasticity may promote the malignant transformation of breast tumors and fuel their heterogeneity. Here, we review recent studies that have yield insights into important regulators of lineage integrity and mechanisms that trigger mammary epithelial lineage derail, and evaluate their impacts on breast tumor development.

Direct activation of transcription factors (TFs) in human pluripotent stem cells (hPSCs) allows more rapid and efficient conversion of cell fates compared with classical approaches. Here, we summarize recent TF screening studies and established forward programming methods for different cell types, and highlight their current limitations and future perspectives.

Previous studies have shown that mitochondria play core roles in not only cancer stem cell (CSC) metabolism but also the regulation of CSC stemness maintenance and differentiation, which are key regulators of cancer progression and therapeutic resistance. Therefore, an in-depth study of the regulatory mechanism of mitochondria in CSCs is expected to provide a new target for cancer therapy. This article mainly introduces the roles played by mitochondria and related mechanisms in CSC stemness maintenance, metabolic transformation, and chemoresistance. The discussion mainly focuses on the following aspects: mitochondrial morphological structure, subcellular localization, mitochondrial DNA, mitochondrial metabolism, and mitophagy. The manuscript also describes the recent clinical research progress on mitochondria-targeted drugs and discusses the basic principles of their targeted strategies. Indeed, an understanding of the application of mitochondria in the regulation of CSCs will promote the development of novel CSC-targeted strategies, thereby significantly improving the long-term survival rate of patients with cancer.

Ovo like zinc finger 2 (OVOL2) is an evolutionarily conserved regulator of epithelial lineage determination and differentiation during embryogenesis. OVOL2 binds to DNA using zinc-finger domains to suppress epithelial-mesenchymal transition (EMT), which is critical for tumor metastasis. However, recent studies have suggested some noncanonical roles of OVOL2 that do not rely on the DNA binding of zinc-finger domains or regulation of EMT. OVOL2 and EMT regulators have emerging roles in adipogenesis, thermogenesis, and lipid metabolism. Here, we review different roles of OVOL2 from embryo development to adult tissue homeostasis, and discuss how OVOL2 and other EMT regulators orchestrate a regulatory network to control energy homeostasis. Last, we propose potential applications of targeting OVOL2 to reduce human obesity.

Duplicating a genome of 3 billion nucleotides is challenged by a variety of obstacles that can cause replication stress and affect the integrity of the genome. Recent studies show that replication fork slowing and stalling is prevalent in early mammalian development, resulting in genome instability and aneuploidy, and constituting a barrier to development in human reproduction. Genome instability resulting from DNA replication stress is a barrier to the cloning of animals and to the reprogramming of differentiated cells to induced pluripotent stem cells, as well as a barrier to cell transformation. Remarkably, the regions most impacted by replication stress are shared in these different cellular contexts, affecting long genes and flanking intergenic areas. In this review we integrate our knowledge of DNA replication stress in mammalian embryos, in programming, and in reprogramming, and we discuss a potential role for fragile sites in sensing replication stress and restricting cell cycle progression in health and disease.

Emergent evidence has shown that abnormal buildup of stray self-nucleic acids is a pathological feature observed across many neurodegenerative conditions. Here, we discuss how these self-nucleic acids act as a driver of disease by triggering harmful inflammatory responses. Understanding these pathways and targeting them has the potential to prevent neuronal death at the early stages of disease.

R-loops, formed transiently during gene transcription, are tightly controlled to avoid conflict with ongoing processes. Marchena-Cruz et al. identified DExD/H box RNA helicase DDX47 using a new R-loop resolving screen and defined a unique role for this helicase in nucleolar R-loops and its interplay with senataxin (SETX) and DDX39B.

Ribosomal DNA (rDNA) is transcribed into RNA in the nucleolus and is often challenged by different stress conditions. However, the underlying mechanisms of nucleolar DNA damage response (DDR) pathways remain elusive. Here, we provide distinct perspectives on how nucleolar DDR checkpoint pathways are activated by different stresses or by liquid-liquid phase separation (LLPS).

The heterogeneity and multiple functions of enteric glia have recently been recognized. Guyer et al. have now confirmed the neurogenetic potential of enteric glial cells and have also found that some have an open chromatin configuration, suggesting that some glial cells are poised and ready to differentiate into neurons.

Mechanisms underlying the development of castration-resistant prostate cancer (CRPC) remain incompletely understood. A recent study by Steiner et al. shows that Ly6d+ prostate tumor cells survive androgen deprivation through an autocrine amphiregulin signaling pathway.

Nickel homeostasis in many bacteria is controlled by the nickel-sensor NikR. A recent study by Cao et al. found that Escherichia coli NikR undergoes phase separation and that this event enhances its function as a nickel-dependent transcriptional repressor. The results suggest that phase separation is functional for bacterial metal homeostasis.

With 3D genome mapping maturing over the past decade, studies exposed the differences between eukaryotic and prokaryotic genome organization. This raises the question of how the complex eukaryotic genome organization originated. Here, I explore potential pathways to answering this question, guided by our changing understanding of the origins of eukaryotes.

Due to the pleiotropic effect of transforming growth factor β (TGFβ) signaling inhibition, function-specific targeted inhibition of TGFβ signaling is required. In a recent study, Yang et al. found that Krüppel-like factor (KLF)-13 acts as a negative regulator of TGFβ. Thus, activating KLF13 in fibrotic tissues may protect them from fibrosis by decreasing TGFβ signaling.