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Necroptosis, a form of programmed cell death, is characterized by the loss of membrane integrity and release of intracellular contents, the execution of which depends on the membrane-disrupting activity of the Mixed Lineage Kinase Domain-Like protein (MLKL) upon its phosphorylation. Here we found myofibers committed MLKL-dependent necroptosis after muscle injury. Either pharmacological inhibition of the necroptosis upstream kinase Receptor Interacting Protein Kinases 1 (RIPK1) or genetic ablation of MLKL expression in myofibers led to significant muscle regeneration defects. By releasing factors into the muscle stem cell (MuSC) microenvironment, necroptotic myofibers facilitated muscle regeneration. Tenascin-C (TNC), released by necroptotic myofibers, was found to be critical for MuSC proliferation. The temporary expression of TNC in myofibers is tightly controlled by necroptosis; the extracellular release of TNC depends on necroptotic membrane rupture. TNC directly activated EGF receptor (EGFR) signaling pathway in MuSCs through its N-terminus assembly domain together with the EGF-like domain. These findings indicate that necroptosis plays a key role in promoting MuSC proliferation to facilitate muscle regeneration.

In recent years, driven by emission reduction targets, an increasing number of manufacturers producing similar products have been compelled to seek emission reduction cooperation even while competing in the market, a phenomenon that has attracted growing attention in recent studies. Based on the carbon cap-and-trade mechanism, this study develops a noncooperative–cooperative biform game model to examine the optimal decisions of technologically complementary manufacturers engaging in emission reduction cooperation under price competition. The model describes alliance profits using a characteristic function and applies the Shapley value for profit allocation, while equilibrium outcomes are derived through noncooperative game analysis. The research results show that the high carbon emission reduction investment coefficient will inhibit the carbon abatement development level of manufacturers and reduce their profits. Without a carbon cap-and-trade mechanism, competitive manufacturers lack incentives for technological collaboration. An increase in carbon trading prices significantly promotes emission reductions and profit growth, whereas the effect of government-allocated initial carbon allowances remains limited. Moreover, the improvement of manufacturers’ technological conversion capability can improve the level of carbon abatement development and enhance their profitability under price competition. In general, this study provides theoretical and practical guidance for the cooperative emission reduction of competitive enterprises under the carbon emission rights trading mechanism.

Pluripotent stem cells hold great promise in regenerative medicine and developmental biology studies. Mitochondrial metabolites, including tricarboxylic acid (TCA) cycle intermediates, have been reported to play critical roles in pluripotency. Here we show that TCA cycle enzymes including Pdha1, Pcb, Aco2, Cs, Idh3a, Ogdh, Sdha and Mdh2 are translocated to the nucleus during somatic cell reprogramming, primed-to-naive transition and totipotency acquisition. The nuclear-localized TCA cycle enzymes Pdha1, Pcb, Aco2, Cs, Idh3a promote somatic cell reprogramming and primed-to-naive transition. In addition, nuclear-localized TCA cycle enzymes, particularly nuclear-targeted Pdha1, facilitate the 2-cell program in pluripotent stem cells. Mechanistically, nuclear Pdha1 increases the acetyl-CoA and metabolite pool in the nucleus, leading to chromatin remodeling at pluripotency genes by enhancing histone H3 acetylation. Our results reveal an important role of mitochondrial TCA cycle enzymes in the epigenetic regulation of pluripotency that constitutes a mitochondria-to-nucleus retrograde signaling mode in different states of pluripotent acquisition. Cellular metabolism is important in pluripotency and cell fate regulation. Here, authors observe chromatin remodeling followed by TCA enzyme translocation from the mitochondria to the nucleus, demonstrating pluripotency regulation by mitochondria to nucleus retrograde signaling.

Skeletal muscle stem cells (also called satellite cells, SCs) are important for maintaining muscle tissue homeostasis and damage-induced regeneration. However, it remains poorly understood how SCs enter cell cycle to become activated upon injury. Here we report that AP-1 family member ATF3 (Activating Transcription Factor 3) prevents SC premature activation. Atf3 is rapidly and transiently induced in SCs upon activation. Short-term deletion of Atf3 in SCs accelerates acute injury-induced regeneration, however, its long-term deletion exhausts the SC pool and thus impairs muscle regeneration. The Atf3 loss also provokes SC activation during voluntary exercise and enhances the activation during endurance exercise. Mechanistically, ATF3 directly activates the transcription of Histone 2B genes, whose reduction accelerates nucleosome displacement and gene transcription required for SC activation. Finally, the ATF3-dependent H2B expression also prevents genome instability and replicative senescence in SCs. Therefore, this study has revealed a previously unknown mechanism for preserving the SC population by actively suppressing precocious activation, in which ATF3 is a key regulator. Muscle regeneration relies on activation and expansion of skeletal muscle stem cells. Here, authors show that ATF3 induction prevents precocious activation of skeletal muscle stem cells by binding and promoting the transcription of Histone2B.

Epigenetic alterations occur in various cells and tissues during aging, but it is not known if such alterations are also associated with aging in skeletal muscle. Here, we examined the changes of a panel of histone modifications and found H3K27ac (an active enhancer mark) is markedly increased in aged human skeletal muscle tissues. Further analyses uncovered that the H3K27ac increase and enhancer activation are associated with the up‐regulation of extracellular matrix (ECM) genes; this may result in alteration of the niche environment for skeletal muscle stem cells, also called satellite cells (SCs), which causes decreased myogenic potential and fibrogenic conversion of SCs. In mice, treatment of aging muscles with JQ1, an inhibitor of enhancer activation, inhibited the ECM up‐regulation and fibrogenic conversion of SCs and restored their myogenic differentiation potential. Altogether, our findings not only uncovered a novel aspect of skeletal muscle aging that is associated with enhancer remodeling but also implicated JQ1 as a potential treatment approach for restoring SC function in aging muscle. H3K27ac is markedly increased in human or mouse muscle during aging, which leads to the enhancer activation and subsequent up‐regulation of ECM genes. It causes the alteration of SC niche and fibrogenic conversion of SCs. In mice, treatment of aging muscles with JQ1, an inhibitor of enhancer activation, reduced the fibrogenesis and improved the myogenic potential of SCs.

The crosstalk between translation and metabolism is fundamental for cellular plasticity. While most studies focus on translation within canonical coding regions, the roles of non-canonical open reading frames (ORFs) in metabolic regulation and early development remain unclear. Here, we show that selective translation of an upstream ORF in the 5′ untranslated region (UTR) of Lin28b produces an 85-amino acid microprotein, PLUM (pluripotency-associated Lin28b uORF-encoded microprotein). Depletion of PLUM leads to deterministic and synchronized (near 100%) induction of naïve pluripotency and causes embryo implantation defects in vivo. Mechanistically, PLUM depletion dissolves L1td1 condensates and enhances L1td1 binding to pluripotency mRNAs such as Tfcp2l1 and Zfp42 , stabilizing them and promoting coordinated gene activation. Concurrently, PLUM loss disrupts P-bodies enriched with a subset of nuclear-encoded mitochondrial mRNA, potentially preventing their degradation. Together, these alterations trigger an early burst of mitochondrial oxidative phosphorylation and synchronized naïve gene expression, accelerating acquisition of the naïve state. Our study identifies the novel uORF-encoded microprotein PLUM as a pluripotency determinant integrating RNA regulation and metabolic remodeling. The study identifies PLUM, a uORF-encoded microprotein from Lin28b, as a key regulator that drives deterministic induction of naïve pluripotency through coordinated RNA regulation and metabolic remodeling.

Traffic information is crucial for managing transportation and city planning, but obtaining national-scale data is difficult due to privacy concerns. Consequently, most current traffic datasets have limitations in terms of time and location coverage, leading to a lack of comprehensive public access to national traffic data. To address this issue, a multi-source highway traffic dataset has been created, featuring 2042 sensors in New Zealand over a 9-year period with 15-minute intervals and accompanying metadata. The dataset includes data of both light-duty and heavy-duty vehicles, as well as weather information like temperature and precipitation. This dataset has diverse potential research applications such as traffic flow prediction and congestion management.

The genome is organized in a delicate hierarchical 3D structure within the nuclear space and consists of distinct regulatory regions. Super enhancers (SEs) are clusters of distal regulatory elements that facilitate transcription through chromosome folding to instruct pivotal regulatory procedures underlying major biological processes. A particular process that undergoes dramatic changes in cell fate is the muscle satellite cell (SCs) development. SCs are normally remain quiescent and will be activated rapidly and undergo proliferation upon injury. While some activated SCs will differentiate to form new myofibers, a subset of SCs return to the quiescent state. Each state of the myogenic lineage progression is orchestrated by complex regulatory networks of intrinsic and extrinsic factors/mechanisms. However, how the 3D genome architecture rewiring affects the epigenetics during cell lineages process, especially SCs activation remains largely elusive. In this thesis, I focus on the dynamics of 3D genome architecture as well as the regulatory mechanism of SEs in multiple cell lines/stages, especially SCs lineage progression.Recently, characterization of chromosome organization has been the focus of many research groups. In the first part of the thesis, I focused on the 3D genome reorganization during SCs lineage development. The integrated analysis with multiple genome-wide NGS datasets identified 3D genome reorganization at different scales and related gene expression changes during SC lineage while the most dynamics changing is happened during early activation process at super enhancers. In-depth analysis of Pax7 revealed a novel regulatory circuitry surrounding the genomic locus. These results led to a better understanding of the relationship between 3D genome reorganization and SCs functionality and uncovered 3D genome rewiring during SCs early activation and pinpoint the distinct regulatory mechanism for Pax7 temporal expression.The enhancers play distinct regulatory roles due to different epigenetic states, transcription factors (TFs) binding and 3D genome folding state. In the second part of my thesis, I optimized a published method to define Enhancer-promoter interaction (EPI) in both human and mice. I predicted EPI in 72 mouse cell lines/stages and used machine-learning evaluation methods to dissect enhancer functions by integrating multiple NGS datasets. These analyses have not only revealed different super enhancer structures, but also the roles of distinct enhancers in SEs organization in multiple cell lines. By utilizing the mouse embryonic development procedure, I also found the timing of silencers activation may affect SEs formation, which enhanced our fundamental knowledge in the intrinsic formation mechanisms of SEs.Due to the insufficient investigation of stage-specific transcription factors (TFs), our understanding of the regulatory mechanism about pivotal TFs in quiescent and early activated SCs remains poorly understood. In the third part of the thesis, I identified a list of key TFs by constructing a regulatory network through SEs at the early activation stages of SCs. Using inhouse developed CRISPR/Cas9/AAV9 system to deplete genes in SCs in vivo, I validated several predicted key TFs and revealed their importance and distinct functions in the early activation stage of SCs. Investigation of Myc in the 3D genome organization of WT/KO from both quiescent satellite cells and freshly isolated satellite cells also revealed the chromatin changing at both compartment and TAD level after Myc depletion.In summary, my work has led to the understanding of the relationship between 3D genome architecture and cell fate transition during SCs lineage as well as formation and organization mechanism of SEs in both mouse and human.