Biology subjects

Imai, Y.

Publications and source records attributed to Imai, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Androgen receptor determines skeletal muscle sexual dimorphism

The molecular and functional bases of sexual dimorphism in skeletal muscle remain poorly understood. The androgen receptor (AR) is a major regulator of sex-biased gene expression in muscle, but its genomic targets and associated coregulators in vivo are incompletely defined. Using ChIL-seq and an AirID-AR knock-in mouse, we mapped AR-bound genes and AR-associated proteins in skeletal muscle and identified histone deacetylase-linked corepressors. We further identified myosin binding protein H (Mybph) as a female-biased AR-repressed gene conserved in mouse and human muscle. Mybph loss disrupted sarcomeric organization and selectively delayed postinjury force recovery in female mice. These findings define an in vivo AR regulatory network and identify AR-dependent Mybph repression as a potential mechanism contributing to skeletal muscle sexual dimorphism.

molecular biology↗

bioRxiv2026

Achiasmatic meiosis underlies propagation of clonal genome and B chromosomes in hexaploid Carassius gibelio females but not males

Sexual reproduction in eukaryotes relies on meiosis, recombination, and fertilization, yet hybridization can lead to transitions to asexuality. Asexual vertebrate hybrids require modified gametogenesis to produce unreduced gametes, but the underlying mechanisms remain poorly understood in various hybrid complexes. Here, we investigated the Carassius gibelio complex, which combines clonal genome propagation to the offspring along with the transmission of B chromosomes. We analyzed meiotic progression and gametogenesis in sexual tetraploid and asexual hexaploid lineages, focusing on sex-specific differences. Cytological analyses of synaptonemal complexes and diplotene chromosomes revealed that both sexes in hexaploid lineages undergo achiasmatic meiosis, characterized by the absence of homologous pairing, recombination, and chiasmata. Chromosomes persist as univalents throughout meiotic prophase. Despite this shared meiotic program, outcomes differ between sexes: females complete oogenesis and produce unreduced eggs, whereas males exhibit disrupted spermatogenesis and reduced fertility. Females bypass the reductional division, enabling clonal gamete formation, while males fail to segregate univalents properly. Furthermore, B chromosomes were detected in both mitosis and meiosis of hexaploid males and females, but not in sexual lineages. B chromosomes were consistently present and varied in number among individuals. B chromosomes varied in number and consistently formed univalents during meiosis, similar to other chromosomes. Significance statementMeiosis normally depends on chromosome pairing and recombination, yet asexual vertebrates can bypass these processes. We demonstrate that asexual hexaploid Carassius gibelio reproduces through achiasmatic meiosis, in which chromosomes fail to pair and recombine. While females successfully produce unreduced clonal eggs, males display reduced fertility, revealing striking sex-specific differences in the ability to overcome meiotic dysfunction. We further show that B chromosomes persist as meiotic univalents and are stably inherited.

genetics↗

bioRxiv2026

MEIOSIN retains an intrinsic STRA8-independent activity that drives meiotic entry across vertebrate evolution

Meiotic entry in vertebrates has been viewed as a transcriptional switch driven by the MEIOSIN-STRA8 axis, but whether this represents the ancestral regulatory logic of meiosis has remained unclear. Here we combine comparative genomics with genetic and single-cell analyses in zebrafish and mice to show that MEIOSIN retains an intrinsic STRA8-independent activity. We identify Meiosin orthologs in zebrafish and hagfish, vertebrate lineages that lack Stra8, and show that these proteins retain the HMG domain but have lost the bHLH domain required for the canonical MEIOSIN-STRA8 interaction. In zebrafish, meiosin is transiently induced at meiotic entry in both sexes, yet its loss selectively disrupts the female germ line, causing failure of oogenesis and female-to-male sex reversal. In mice, MEIOSIN lacking the bHLH domain still initiates key features of meiotic entry and partially activates meiotic target genes, although it fails to support full meiotic progression. Together, these findings identify HMG-containing MEIOSIN as a conserved core regulator of meiotic entry and position STRA8 as a later-acting module that enhances the efficiency and robustness of meiotic gene activation.

developmental biology↗

bioRxiv2025

Lamin B1 physically regulates neuronal migration by modulating nuclear deformability in the developing cortex

Neuronal migration is a vital process that positions billions of neurons to create a functional brain. To navigate the constrained microenvironments within the cortex, precise control over the nuclear mechanics in migrating neurons is indispensable. Here, we show that Lamin B1 (LB1) regulates neuronal migration by modulating nuclear deformability. Excess LB1 in neurons halted migration without altering laminar identity or overall gene expressions in vivo, while in vitro, it elevated nuclear stiffness and impaired neuronal motility in confined spaces. Moreover, mispositioned neurons resulted in electrophysiological defects in the brain. Computational modeling predicted a temporal relationship between nuclear deformation and enhanced migration velocity, which was validated experimentally through live imaging. Notably, cerebral organoid assays using iPS cells established from patients with LMNB1 duplication exhibited impaired neuronal migration in a human model. Collectively, these findings demonstrate that LB1 is a critical regulator of nuclear mechanics, ensuring the accurate spatiotemporal positioning of neurons.

neuroscience↗

bioRxiv2025

Ultra-parallel ribosome profiling platform with RNA-dependent RNA amplification

Translation regulation plays a pivotal role in the diversification of gene expression and the response to intra- and extracellular environmental cues. Ribosome profiling (or Ribo-Seq) serves as a sensitive, quantitative, comprehensive, and data-rich technique to survey ribosome traversal across the cellular transcriptome. However, due to the intricacy of library preparation, applications to low-input and a large number of samples have presented analytic challenges. Here, we developed the semi-automated platform of Ribo-Seq and Disome-Seq, which allowed us to assess the translation status from a vast collection of samples with reduced amounts in a plate format. Through an siRNA-mediated knockdown screen for ribosome-associated proteins, this technique identified factors that (i) mediate regulation via RNA elements such as the TOP motif, (ii) assist efficient ribosome recycling, (iii) support ribosome-associated quality control (RQC), (iv) enhance translation elongation across inhibitory G-quadruplex sequences, and (v) repress mitochondrial translation. The application to human-derived samples revealed that stop codon readthrough and mitochondrial translation deficiency are associated with severe symptoms in COVID-19. Our approach provides a versatile option to investigate the translatome in a highly parallel manner.

molecular biology↗

bioRxiv2025

ALPHA/BETA HYDROLASE DOMAIN CONTAINING 5 SUPPORTS GLUCOSE-STIMULATED-LIPOLYSIS AND INSULIN SECRETION IN PANCREATIC BETA CELLS

PNPLA2 (aka adipose triglyceride lipase) is the rate limiting enzyme of triglyceride (TG) catabolism at the surface of lipid droplets (LDs). Lipolysis by PNPLA2 increases with glucose in pancreatic beta cells and produces metabolites that support glucose-stimulated insulin secretion (GSIS). Upregulation of lipolysis by glucose is blunted in human islets affected by type 2 diabetes. Here, we aim to determine how glucose regulates lipolysis in beta cells. We found that glucose recruits alpha/beta hydrolase domain containing 5 (ABHD5), a co-activator of PNPLA2 to LDs where lipolysis occurs. ABHD5 recruitment to LDs was reduced by the addition of H-89 and the expression of a mutant ABHD5 that is resistant to phosphorylation by a cAMP dependent kinase (PKA) indicating partial dependence of recruitment on PKA. Importantly, ABHD5 was indispensable for glucose responsiveness of lipolysis in INS-1 832/13 (INS-1) cells. Downregulation of ABHD5 increased LDs and TG content in INS-1 cells and human islets indicating that ABHD5 is highly active in beta cells. Additionally, glucose-stimulated insulin secretion was impaired in ABHD5 downregulated INS-1 and human pseudoislets, which agrees with impaired GSIS in ATGL downregulated beta cells. Thus, ABHD5 plays an important role in conferring glucose responsiveness of lipolysis and supporting insulin secretion in beta cells.

cell biology↗

bioRxiv2024

Cnot4 heterozygosity attenuates high fat diet-induced obesity in mice and impairs PPARγ-mediated adipocyte differentiation.

Adipocyte differentiation is crucial for formation and expansion of white adipose tissue and is also associated with the pathologies of obesity. CNOT4 is an E3 ubiquitin ligase and also contains RNA binding domain. In mammals CNOT4 has been suggested to interact with CCR4-NOT complex, a major executor of mRNA poly(A) shortening. While several subunits within the CCR4-NOT complex were shown to be involved in obesity and energy metabolism, the roles of CNOT4 in obesity remain unexplored. In this study, we generated and analyzed Cnot4 knockout mice and found that Cnot4 heterozygous (Cnot4 Het) mice exhibit resistance to high fat diet-induced obesity, including significant reduction in adipose tissue mass and hepatic lipid depots. However, Cnot4 Het did not affect mRNA expression of metabolic genes as well as serum lipid levels or glucose tolerance. Mechanistically, Cnot4 Het fibroblasts significantly reduced the capability of differentiation into adipocytes and down-regulated adipogenic gene expression compared to wild type fibroblasts. Heterozygous deletion of Cnot4 down-regulated the transcriptional activity of PPAR{gamma}, thereby suppressing up-regulation of adipocyte marker gene expression in response to rosiglitazone, a PPAR{gamma} agonist. These results suggest that CNOT4 mediates adipocyte differentiation during formation and growth of adipose tissue partly through positively regulating transcriptional activity of PPAR{gamma}.

biophysics↗

bioRxiv2024

Lipid droplet protein Perilipin 2 is critical for the regulation of insulin secretion through beta cell lipophagy and glucagon expression in pancreatic islets

Knockdown (KD) of lipid droplet (LD) protein perilipin 2 (PLIN2) in beta cells impairs glucose-stimulated insulin secretion (GSIS) and mitochondrial function. Here, we addressed a pathway responsible for compromised mitochondrial integrity in PLIN2 KD beta cells. In PLIN2 KD human islets, mitochondria were fragmented in beta cells but not in alpha cells. Glucagon but not insulin level was elevated. While the formation of early LDs followed by fluorescent fatty acids (FA) analog Bodipy C12 (C12) was preserved, C12 accumulated in mitochondria over time in PLIN2 KD INS-1 cells. A lysosomal acid lipase inhibitor Lali2 prevented C12 transfer to mitochondria, mitochondrial fragmentation, and the impairment of GSIS. Direct interactions between LD-lysosome and lysosome-mitochondria were increased in PLIN2 KD INS-1 cells. Thus, FA released from LDs by microlipophagy cause mitochondrial changes and impair GSIS in PLIN2 KD beta cells. Interestingly, glucolipotoxic condition (GLT) caused C12 accumulation and mitochondrial fragmentation similar to PLIN2 KD in beta cells. Moreover, Lali2 reversed mitochondrial fragmentation and improved GSIS in human islets under GLT. In summary, PLIN2 regulates microlipophagy to prevent excess FA flux to mitochondria in beta cells. This pathway also contributes to GSIS impairment when LD pool expands under nutrient load in beta cells.

molecular biology↗

bioRxiv2024

Acute Inhibition of Adipose Triglyceride Lipase by NG497 Dysregulates Insulin and Glucagon Secretion from Human Islets

Adipose triglyceride lipase (ATGL), which catalyzes the breakdown of triglycerides in lipid droplets (LDs), plays a critical role in releasing fatty acids to support insulin secretion in pancreatic beta cells. Based on genetic downregulation of ATGL in beta cells, multiple mechanisms are proposed that acutely or chronically regulate insulin secretion. Currently, the contribution of acute versus chronic mechanisms in the regulation of insulin secretion is unclear. Also, little is known whether ATGL affects alpha cell function. Using the human-specific ATGL inhibitor, NG497, this study investigates the impact of acute inhibition of ATGL on hormone secretion from human islets. When lipolysis by ATGL was assessed via morphological differences in LDs in confocal images of beta and alpha cells, beta cells exposed to NG497 showed notable increases in LD size and number under glucose-sufficient culture. The effect of NG497 on LD accumulation in alpha cells was more prominent under fasting-simulated conditions than glucose-sufficient conditions, pointing toward a critical role for ATGL lipolysis under conditions that stimulate hormone secretion in beta and alpha cells. When exposed to NG497 acutely, human islets reduced glucose-stimulated insulin secretion mildly, particularly first-phase insulin secretion, to an extent less pronounced than the impacts of chronic ATGL downregulation. Thus, chronic mechanisms play a predominant role in reducing insulin secretion when ATGL is downregulated. Acute exposure of human islets to NG497 significantly reduced glucagon secretion at low glucose concentration, highlighting an important potential role of ATGL lipolysis in promoting hormone secretion acutely from alpha cells.

cell biology↗

bioRxiv2024

Perilipin 5 Phosphorylation is Dispensable for Upregulation of Hepatic Lipid Metabolism Genes upon Fasting but Required for Insulin Receptor Substrate 2 Expression in Male Mice

ObjectivePerilipin 5 (PLIN5) is a lipid droplet protein highly expressed in cells that actively oxidize fatty acids. Previous in vitro studies have revealed that PLIN5 phosphorylation (p-PLIN5) at serine 155 by PKA is critical for transcriptional regulation of PPARa target genes by which PLIN5 adapt cells for fatty acid oxidation. We aim to determine the extent of p-PLIN5 in vivo and the consequence of impaired PLIN5 phosphorylation in the liver by using a whole-body knock-in of phosphorylation resistant PLIN5 (SA/SA) in mice. MethodsWe measured PLIN5 and p-PLIN5 with mass spectrometry and Phos-tag gels. We assessed serum chemistry in WT and SA/SA mice upon fasting. RNA sequencing and qPCR compared the gene expression in the liver of SA/SA and WT mice after overnight fast. ResultsPlin5 phosphorylation at S155 was increased in the liver LD fraction of fasted mice compared with that of fed mice by mass spectrometry (p<0.05). qPCR of key lipid metabolism genes did not differ between WT and SA/SA liver upon fasting. Male SA/SA mice had a higher fasting blood glucose (p<0.05) without a difference in body weight, serum insulin, or serum lipids. IRS2 was reduced in the liver of fasted male SA/SA mice (p<0.05). ConclusionPLIN5 S155 phosphorylation is dispensable for the upregulation of lipid metabolism genes important for fasting response in vivo. Impaired phosphorylation also had little effect on serum lipids or liver TG. However, SA/SA mice showed decreased IRS2 expression in the liver, which may contribute to glucose intolerance in SA/SA male mice.

molecular biology↗

bioRxiv2024

Dnmt1 determines bone length by regulating energy metabolism of growth plate chondrocytes

Chondrocytes differentiated from mesenchymal stem cells play a role in determining skeletal patterns by ossification. However, the mechanism by which maintenance DNA methylation in chondrocytes regulates differentiation and skeletal formation is unclear. In the Musculoskeletal Knowledge Portal, Dnmt1 was significantly associated with "Height". Long bones in the limbs of Dnmt1-deficient (Dnmt1{Delta}Prx1) mice are significantly shortened due to decreased chondrocyte proliferation and accelerated differentiation. Integrated analysis of RNA-Seq and MBD-Seq revealed that in Dnmt1{Delta}Prx1 chondrocytes reduced DNA methylation resulted in increased expression of genes related to energy metabolism and to ossification. Metabolomic analyses confirmed that levels of nearly all energy metabolites were increased in Dnmt1{Delta}Prx1 chondrocytes. These results indicate that Dnmt1-mediated maintenance DNA methylation governs chondrocyte differentiation by regulating energy metabolism through both gene expression and modulation of metabolite supplies. Taken together, this study suggests that appropriate DNA methylation status in chondrocytes can orchestrate growth plate mineralization and subsequently determine bone length.

developmental biology↗

bioRxiv2024

Aromatase in adipose tissue exerts an osteoprotective function in male mice via phosphate regulation

Aromatase contributes to maintenance of bone mass because male patients with loss-of-function mutations of CYP19A1 exhibit bone loss. Treatment with aromatase inhibitor also causes bone loss in men and post-menopausal women, suggesting that part of the anabolic effect of testosterone in men is dependent on estradiol (E2) biosynthesized by aromatase in non-gonadal tissues. It remains unclear how locally biosynthesized E2 contributes to maintenance of bone mass. We examined the function of aromatase in local tissues rather than gonads using cell-type specific aromatase knockout (KO) mice. Because osteoblast-specific aromatase KO mice exhibited no bone phenotype, we focused on adipose tissue, known as a reservoir of steroid hormones and analyzed the bone phenotypes of adipose tissue-specific aromatase KO (Aro{Delta}aP2) mice. Sixteen-week-old male Aro{Delta}aP2 mice exhibited significantly lower bone mineral density in tibia and femur, especially in trabecular bone, than controls. Bone histomorphometry showed that Aro{Delta}aP2 mice exhibited an insufficient calcification bone phenotype with increased osteoid volume and width, and decreased osteoclast area and numbers. Moreover, serum phosphate, renal phosphate reabsorption and FGF23 were significantly lower in Aro{Delta}aP2, suggesting that the insufficient calcification phenotype in Aro{Delta}aP2 was not caused by excessive FGF23 activities. Finally, we analyzed NaPi2a and NaPi2c, phosphate transporters localized in the kidney, and found that protein levels in renal brush border membrane vesicles were lower in Aro{Delta}aP2. These results indicate that estrogens locally biosynthesized by aromatase in adipocytes can play a significant role in bone mass maintenance via regulation of phosphate reabsorption in the kidney by NaPi2. Impact StatementMale adipocyte-specific aromatase KO mice (Aro{Delta}aP2) exhibited bone loss and increased osteoid due to decreased serum phosphate and urinary phosphate reabsorption as a result of reduced NaPi2 proteins expression in the kidney.

physiology↗

bioRxiv2024

PRDM9 drives the location and rapid evolution of recombination hotspots in salmonids

In many eukaryotes, meiotic recombination occurs preferentially at discrete sites, called recombination hotspots. In various lineages, recombination hotspots are located in regions with promoter-like features and are evolutionarily stable. Conversely, in some mammals, hotspots are driven by PRDM9 that targets recombination away from promoters. Paradoxically, PRDM9 induces the self-destruction of its targets and this triggers an ultra-fast evolution of mammalian hotspots. PRDM9 is ancestral to all animals, suggesting a critical importance for the meiotic program, but has been lost in many lineages with surprisingly little effect on meiosis success. However, it is unclear whether the function of PRDM9 described in mammals is shared by other species. To investigate this, we analyzed the recombination landscape of several salmonids, the genome of which harbors one full-length PRDM9 and several truncated paralogs. We identified recombination initiation sites in Oncorhynchus mykiss by mapping meiotic DNA double-strand breaks (DSBs). We found that DNA DSBs clustered at hotspots positioned away from promoters, enriched for the H3K4me3 and H3K4me36 marks and the location of which depended on the genotype of full-length Prdm9. We observed a high level of polymorphism in the zinc finger domain of full-length Prdm9, but not of the truncated paralogs. Moreover, population-scaled recombination maps in O. mykiss, Oncorhynchus kisutch and Salmo salar revealed a rapid turnover of recombination hotspots caused by PRDM9 target motif erosion. Our results imply that PRDM9 function is conserved across vertebrates and that the peculiar evolutionary runaway caused by PRDM9 has been active for several hundred million years.

evolutionary biology↗

bioRxiv2023

The androgen receptor in mesenchymal progenitors regulates skeletal muscle mass via Igf1 expression in male mice.

Androgens exert their effects primarily by binding to the androgen receptor (AR), a ligand-dependent nuclear receptor. While androgens have anabolic effects on skeletal muscle, previous studies reported that AR functions in myofibers to regulate skeletal muscle quality, rather than skeletal muscle mass. Therefore, the anabolic effects of androgens are exerted via extra-myofiber cells or tissues. In this context, the cellular and molecular mechanisms of AR in mesenchymal progenitors, which play a crucial role in maintaining skeletal muscle homeostasis, remain largely unknown. In this study, we demonstrated expression of AR in mesenchymal progenitors and found that targeted AR ablation in mesenchymal progenitors reduced limb muscle mass in mature adult, but not young or aged, male mice, although fatty infiltration of muscle was not affected. The absence of AR in mesenchymal progenitors led to remarkable perineal muscle hypotrophy, regardless of age, due to abnormal regulation of transcripts associated with cell death and extracellular matrix organization. Additionally, we revealed that AR in mesenchymal progenitors regulates the expression of insulin-like growth factor 1 (Igf1), and that IGF1 administration prevents perineal muscles atrophy in a paracrine manner. These findings indicate that the anabolic effects of androgens regulate skeletal muscle mass via, at least in part, AR signaling in mesenchymal progenitors. Significance statementAndrogens are essential not only for the development of male sexual characteristics but also for a range of physiological functions, including the regulation of skeletal muscle growth and function. Understanding the functionality of the androgen receptor (AR) is essential for comprehending the mechanisms through which androgens exert their effects on skeletal muscles, as these effects are mediated through AR binding. We demonstrate that AR is expressed in mesenchymal progenitors, which play a vital role in muscle homeostasis, and regulates the expression of insulin-like growth factor 1 (Igf1)--a key player in skeletal muscle growth--to control muscle mass. Our study provides significant insights into potential therapeutic strategies for addressing muscle atrophy conditions like sarcopenia.

molecular biology↗

bioRxiv2023

A single-cell atlas of transcribed cis-regulatory elements in the human genome

Transcribed cis-regulatory elements (tCREs), such as promoters and enhancers, are fundamental to modulate gene expression and define cell identity. The detailed mapping of tCREs at single-cell resolution is essential for understanding the regulatory mechanisms that govern cellular functions. Prior tCRE catalogs, limited by bulk analysis, have often overlooked cellular heterogeneity. We have constructed a tCRE atlas using single-cell 5-RNA-seq, capturing over 340,000 single-cells from 23 human tissues and annotating more than 175,000 tCREs, substantially enhancing the scope and granularity of existing cis-regulatory element annotations in the human genome. This atlas unveils patterns of gene regulation, revealing connections between broadly expressed promoters and cell type-specific distal tCREs. Assessing trait heritability at single-cell resolution with a novel tCRE module-based approach, we uncovered the nuanced trait-gene regulatory relationships across a continuum of cell populations, offering insights beyond traditional gene-level and bulk-sample analyses. Our study bridges the gap between gene regulation and trait heritability, underscoring the potential of single-cell analysis to elucidate the genetic foundations of complex traits. These insights set the stage for future research to investigate the impact of genetic variations on diseases at the individual level, advancing the understanding of cellular and molecular basis of trait heritability.

genomics↗

bioRxiv2023

Position-dependent changes in phycobilisome abundance in multicellular cyanobacterial filaments revealed by Raman spectral analysis

The one-dimensional filamentous cyanobacterium, Anabaena sp. PCC 7120, shows a simple pattern consisting of two types of cells under the nitrogen-deprived conditions. We found that the microbial pigment composition in differentiated (heterocyst) and undifferentiated cells (vegetative cells) were distinguished by using a Raman microscope. The Raman bands of phycocyanin and allophycocyanin were higher in the vegetative cells than those in the heterocysts. However, these bands were statistically lower in a part of vegetative cells, which were located far from a nearby heterocyst. That is, the pigment composition in the individual cells was affected by a locational information in a filament.

microbiology↗

bioRxiv2021

Intensive Single Cell Analysis Reveals Immune Cell Diversity among Healthy Individuals

It is believed that immune responses are different between individuals and at different times. In addition, personal health histories and unique environmental conditions should collectively determine the present state of immune cells. However, the cellular and molecular system mechanisms underlying such heterogeneity remain largely elusive. In this study, we conducted a systematic time-lapse single-cell analysis, using 171 single-cell libraries and 30 mass cytometry datasets intensively for seven healthy individuals. We found substantial diversity in immune cell populations and their gene expression patterns between different individuals. These patterns showed daily fluctuations even within the same individual spending a usual life. Similar diversities were also observed for the T cell receptor and B cell receptor repertoires. Detailed immune cell profiles at healthy statuses should give an essential background information to understand their immune responses, when the individual is exposed to various environmental conditions. To demonstrate this idea, we conducted the similar analysis for the same individuals on the vaccination of Influenza and SARS-CoV-2, since the date and the dose of the antigens are well-defined in these cases. In fact, we found that the distinct responses to vaccines between individuals, althougth key responses are common. Single cell immune cell profile data should make fundamental data resource to understand variable immune responses, which are unique to each individual.

genomics↗

bioRxiv2021

Uhrf1 governs the proliferation and differentiation of muscle satellite cells

DNA methylation is an essential form of epigenetic regulation responsible for cellular identity. In muscle stem cells, termed satellite cells, DNA methylation patterns are tightly regulated during differentiation. However, it is unclear how these DNA methylation patterns are maintained. We demonstrate that a key epigenetic regulator, ubiquitin like with PHD and RING finger domains 1 (Uhrf1), is activated in proliferating myogenic cells but not expressed in quiescent or differentiated myogenic cells in mice. Ablation of Uhrf1 in mouse satellite cells impairs their proliferation and differentiation, leading to failed muscle regeneration. Loss of Uhrf1 in satellite cells alters transcriptional programs, leading to DNA hypomethylation with activation of Cdkn1a and Notch signaling. Although down-regulation of Cdkn1a rescued proliferation but not differentiation, inhibition of Notch signaling rescued impaired differentiation of Uhrf1-deficient satellite cells. These findings point to Uhrf1 as a regulator of self-renewal and differentiation of satellite cells via genome-wide DNA methylation patterning.

molecular biology↗