Cellular and Molecular Life Sciences最新文献

{"title":"Downregulation of FcRn promotes ferroptosis in herpes simplex virus-1-induced lung injury.","authors":"Shaoju Qian, Danqiong Zhang, Ruixue Li, Xiaoming Sha, Shuao Lu, Lin Pan, Xianfeng Hui, Tiesuo Zhao, Xiangfeng Song, Lili Yu","doi":"10.1007/s00018-024-05555-y","DOIUrl":"10.1007/s00018-024-05555-y","url":null,"abstract":"<p><p>Herpes simplex virus type I (HSV-1) infection is associated with lung injury; however, no specific treatment is currently available. In this study, we found a significant negative correlation between FcRn levels and the severity of HSV-1-induced lung injury. HSV-1 infection increases the methylation of the FcRn promoter, which suppresses FcRn expression by upregulating DNMT3b expression. Analysis of the FcRn promoter revealed that the -1296- to -919-bp region is the key regulatory region, with the CG site at -967/-966 bp being the critical methylation site. The transcription factor JUN binds to this CG site to increase FcRn transcription; however, its activity was significantly inhibited by DNMT3b overexpression. Moreover, 5-Aza-2 effectively reduced HSV-1-induced lung injury and inhibited ferroptosis. Transcriptomic sequencing revealed that the ferroptosis pathway was highly activated in the lung tissues of FcRn-knockout mice via the p53/SLC7A11 pathway. Furthermore, in vivo and in vivo experiments showed that FcRn knockout aggravated lung epithelial cell inflammation by promoting ferroptosis; however, this effect was reversed by a ferroptosis inhibitor. Thus, HSV-1 infection suppressed FcRn expression through promoter methylation and promoted ferroptosis and lung injury. These findings reveal a novel molecular mechanism underlying viral lung injury and suggest potential therapeutic strategies for targeting FcRn.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"36"},"PeriodicalIF":6.2,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11704097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connexin 43 contributes to perioperative neurocognitive disorder by attenuating perineuronal net of hippocampus in aged mice.","authors":"Qian Zhang, Yuxin Zhang, Peilin Cong, Qianqian Wu, Hanxi Wan, Xinwei Huang, Xinyang Li, Zhouxiang Li, Jingxuan Li, Huanghui Wu, Li Tian, Lize Xiong","doi":"10.1007/s00018-024-05530-7","DOIUrl":"https://doi.org/10.1007/s00018-024-05530-7","url":null,"abstract":"<p><strong>Background: </strong>Perioperative neurocognitive disorder (PND) is a prevalent form of cognitive impairment in elderly patients following anesthesia and surgery. The underlying mechanisms of PND are closely related to perineuronal nets (PNNs). PNNs, which are complexes of extracellular matrix primarily surrounding neurons in the hippocampus, play a critical role in neurocognitive function. Connexin 43 (Cx43) contributes to cognitive function by modulating the components of PNNs. This study was designed to investigate the specific regulatory mechanisms of Cx43 on PNNs and its pivotal role in the development of PND.</p><p><strong>Methods: </strong>Eighteen-month-old wild-type and Gja1^fl/fl C57BL/6 mice were subjected to abdominal surgery under 1.4% isoflurane anesthesia. Cognitive functions, particularly learning and memory, were evaluated via the Y-maze test, Barnes maze (BM) and contextual fear conditioning test (CFT). The mRNA and protein expression levels of Cx43 were assessed by using quantitative reverse transcription polymerase chain reaction (qRT-PCR), fluorescent in situ hybridization (FISH), western blotting and flow cytometry. The quantity of PNNs was measured by Wisteria floribunda agglutinin (WFA) and Aggrecan staining.</p><p><strong>Results: </strong>Aged mice subjected to anesthesia and surgery exhibited deficits in hippocampus-dependent cognitive functions, which were accompanied by increased Cx43 mRNA and protein expression. Conditional knockout (cKO) of Cx43 in astrocytes alleviated cognitive deficits and promoted the number of PNNs and dendritic spines in the hippocampus by targeting Dmp1. Knockdown of Dmp1 attenuated the beneficial effects of Cx43 cKO on cognitive deficits induced by anesthesia and surgery.</p><p><strong>Conclusion: </strong>Our findings indicate that anesthesia and surgery induce an increase in Cx43 expression, which inhibits the formation of PNNs and dendritic spines in hippocampus by suppressing Dmp1 transcription, leading to cognitive deficits in aged mice. These results offer new mechanistic insights into the pathogenesis of PND and identify potential targets for therapeutic intervention.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"37"},"PeriodicalIF":6.2,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11703800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALG5 downregulation inhibits osteogenesis and promotes adipogenesis by regulating the N-glycosylation of SLC6A9 in osteoporosis.","authors":"Quanfeng Li, Wenjie Liu, Yunhui Zhang, Jiahao Jin, Pengfei Ji, Zihao Yuan, Yibin Zhang, Pei Feng, Yanfeng Wu, Huiyong Shen, Peng Wang","doi":"10.1007/s00018-024-05566-9","DOIUrl":"10.1007/s00018-024-05566-9","url":null,"abstract":"<p><p>Osteoporosis is characterized by decreased bone mass and accumulation of adipocytes in the bone marrow. The mechanism underlying the imbalance between osteoblastogenesis and adipogenesis in bone marrow mesenchymal stem cells (BMSCs) remains unclear. We found that ALG5 was significantly downregulated in BMSCs from osteoporotic specimens. ALG5 knockdown inhibited osteogenic differentiation and increased adipogenic differentiation of BMSCs. ALG5 deficiency diminished the N-glycosylation of SLC6A9, thereby altering its protein stability and disrupting SLC6A9-mediated glycine uptake in BMSCs. ALG5 overexpression by adeno-associated virus serotype 9 (rAAV9) alleviated bone loss in OVX mice. Taken together, our findings suggest a novel role for the ALG5-SLC6A9-glycine axis in the imbalance of BMSC differentiation in osteoporosis. Moreover, we identify ALG5 overexpression as a potential therapeutic strategy for treating osteoporosis.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"35"},"PeriodicalIF":6.2,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11703790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Establishment of nasal and olfactory epithelium organoids for unveiling mechanism of tissue regeneration and pathogenesis of nasal diseases.","authors":"Jinxia Liu, Yunfeng Zhang, Yiqun Yu","doi":"10.1007/s00018-024-05557-w","DOIUrl":"10.1007/s00018-024-05557-w","url":null,"abstract":"<p><p>Organoid is an ideal in vitro model with cellular heterogeneity and genetic stability when passaging. Currently, organoids are exploited as new tools in a variety of preclinical researches and applications for disease modeling, drug screening, host-microbial interactions, and regenerative therapy. Advances have been made in the establishment of nasal and olfactory epithelium organoids that are used to investigate the pathogenesis of smell-related diseases and cellular/molecular mechanism underlying the regeneration of olfactory epithelium. A set of critical genes are identified to function in cell proliferation and neuronal differentiation in olfactory epithelium organoids. Besides, nasal epithelium organoids derived from chronic rhinosinusitis patients have been established to reveal the pathogenesis of this disease, potentially applied in drug responses in individual patient. The present article reviews recent research progresses of nasal and olfactory epithelium organoids in fundamental and preclinical researches, and proposes current advances and potential future direction in the field of organoid research and application.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"33"},"PeriodicalIF":6.2,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microtubule acetylation and PERK activation facilitate eribulin-induced mitochondrial calcium accumulation and cell death.","authors":"Seongeun Song, Panseon Ko, Seula Keum, Jangho Jeong, Ye Eun Hwang, Minwoo Lee, Jee-Hye Choi, Youn-Sang Jung, Sung Hyun Kim, Sangmyung Rhee","doi":"10.1007/s00018-024-05565-w","DOIUrl":"10.1007/s00018-024-05565-w","url":null,"abstract":"<p><p>Over the past few decades, microtubules have been targeted by various anticancer drugs, including paclitaxel and eribulin. Despite their promising effects, the development of drug resistance remains a challenge. We aimed to define a novel cell death mechanism that targets microtubules using eribulin and to assess its potential in overcoming eribulin resistance. Notably, treating non-resistant breast cancer cells with eribulin led to increased microtubule acetylation around the nucleus and cell death. Conversely, eribulin-resistant (EriR) cells did not exhibit a similar increase in acetylation, even at half-maximal inhibitory concentrations. Interestingly, silencing the ATAT1 gene, which encodes the α-tubulin N-acetyltransferase 1 (the enzyme responsible for microtubule acetylation), induces eribulin resistance, mirroring the phenotype of EriR cells. Moreover, eribulin-induced acetylation of microtubules facilitates the transport of Ca²⁺ from the ER to the mitochondria, releasing cytochrome c and subsequent cell death. Transcriptome analysis of EriR cells revealed a significant downregulation of ER stress-induced apoptotic signals, particularly the activity of protein kinase RNA-like ER kinase (PERK), within the unfolded protein response signaling system. Pharmacological induction of microtubule acetylation through a histone deacetylase 6 inhibitor combined with the activation of PERK signaling using the PERK activator CCT020312 in EriR cells enhanced mitochondrial Ca²⁺ accumulation and subsequent cell death. These findings reveal a novel mechanism by which eribulin-induced microtubule acetylation and increased PERK activity lead to Ca²⁺ overload from the ER to the mitochondria, ultimately triggering cell death. This study offers new insights into strategies for overcoming resistance to microtubule-targeting agents.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"32"},"PeriodicalIF":6.2,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11688268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amiloride sensitizes prostate cancer cells to the reversible tyrosine kinase inhibitor lapatinib by modulating Erbb3 subcellular localization.","authors":"Maitreyee K Jathal, Maria Mudryj, Marc A Dall'Era, Paramita M Ghosh","doi":"10.1007/s00018-024-05540-5","DOIUrl":"10.1007/s00018-024-05540-5","url":null,"abstract":"<p><p>Neoadjuvant therapy (NAT) has been studied in clinically localized prostate cancer (PCa) to improve the outcomes from radical prostatectomy (RP) by 'debulking' of high-risk PCa; however, using androgen deprivation therapy (ADT) at this point risks castration resistant PCa (CRPC) clonal proliferation. Our goal is to identify alternative NAT that reduce hormone sensitive PCa (HSPC) without affecting androgen receptor (AR) transcriptional activity. PCa is associated with increased expression and activation of the epidermal growth factor receptor (EGFR) family, including HER2 and ErbB3. The FDA-approved HER2 inhibitor lapatinib has been tested in PCa but was ineffective due to continued activation of ErbB3. We now demonstrate that this is due to ErbB3 being localized to the nucleus in HSPC and thus protected from lapatinib which affect membrane localized HER2/ErbB3 dimers. Here, we show that the well-established, well-tolerated potassium-sparing diuretic amiloride hydrochloride dose dependently prevented ErbB3 nuclear localization via formation of plasma membrane localized HER2/ErbB3 dimers. This in turn allowed lapatinib inactivation of these dimers via inhibition of its target HER2, which dephosphorylated ERK1/2 and inhibited survival. Amiloride combined with lapatinib significantly increased apoptosis at relatively low doses of both drugs but did not affect AR transcriptional activity. Thus, our data indicate that a combination of amiloride and lapatinib could target HSPC tumors without problems associated with using ADT as NAT in HSPC.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"24"},"PeriodicalIF":6.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HFM1 is essential for the germ cell intercellular bridge transport in primordial follicle formation in mice.","authors":"Yuheng He, Huiyuan Wang, Tongtong Hong, Luanqian Hu, Chao Gao, Li Gao, Yugui Cui, Rongrong Tan, Danhua Pu, Jie Wu","doi":"10.1007/s00018-024-05541-4","DOIUrl":"10.1007/s00018-024-05541-4","url":null,"abstract":"<p><p>The reproductive lifespan of female mammals is determined by the size of the primordial follicle pool, which comprises oocytes enclosed by a layer of flattened pre-granulosa cells. Oocyte differentiation needs acquiring organelles and cytoplasm from sister germ cells in cysts, but the mechanisms regulating this process remain unknown. Previously helicase for meiosis 1 (HFM1) is reported to be related to the development of premature ovarian insufficiency. Here, it is found that HFM1 is involved in oocyte differentiation through organelle enrichment from sister germ cells. Further study indicates that HFM1 is involved in intercellular directional transport through intercellular bridges via the RAC1/ANLN/E-cad signaling pathway, which is indispensable for oocyte differentiation and primordial follicle formation. These findings shed light on the critical role of HFM1 in intercellular bridge transport, which is essential for the establishment of the primordial follicle pool and presenting new horizons for female fertility protection.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"28"},"PeriodicalIF":6.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The splicing machinery is dysregulated and represents a therapeutic vulnerability in breast cancer.","authors":"Natalia Hermán-Sánchez, Miguel E G-García, Juan M Jiménez-Vacas, Elena M Yubero-Serrano, Laura M López-Sánchez, Sara Romero-Martín, Jose L Raya-Povedano, Marina Álvarez-Benito, Justo P Castaño, Raúl M Luque, Manuel D Gahete","doi":"10.1007/s00018-024-05515-6","DOIUrl":"10.1007/s00018-024-05515-6","url":null,"abstract":"<p><p>Breast cancer (BCa) is a highly prevalent pathological condition (̴30% in women) with limited and subtype-dependent prognosis and therapeutic options. Therefore, BCa management might benefit from the identification of novel molecular elements with clinical potential. Since splicing process is gaining a great relevance in cancer, this work analysed the expression of multiple Spliceosome Components (SCs = 17) and Splicing Factors (SFs = 26) and found a drastic dysregulation in BCa (n = 69) vs. control (negative biopsies; n = 50) samples. Among all the components analysed, we highlight the upregulation of ESRP1 and down-regulation of PRPF8 and NOVA1 in BCa vs. control samples. Indeed, ESRP1 was specially overexpressed in triple-negative BCa (TNBCa) and associated with worse prognosis (i.e., higher BCa grade and lower overall survival), suggesting an association of ESRP1 with BCa aggressiveness. On the other hand, PRPF8 expression was generally downregulated in BCa with no associations to clinical characteristics, while NOVA1 expression was lower in TNBCa patients and highly aggressive tumours. Consistently, NOVA1 overexpression in vitro reduced functional parameters of aggressiveness in ER-/PR- cell lines (MDA-MB-231 and BT-549) but not in ER+/PR+ cells (MCF7), suggesting a critical role of NOVA1 in subtype-specific BCa. Finally, the in vitro pharmacological inhibition of splicing machinery using pladienolide B decreased aggressiveness features in all the BCa cell lines, showing a subtype-independent inhibitory potential, but being relatively innocuous in normal-like breast cells. These results demonstrate the profound dysregulation of the splicing machinery in BCa and their potential as source of promising diagnosis/prognosis markers, as well as valuable therapeutic targets for BCa.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"18"},"PeriodicalIF":6.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic modeling of degenerative diseases and mechanisms of neuronal regeneration in the zebrafish cerebellum.","authors":"Kazuhiko Namikawa, Sol Pose-Méndez, Reinhard W Köster","doi":"10.1007/s00018-024-05538-z","DOIUrl":"10.1007/s00018-024-05538-z","url":null,"abstract":"<p><p>The cerebellum is a highly conserved brain compartment of vertebrates. Genetic diseases of the human cerebellum often lead to degeneration of the principal neuron, the Purkinje cell, resulting in locomotive deficits and socio-emotional impairments. Due to its relatively simple but highly conserved neuroanatomy and circuitry, these human diseases can be modeled well in vertebrates amenable for genetic manipulation. In the recent years, cerebellar research in zebrafish has contributed to understanding cerebellum development and function, since zebrafish larvae are not only molecularly tractable, but also accessible for high resolution in vivo imaging due to the transparency of the larvae and the ease of access to the zebrafish cerebellar cortex for microscopy approaches. Therefore, zebrafish is increasingly used for genetic modeling of human cerebellar neurodegenerative diseases and in particular of different types of Spinocerebellar Ataxias (SCAs). These models are well suited to address the underlying pathogenic mechanisms by means of in vivo cell biological studies. Furthermore, accompanying circuitry characterizations, physiological studies and behavioral analysis allow for unraveling molecular, structural and functional relationships. Moreover, unlike in mammals, zebrafish possess an astonishing ability to regenerate neuronal populations and their functional circuitry in the central nervous system including the cerebellum. Understanding the cellular and molecular processes of these regenerative processes could well serve to counteract acute and chronic loss of neurons in humans. Based on the high evolutionary conservation of the cerebellum these regeneration studies in zebrafish promise to open therapeutic avenues for counteracting cerebellar neuronal degeneration. The current review aims to provide an overview over currently existing genetic models of human cerebellar neurodegenerative diseases in zebrafish as well as neuroregeneration studies using the zebrafish cerebellum. Due to this solid foundation in cerebellar disease modeling and neuronal regeneration analysis, the zebrafish promises to become a popular model organism for both unraveling pathogenic mechanisms of human cerebellar diseases and providing entry points for therapeutic neuronal regeneration approaches.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"26"},"PeriodicalIF":6.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinoic acid drives surface epithelium fate determination through the TCF7-MSX2 axis.","authors":"Huaxing Huang, Jiafeng Liu, Fengjiao An, Siqi Wu, Huizhen Guo, Bofeng Wang, Kunlun Mo, Ying Huang, Jieying Tan, Jin Zhu, Zesong Lin, Zhuo Han, Mingsen Li, Li Wang, Zhen Mao, Hong Ouyang","doi":"10.1007/s00018-024-05525-4","DOIUrl":"10.1007/s00018-024-05525-4","url":null,"abstract":"<p><p>Understanding how embryonic progenitors decode extrinsic signals and transform into lineage-specific regulatory networks to drive cell fate specification is a fundamental, yet challenging question. Here, we develop a new model of surface epithelium (SE) differentiation induced by human embryonic stem cells (hESCs) using retinoic acid (RA), and identify BMP4 as an essential downstream signal in this process. We show that the retinoid X receptors, RXRA and RXRB, orchestrate SE commitment by shaping lineage-specific epigenetic and transcriptomic landscapes. Moreover, we find that TCF7, as a RA effector, regulates the transition from pluripotency to SE initiation by directly silencing pluripotency genes and activating SE genes. MSX2, a downstream activator of TCF7, primes the SE chromatin accessibility landscape and activates SE genes. Our work reveals the regulatory hierarchy between key morphogens RA and BMP4 in SE development, and demonstrates how the TCF7-MSX2 axis governs SE fate, providing novel insights into RA-mediated regulatory principles.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"16"},"PeriodicalIF":6.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}