Pub Date : 2024-12-24DOI: 10.1016/j.cellin.2024.100226
Rui-Jin Ji , Mu-Yao Wang , Ying Zhang
The ability to recognize antigen epitope is crucial for generating an effective immune response. By engineering these epitopes, researchers can reduce on-target/off-tumor toxicity associated with targeted immunotherapy. Recent studies indicate that employing various gene editing tools to modify the epitopes of healthy hematopoietic stem and progenitor cells (HSPCs) can protect these cells from toxicity during tumor eradication, all while preserving their differentiation and function. This advancement greatly enhances the safety and efficacy of tumor immunotherapy.
{"title":"Precision epitope editing: A path to advanced immunotherapies","authors":"Rui-Jin Ji , Mu-Yao Wang , Ying Zhang","doi":"10.1016/j.cellin.2024.100226","DOIUrl":"10.1016/j.cellin.2024.100226","url":null,"abstract":"<div><div>The ability to recognize antigen epitope is crucial for generating an effective immune response. By engineering these epitopes, researchers can reduce on-target/off-tumor toxicity associated with targeted immunotherapy. Recent studies indicate that employing various gene editing tools to modify the epitopes of healthy hematopoietic stem and progenitor cells (HSPCs) can protect these cells from toxicity during tumor eradication, all while preserving their differentiation and function. This advancement greatly enhances the safety and efficacy of tumor immunotherapy.</div></div>","PeriodicalId":72541,"journal":{"name":"Cell insight","volume":"4 2","pages":"Article 100226"},"PeriodicalIF":0.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143138740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-12DOI: 10.1016/j.cellin.2024.100213
Xin Li , Chengzhi Liu , Zhichao Lei , Huan Chen , Liang Wang
Eukaryotic genomes are organized into distinct chromatin compartments, some of which exhibit properties of biomolecular condensates. These condensates primarily form due to chromatin-associated proteins/complexes (CAPs). CAPs play a crucial role in gene expression, functioning as either transcriptional repressors or activators. Phase separation, a well-established biophysical phenomenon, is a key driver of chromatin condensate formation by CAPs. Notably, multivalent CAPs with the ability to engage in diverse interactions promote chromatin compaction, leading to the formation of transcriptionally repressed compartments. Conversely, interactions between intrinsically disordered region (IDR)-containing transcriptional regulators, mediated by their multivalent IDRs, lead to the formation of protein-rich, transcriptionally active droplets on decondensed genomic regions. Interestingly, both repressive heterochromatin and activating euchromatin condensates exhibit spontaneous phase separation and selectively enrich components with concordant transcriptional functions. This review delves into the mechanisms by which transcriptionally repressive CAPs orchestrate the formation of repressed chromatin domains. We further explore how a diverse array of transcription-related CAPs or core histone variants, via phase separation, influence gene expression by inducing erroneous transcription events, regulating expression levels, and facilitating the interconversion of transcriptionally repressed and active regions.
真核生物基因组被组织成不同的染色质区室，其中一些表现出生物分子凝聚物的特性。这些凝聚体主要是由染色质相关蛋白/复合物（CAPs）形成的。CAPs 在基因表达中起着至关重要的作用，可作为转录抑制因子或激活因子发挥作用。相分离是一种公认的生物物理现象，是 CAPs 形成染色质凝聚物的关键驱动因素。值得注意的是，能够参与多种相互作用的多价 CAP 可促进染色质的压实，从而形成转录抑制区。与此相反，含有内在紊乱区（IDR）的转录调节因子在多价 IDR 的介导下相互作用，导致在解聚的基因组区域形成富含蛋白质、转录活跃的液滴。有趣的是，抑制性异染色质和激活性超染色质凝集物都表现出自发的相分离，并选择性地富集具有一致转录功能的成分。本综述深入探讨了转录抑制性 CAP 协调形成抑制性染色质域的机制。我们将进一步探讨各种与转录相关的 CAP 或核心组蛋白变体如何通过相分离，诱导错误的转录事件、调节表达水平以及促进转录抑制区和活性区的相互转换，从而影响基因表达。
{"title":"Phase-separated chromatin compartments: Orchestrating gene expression through condensation","authors":"Xin Li , Chengzhi Liu , Zhichao Lei , Huan Chen , Liang Wang","doi":"10.1016/j.cellin.2024.100213","DOIUrl":"10.1016/j.cellin.2024.100213","url":null,"abstract":"<div><div>Eukaryotic genomes are organized into distinct chromatin compartments, some of which exhibit properties of biomolecular condensates. These condensates primarily form due to chromatin-associated proteins/complexes (CAPs). CAPs play a crucial role in gene expression, functioning as either transcriptional repressors or activators. Phase separation, a well-established biophysical phenomenon, is a key driver of chromatin condensate formation by CAPs. Notably, multivalent CAPs with the ability to engage in diverse interactions promote chromatin compaction, leading to the formation of transcriptionally repressed compartments. Conversely, interactions between intrinsically disordered region (IDR)-containing transcriptional regulators, mediated by their multivalent IDRs, lead to the formation of protein-rich, transcriptionally active droplets on decondensed genomic regions. Interestingly, both repressive heterochromatin and activating euchromatin condensates exhibit spontaneous phase separation and selectively enrich components with concordant transcriptional functions. This review delves into the mechanisms by which transcriptionally repressive CAPs orchestrate the formation of repressed chromatin domains. We further explore how a diverse array of transcription-related CAPs or core histone variants, via phase separation, influence gene expression by inducing erroneous transcription events, regulating expression levels, and facilitating the interconversion of transcriptionally repressed and active regions.</div></div>","PeriodicalId":72541,"journal":{"name":"Cell insight","volume":"3 6","pages":"Article 100213"},"PeriodicalIF":0.0,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142532224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-11DOI: 10.1016/j.cellin.2024.100212
Chen Zhao , Liang Wang , Junbao Wang, Kuan Tian, Xiaojiao Hua, Fangyu Wang, Yan Zhou
{"title":"Transcripts derived from the neocortical enhancer of Ctnnb1 promote the enhancer-promoter interaction and maintain Ctnnb1 transcription","authors":"Chen Zhao , Liang Wang , Junbao Wang, Kuan Tian, Xiaojiao Hua, Fangyu Wang, Yan Zhou","doi":"10.1016/j.cellin.2024.100212","DOIUrl":"10.1016/j.cellin.2024.100212","url":null,"abstract":"","PeriodicalId":72541,"journal":{"name":"Cell insight","volume":"4 1","pages":"Article 100212"},"PeriodicalIF":0.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142651970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-11DOI: 10.1016/j.cellin.2024.100210
Yong Wang , Xinping Liu , Zheng Liu , Shasha Hua , Kai Jiang
Tumor suppressor protein Adenomatous polyposis coli protein (APC) is an EB-binding and microtubule (MT) plus end-tracking protein; however, how exactly APC regulates MT dynamics remains elusive. Here, we show that in LLC-PK1 cells, APC and KIF2A, an MT depolymerase, form a complex clustering at the cell edge and destabilize MTs at the MT plus ends. Further biochemical characterization and mutational analysis reveal key residues for the APC-KIF2A interaction. In addition, APC counteracts the major MT-stabilizer CLASPs at MT plus ends and promotes directional cell migration via modulating cell adhesion force. Reconstitution experiments demonstrate that APC potentiates KIF2A-induced MT catastrophes and antagonizes the stabilizing effect of CLASP2 in vitro. In summary, APC functions as a positive regulator of MT-destabilizer and a negative regulator of MT-stabilizer to orchestrate MT dynamics.
{"title":"APC orchestrates microtubule dynamics by acting as a positive regulator of KIF2A and a negative regulator of CLASPs","authors":"Yong Wang , Xinping Liu , Zheng Liu , Shasha Hua , Kai Jiang","doi":"10.1016/j.cellin.2024.100210","DOIUrl":"10.1016/j.cellin.2024.100210","url":null,"abstract":"<div><div>Tumor suppressor protein Adenomatous polyposis coli protein (APC) is an EB-binding and microtubule (MT) plus end-tracking protein; however, how exactly APC regulates MT dynamics remains elusive. Here, we show that in LLC-PK1 cells, APC and KIF2A, an MT depolymerase, form a complex clustering at the cell edge and destabilize MTs at the MT plus ends. Further biochemical characterization and mutational analysis reveal key residues for the APC-KIF2A interaction. In addition, APC counteracts the major MT-stabilizer CLASPs at MT plus ends and promotes directional cell migration via modulating cell adhesion force. Reconstitution experiments demonstrate that APC potentiates KIF2A-induced MT catastrophes and antagonizes the stabilizing effect of CLASP2 <em>in vitro</em>. In summary, APC functions as a positive regulator of MT-destabilizer and a negative regulator of MT-stabilizer to orchestrate MT dynamics.</div></div>","PeriodicalId":72541,"journal":{"name":"Cell insight","volume":"4 1","pages":"Article 100210"},"PeriodicalIF":0.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142704837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-10DOI: 10.1016/j.cellin.2024.100214
Katherine N. Degner , Jessica L. Bell , Sean D. Jones , Hyejung Won
The human genome is largely noncoding, yet the field is still grasping to understand how noncoding variants impact transcription and contribute to disease etiology. The massively parallel reporter assay (MPRA) has been employed to characterize the function of noncoding variants at unprecedented scales, but its application has been largely limited by the in vitro context. The field will benefit from establishing a systemic platform to study noncoding variant function across multiple tissue types under physiologically relevant conditions. However, to date, MPRA has been applied to only a handful of in vivo conditions. Given the complexity of the central nervous system and its widespread interactions with all other organ systems, our understanding of neuropsychiatric disorder-associated noncoding variants would be greatly advanced by studying their functional impact in the intact brain. In this review, we discuss the importance, technical considerations, and future applications of implementing MPRA in the in vivo space with the focus on neuropsychiatric disorders.
{"title":"Just a SNP away: The future of in vivo massively parallel reporter assay","authors":"Katherine N. Degner , Jessica L. Bell , Sean D. Jones , Hyejung Won","doi":"10.1016/j.cellin.2024.100214","DOIUrl":"10.1016/j.cellin.2024.100214","url":null,"abstract":"<div><div>The human genome is largely noncoding, yet the field is still grasping to understand how noncoding variants impact transcription and contribute to disease etiology. The massively parallel reporter assay (MPRA) has been employed to characterize the function of noncoding variants at unprecedented scales, but its application has been largely limited by the <em>in vitro</em> context. The field will benefit from establishing a systemic platform to study noncoding variant function across multiple tissue types under physiologically relevant conditions. However, to date, MPRA has been applied to only a handful of <em>in vivo</em> conditions. Given the complexity of the central nervous system and its widespread interactions with all other organ systems, our understanding of neuropsychiatric disorder-associated noncoding variants would be greatly advanced by studying their functional impact in the intact brain. In this review, we discuss the importance, technical considerations, and future applications of implementing MPRA in the <em>in vivo</em> space with the focus on neuropsychiatric disorders.</div></div>","PeriodicalId":72541,"journal":{"name":"Cell insight","volume":"4 1","pages":"Article 100214"},"PeriodicalIF":0.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142651969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-09DOI: 10.1016/j.cellin.2024.100211
Qiu Pan , Xiao-Lian Zhang
Core fucosylation, catalyzed by α1,6-fucosyltransferase (FUT8), is an important N-glycosylation modification process that attaches a fucose residue via an α1,6-linkage to the core N-acetylglucosamine of N-glycans in mammals. Research over the past three decades has revealed the critical role of FUT8-mediated core fucosylation modification in various physiological and pathological processes, including cell growth, adhesion, receptor activation, antibody-dependent cellular cytotoxicity (ADCC), tumor metastasis and infections. This review discusses the immune system function involving FUT8 and the mechanisms by which core fucosylation regulates immunity and contributes to disease. A deeper understanding of these mechanisms can provide insights into cellular biology and suggest new therapeutic approaches and targets for related diseases.
{"title":"Roles of core fucosylation modification in immune system and diseases","authors":"Qiu Pan , Xiao-Lian Zhang","doi":"10.1016/j.cellin.2024.100211","DOIUrl":"10.1016/j.cellin.2024.100211","url":null,"abstract":"<div><div>Core fucosylation, catalyzed by α1,6-fucosyltransferase (FUT8), is an important <em>N-</em>glycosylation modification process that attaches a fucose residue via an α1,6-linkage to the core <em>N</em>-acetylglucosamine of <em>N</em>-glycans in mammals. Research over the past three decades has revealed the critical role of FUT8-mediated core fucosylation modification in various physiological and pathological processes, including cell growth, adhesion, receptor activation, antibody-dependent cellular cytotoxicity (ADCC), tumor metastasis and infections. This review discusses the immune system function involving FUT8 and the mechanisms by which core fucosylation regulates immunity and contributes to disease. A deeper understanding of these mechanisms can provide insights into cellular biology and suggest new therapeutic approaches and targets for related diseases.</div></div>","PeriodicalId":72541,"journal":{"name":"Cell insight","volume":"4 1","pages":"Article 100211"},"PeriodicalIF":0.0,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142651844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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