Protein&Cell

Current Articles
2023, Volume 14, Issue 5

Emerging evidence suggests that intron-detaining transcripts are a nucleus-detained, polyadenylated, and post-transcriptional mRNA pool essential for cell to quickly respond to environmental stimuli and stress. Meng et al. demonstrated that the detained intron (DI) splicing is paused at Bact state, an active spliceosome but not catalytically primed, which differs from constitutively splicing introns that are co-transcriptionally spliced. RNPS1 recognizes the DIs and its neighboring sequences through its RRM (RNA recognition motif), which is sufficient to induce the intron detention. SNIP1 forkhead-associated domain and RNPS1 serine-rich domain are required not only for their interaction but the intron detention. SNIP1 knockout decreases DI splicing and causes neurodegeneration, likely through sequester of spliceosome pausing complex, a new molecular mechanism for neurodegenerative diseases.

Recollection

Ko Kuei Chen: a pioneer of modern pharmacological research in China

Huan Liu, Zhaoqi Liu, Xue Gong, Hao Cheng

2023, 14(5): 315-317. doi: 10.1093/procel/pwac049

[Abstract](58) [PDF 1057KB](5)

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Research articles

A molecular brake that modulates spliceosome pausing at detained introns contributes to neurodegeneration

Dawei Meng, Qian Zheng, Xue Zhang, Xuejiao Piao, Li Luo, Yichang Jia

2023, 14(5): 318-336. doi: 10.1093/procel/pwac008

[Abstract](88) [PDF 12826KB](18)

Abstract:
Emerging evidence suggests that intron-detaining transcripts (IDTs) are a nucleus-detained and polyadenylated mRNA pool for cell to quickly and effectively respond to environmental stimuli and stress. However, the underlying mechanisms of detained intron (DI) splicing are still largely unknown. Here, we suggest that post-transcriptional DI splicing is paused at the B^act state, an active spliceosome but not catalytically primed, which depends on Smad Nuclear Interacting Protein 1 (SNIP1) and RNPS1 (a serine-rich RNA binding protein) interaction. RNPS1 and B^act components preferentially dock at DIs and the RNPS1 docking is sufficient to trigger spliceosome pausing. Haploinsufficiency of Snip1 attenuates neurodegeneration and globally rescues IDT accumulation caused by a previously reported mutant U2 snRNA, a basal spliceosomal component. Snip1 conditional knockout in the cerebellum decreases DI splicing efficiency and causes neurodegeneration. Therefore, we suggest that SNIP1 and RNPS1 form a molecular brake to promote spliceosome pausing, and that its misregulation contributes to neurodegeneration.

Modeling human pregastrulation development by 3D culture of blastoids generated from primed-to-naïve transitioning intermediates

Zhifen Tu, Yan Bi, Xuehao Zhu, Wenqiang Liu, Jindian Hu, Li Wu, Tengyan Mao, Jianfeng Zhou, Hanwei Wang, Hong Wang, Shaorong Gao, Yixuan Wang

2023, 14(5): 337-349. doi: 10.1093/procel/pwac041

[Abstract](45) [PDF 35435KB](5)

Abstract:
Human pluripotent stem cells provide an inexhaustible model to study human embryogenesis in vitro. Recent studies have provided diverse models to generate human blastoids by self-organization of different pluripotent stem cells or somatic reprogramming intermediates. However, whether blastoids can be generated from other cell types or whether they can recapitulate postimplantation development in vitro is unknown. Here, we develop a strategy to generate human blastoids from heterogeneous intermediates with epiblast, trophectoderm, and primitive endoderm signatures of the primed-to-naïve conversion process, which resemble natural blastocysts in morphological architecture, composition of cell lineages, transcriptome, and lineage differentiation potential. In addition, these blastoids reflect many features of human peri-implantation and pregastrulation development when further cultured in an in vitro 3D culture system. In summary, our study provides an alternative strategy to generate human blastoids and offers insights into human early embryogenesis by modeling peri- and postimplantation development in vitro.

Single-cell analysis reveals an Angpt4-initiated EPDC-EC-CM cellular coordination cascade during heart regeneration

Zekai Wu, Yuan Shi, Yueli Cui, Xin Xing, Liya Zhang, Da Liu, Yutian Zhang, Ji Dong, Li Jin, Meijun Pang, Rui-Ping Xiao, Zuoyan Zhu, Jing-Wei Xiong, Xiangjun Tong, Yan Zhang, Shiqiang Wang, Fuchou Tang, Bo Zhang

2023, 14(5): 350-368. doi: 10.1093/procel/pwac010

[Abstract](78) [PDF 48172KB](16)

Abstract:
Mammals exhibit limited heart regeneration ability, which can lead to heart failure after myocardial infarction. In contrast, zebrafish exhibit remarkable cardiac regeneration capacity. Several cell types and signaling pathways have been reported to participate in this process. However, a comprehensive analysis of how different cells and signals interact and coordinate to regulate cardiac regeneration is unavailable. We collected major cardiac cell types from zebrafish and performed high-precision single-cell transcriptome analyses during both development and post-injury regeneration. We revealed the cellular heterogeneity as well as the molecular progress of cardiomyocytes during these processes, and identified a subtype of atrial cardiomyocyte exhibiting a stem-like state which may transdifferentiate into ventricular cardiomyocytes during regeneration. Furthermore, we identified a regeneration-induced cell (RIC) population in the epicardium-derived cells (EPDC), and demonstrated Angiopoietin 4 (Angpt4) as a specific regulator of heart regeneration. angpt4 expression is specifically and transiently activated in RIC, which initiates a signaling cascade from EPDC to endocardium through the Tie2-MAPK pathway, and further induces activation of cathepsin K in cardiomyocytes through RA signaling. Loss of angpt4 leads to defects in scar tissue resolution and cardiomyocyte proliferation, while overexpression of angpt4 accelerates regeneration. Furthermore, we found that ANGPT4 could enhance proliferation of neonatal rat cardiomyocytes, and promote cardiac repair in mice after myocardial infarction, indicating that the function of Angpt4 is conserved in mammals. Our study provides a mechanistic understanding of heart regeneration at single-cell precision, identifies Angpt4 as a key regulator of cardiomyocyte proliferation and regeneration, and offers a novel therapeutic target for improved recovery after human heart injuries.

Letters

IDDoR: a novel reporter mouse system for simultaneous and quantitative in vivo analysis of both DNA double-strand break repair pathways

Yu Chen, Zhen Cui, Zhixi Chen, Ying Jiang, Zhiyong Mao

2023, 14(5): 369-375. doi: 10.1093/procel/pwac001

[Abstract](44) [PDF 7187KB](10)

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Oxidative phosphorylation safeguards pluripotency via UDP-N-acetylglucosamine

Jiani Cao, Meng Li, Kun Liu, Xingxing Shi, Ning Sui, Yuchen Yao, Xiaojing Wang, Shiyu Li, Yuchang Tian, Shaojing Tan, Qian Zhao, Liang Wang, Xiahua Chai, Lin Zhang, Chong Liu, Xing Li, Zhijie Chang, Dong Li, Tongbiao Zhao

2023, 14(5): 376-381. doi: 10.1093/procel/pwac009

[Abstract](62) [PDF 4185KB](18)

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