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The function of the cancer-associated lncRNA Malat1 during aging is as-of-yet uncharacterized. Here, we show that Malat1 interacts with Nucleophosmin (NPM) in young mouse brain, and with Lamin A/C, hnRNP C, and KAP1 with age. RNA-seq and RT-qPCR reveal a persistent expression of Malat1_ 2 (the 3'isoform of Malat1 ) in Malat1 Δ1 (5'-1.5 kb deletion) mouse retinas and brains at 1/4 th level of the full-length Malat1 , while Malat1_ 1 (the 5'isoform) in Malat1 Δ2 (deletion of 3'-conserved 5.7 kb) at a much lower level, suggesting an internal promoter driving the 3' isoform. The 1774 and 496 differentially expressed genes in Malat1 Δ2 and Malat1 Δ1 brains, respectively, suggest the 3' isoform regulates gene expression in trans and the 5' isoform in cis . Consistently, Malat1 Δ2 mice show increased age-dependent retinal oxidative stress and corneal opacity, while Malat1 Δ1 mice show no obvious phenotype. Collectively, this study reveals a physiological function of the lncRNA Malat1 3'-isoform during the aging process., Competing Interests: All the authors declare no competing interests., (© 2022 The Author(s).)

All current smooth muscle cell (SMC) Cre mice similarly recombine floxed alleles in vascular and visceral SMCs. Here, we present an Itga8-CreER T2 knock-in mouse and compare its activity with a Myh11-CreER T2 mouse. Both Cre drivers demonstrate equivalent recombination in vascular SMCs. However, Myh11-CreER T2 mice, but not Itga8-CreER T2 mice, display high activity in visceral SMC-containing tissues such as intestine, show early tamoxifen-independent activity, and produce high levels of CreER T2 protein. Whereas Myh11-CreER T2 -mediated knockout of serum response factor ( Srf ) causes a lethal intestinal phenotype precluding analysis of the vasculature, loss of Srf with Itga8-CreER T2 ( Srf Itga8 ) yields viable mice with no evidence of intestinal pathology. Male and female Srf Itga8 mice exhibit vascular contractile incompetence, and angiotensin II causes elevated blood pressure in wild type, but not Srf Itga8 , male mice. These findings establish the Itga8-CreER T2 mouse as an alternative to existing SMC Cre mice for unfettered phenotyping of vascular SMCs following selective gene loss.

The number of human LncRNAs has now exceeded all known protein-coding genes. Most studies of human LncRNAs have been conducted in cell culture systems where various mechanisms of action have been worked out. On the other hand, efforts to elucidate the function of human LncRNAs in an in vivo setting have been limited. In this brief review, we highlight some strengths and weaknesses of studying human LncRNAs in the mouse. Special consideration is given to bacterial artificial chromosome transgenesis and genome editing. The integration of these technical innovations offers an unprecedented opportunity to complement and extend the expansive literature of cell culture models for the study of human LncRNAs. Two different examples of how BAC transgenesis and genome editing can be leveraged to gain insight into human LncRNA regulation and function in mice are presented: the random integration of a vascular cell-enriched LncRNA and a targeted approach for a new LncRNA immediately upstream of the ACE2 gene, which encodes the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent underlying the coronavirus disease-19 (COVID-19) pandemic., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Most single nucleotide variants (SNVs) occur in noncoding sequence where millions of transcription factor binding sites (TFBS) reside. Here, a comparative analysis of CRISPR-mediated homology-directed repair (HDR) versus the recently reported prime editing 2 (PE2) system was carried out in mice over a TFBS called a CArG box in the Tspan2 promoter., Results: Quantitative RT-PCR showed loss of Tspan2 mRNA in aorta and bladder, but not heart or brain, of mice homozygous for an HDR-mediated three base pair substitution in the Tspan2 CArG box. Using the same protospacer, mice homozygous for a PE2-mediated single-base substitution in the Tspan2 CArG box displayed similar cell-specific loss of Tspan2 mRNA; expression of an overlapping long noncoding RNA was also nearly abolished in aorta and bladder. Immuno-RNA fluorescence in situ hybridization validated loss of Tspan2 in vascular smooth muscle cells of HDR and PE2 CArG box mutant mice. Targeted sequencing demonstrated variable frequencies of on-target editing in all PE2 and HDR founders. However, whereas no on-target indels were detected in any of the PE2 founders, all HDR founders showed varying levels of on-target indels. Off-target analysis by targeted sequencing revealed mutations in many HDR founders, but none in PE2 founders., Conclusions: PE2 directs high-fidelity editing of a single base in a TFBS leading to cell-specific loss in expression of an mRNA/long noncoding RNA gene pair. The PE2 platform expands the genome editing toolbox for modeling and correcting relevant noncoding SNVs in the mouse.

Tissue aging is the gradual decline of physiological homeostasis accompanied with accumulation of senescent cells, decreased clearance of unwanted biological compounds, and depletion of stem cells. Senescent cells were cell cycle arrested in response to various stimuli and identified using distinct phenotypes and changes in gene expression. Senescent cells that accumulate with aging can compromise normal tissue function and inhibit or stop repair and regeneration. Selective removal of senescent cells can slow the aging process and inhibits age-associated diseases leading to extended lifespans in mice and thus provides a possibility for developing antiaging therapy. To monitor the appearance of senescent cells in vivo and target them, a clearer understanding of senescent cell expression markers is needed. We investigated the age-associated expression of three molecular hallmarks of aging: SA- β -gal, P16 INK4a , and retrotransposable elements (RTEs), in different mouse tissues during chronological aging. Our data showed that the expression of these markers is variable with aging in the different tissues. P16 INK4a showed consistent increases with age in most tissues, while expression of RTEs was variable among different tissues examined. These data suggest that biological changes occurring with physiological aging may be useful in choosing the appropriate timing of therapeutic interventions to slow the aging process or keep more susceptible organs healthier in the aging process.

In the original publication, the funding information was incorrectly published. The correct funding information is provided in this correction. This work is supported by grants from the Projects of International Cooperation and Exchanges Ministry of Science and Technology of China (2013DFG32390) and the National Natural Science Foundation of China (31472059) to X.S. X.S is a recipient of the Young Thousand Talents program (KJ2070000026).

Cellular senescence can be described as a complex stress response that leads to irreversible cell cycle arrest. This process was originally described as an event that primary cells go through after many passages of cells during cell culture. More recently, cellular senescence is viewed as a programmed process by which the cell displays a senescence phenotype when exposed to a variety of stresses. Cellular senescence has been implicated in tumor suppression and aging such that senescence may contribute to both tumor progression and normal tissue repair. Here, we review different forms of cellular senescence, as well as current biomarkers used to identify senescent cells in vitro and in vivo . Additionally, we highlight the role of senescence-associated long noncoding RNAs (lncRNAs).

Meiotic recombination is carried out through a specialized pathway for the formation and repair of DNA double-strand breaks (DSBs) made by the Spo11 protein. The present study shed light on the functional role of cyclin, CYC2, in Tetrahymena thermophila which has transcriptionally high expression level during meiosis process. Knocking out the CYC2 gene results in arrest of meiotic conjugation process at 2.5-3.5 h after conjugation initiation, before the meiosis division starts, and in company with the absence of DSBs. To investigate the underlying mechanism of this phenomenon, a complete transcriptome profile was performed between wild-type strain and CYC2 knock-out strain. Functional analysis of RNA-Seq results identifies related differentially expressed genes (DEGs) including SPO11 and these DEGs are enriched in DNA repair/mismatch repair (MMR) terms in homologous recombination (HR), which indicates that CYC2 could play a crucial role in meiosis by regulating SPO11 and participating in HR.