SRSF1 governs progenitor-specific alternative splicing to maintain adult epithelial tissue homeostasis and renewal

Yu, Tingsheng; Cazares, Oscar; Tang, Alison D.; Kim, Hyun-Yi; Wald, Tomáš; Verma, Adya; Liu, Qi; Barcellos‐Hoff, Mary Helen; Floor, Stephen N.; Jung, Han‐Sung; Brooks, Angela N.; Klein, Ophir D.

doi:10.1016/j.devcel.2022.01.011

Cited by 14 publications

(10 citation statements)

References 62 publications

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“…Among the nucleus-localized proteins acquired from the DNA pull-down assay, 40S ribosomal protein S5, 60S ribosomal protein L9 and 40S ribosomal protein S3 are component of the ribosome involved in translation process; Cilia- and flagella-associated protein 20 is involved in post-translational modification of the tubulin subunits of microtubules [ 36 ]; Peroxiredoxin-1 is an antioxidant enzyme [ 37 ]. Serine/arginine-rich splicing factor 1 and pre-mRNA-processing factor 40 homolog A are involved in pre-mRNA splicing [ 38 , 39 ]; DNA mismatch repair protein Msh2 is involved in DNA repair [ 40 ]; Elongin-A is a transcription elongation factor increasing the overall rate of mRNA chain elongation by RNA polymerase II [ 41 ]. Since the asYb8c4 inhibits gene expression, the proper binding factor presumably should be transcription repressor for asYb8c4 ins allele and transcription activator for asYb8c4 del allele.…”

Section: Discussionmentioning

confidence: 99%

An antisense Alu transposon insertion/deletion polymorphism of ALDH1A1 may functionally associate with Parkinson’s disease

et al. 2022

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Background Aldehyde dehydrogenase 1 (encoded by ALDH1A1) has been shown to protect against Parkinson’s disease (PD) by reducing toxic metabolites of dopamine. We herein revealed an antisense Alu element insertion/deletion polymorphism in intron 4 of ALDH1A1, and hypothesized that it might play a role in PD. Methods A Han Chinese cohort comprising 488 PD patients and 515 controls was recruited to validate the Alu insertion/deletion polymorphism following a previous study of tag-single nucleotide polymorphisms, where rs7043217 was shown to be significantly associated with PD. Functional analyses of the Alu element insertion were performed. Results The Alu element of ALDH1A1 was identified to be a variant of Yb8 subfamily and termed as Yb8c4. The antisense Yb8c4 insertion/deletion polymorphism (named asYb8c4ins and asYb8c4del, respectively) appeared to be in a complete linkage disequilibrium with rs7043217 and was validated to be significantly associated with PD susceptibility with asYb8c4ins serving as a risk allele (P = 0.030, OR = 1.224, 95% CI = 1.020–1.470). Multiple functional analyses including ALDH1A1 mRNA expression in blood cells of carriers, and reporters of EGFP and luciferase showed that the asYb8c4ins had a suppressive activity on gene transcription. Mechanistic explorations suggested that the asYb8c4ins induced no changes in CpG methylation and mRNA splicing of ALDH1A1 and appeared no binding of transcription factors. Conclusions Our results consolidate an involvement of ALDH1 in PD pathogenesis. The asYb8c4 polymorphism may be a functional output of its linkage disequilibrium-linked single nucleotide polymorphisms.

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Section: Discussionmentioning

confidence: 99%

An antisense Alu transposon insertion/deletion polymorphism of ALDH1A1 may functionally associate with Parkinson’s disease

et al. 2022

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“…Notably, the difficulty in segregating ISC from early progenitors suggest their high-degree of similarity and may indicate they co-exist in closely comparable cellular states. Analysis of the factors that best associate with inferred cell potency revealed multiple chromatin remodelers, including Atad2, which has been recently shown to determine cell potency in the skin 35 , as well as other factors previously suggested to regulate intestinal stemness 37,38 . Similarly, to Lgr5, other proposed markers for ISC, such as Ascl2 63 , also failed to correlate with inferred cell potency and were rather broadly expressed within the secretory lineage.…”

Section: Discussionmentioning

confidence: 88%

“…Several chromatin remodeler enzymes also emerged from the analysis— including Smarca5 34 and Atad2 35 , which have been previously associated with stemness—thus highlighting the crucial role of chromatin remodeling in cell potency. Interestingly, several splicing factors also emerged within the broad group of transcriptional regulators associated with cell potency, including members of the Srsf family, which were recently shown to play an important role in regulating the intestinal epithelium 38 .…”

Section: Resultsmentioning

confidence: 99%

“…4, Table 7). Regulatory proteins, whose activity presented the most significant correlation with CytoTRACE scores were highly enriched for factors known to regulate stemness across different tissues, including the intestine [33][34][35][36][37][38][39] . Consistently, known regulators of intestinal differentiation 1 had negative correlation scores.…”

Section: An Unbiased Approach To Elucidate the Organization Of Intest...mentioning

confidence: 99%

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Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury

Malagola

Vasciaveo

Ochiai

et al. 2022

Preprint

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SummaryThe currently accepted intestinal epithelial cell organization model equates crypt base columnar (CBC) cells, marked by high levels of Lgr5 expression, with the intestinal stem cell (ISC)1. However, recent intestinal regeneration studies have uncovered limitations of the ‘Lgr5-CBC’ model2, 3, leading to two major views: one favoring the presence of a quiescent reserve stem cell population4–7, the other calling for differentiated cell plasticity8–11. To test if an alternative model may help reconcile these perspectives, we studied the hierarchical organization of crypt epithelial cells in an unbiased fashion, by combining high-resolution, single-cell profiling and lineage tracing in multiple transgenic mouse models. These show that Lgr5 is not a specific ISC marker; rather, cells located in the crypt isthmus, which include Lgr5low cells, comprise the ISCs that sustain tissue homeostasis. Following irradiation or intestinal injury, surviving ISCs and progenitors, but not differentiated cells, participate in intestinal regeneration, suggesting that neither de-differentiation nor reserve stem cell populations are drivers of intestinal regeneration. Our results provide a novel viewpoint for the intestinal crypt epithelium, in which ISCs localize to the crypt isthmus, and ISC potential is restricted to stem and progenitor cells.

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“…This aligns with our in vivo data showing that moderate induction of SRSF1 is beneficial, but high overexpression levels have no observable benefits or toxicity, likely due to the factor's negative feedback loop. Given that SRSF1 is endogenously expressed in most cells and is transiently activated upon regeneration signals 50 , we believe that the splicing factor can be used as a safe and effective target for fibroblast age reversal. In conclusion, we envision similar transcriptomic reprogramming screens to uncover cell-type specific rejuvenation targets that will serve as the basis for future rejuvenation gene therapies.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic reprogramming screen identifies SRSF1 as rejuvenation factor

Plesa,

Jung,

Wang

et al. 2023

Preprint

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Aging is a complex process that manifests through the time-dependent functional decline of a biological system. Age-related changes in epigenetic and transcriptomic profiles have been successfully used to measure the aging process1,2. Moreover, modulating gene regulatory networks through interventions such as the induction of the Yamanaka factors has been shown to reverse aging signatures and improve cell function3,4. However, this intervention has safety and efficacy limitations forin vivorejuvenation5,6, underscoring the need for identifying novel age reversal factors. Here, we discovered SRSF1 as a new rejuvenation factor that can improve cellular functionin vitroandin vivo. Using a cDNA overexpression screen with a transcriptomic readout we identified that SRSF1 induction reprograms the cell transcriptome towards a younger state. Furthermore, we observed beneficial changes in senescence, proteasome function, collagen production, and ROS stress upon SRSF1 overexpression. Lastly, we showed that SRSF1 can improve wound healingin vitroandin vivoand is linked to organismal longevity. Our study provides a proof of concept for using transcriptomic reprogramming screens in the discovery of age reversal interventions and identifies SRSF1 as a promising target for cellular rejuvenation.

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SRSF1 governs progenitor-specific alternative splicing to maintain adult epithelial tissue homeostasis and renewal

Cited by 14 publications

References 62 publications

An antisense Alu transposon insertion/deletion polymorphism of ALDH1A1 may functionally associate with Parkinson’s disease

An antisense Alu transposon insertion/deletion polymorphism of ALDH1A1 may functionally associate with Parkinson’s disease

Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury

Transcriptomic reprogramming screen identifies SRSF1 as rejuvenation factor

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