Alternative Polyadenylation in Stem Cell Self-Renewal and Differentiation

Cellular function is shaped by transcriptional and post-transcriptional mechanisms, including alternative polyadenylation (APA). By directly controlling 3′- untranslated region (UTR) length and the selection of the last exon, APA regulates up to 70% of all cellular transcripts influencing RNA stability, output, and protein isoform expression. Cell-state-dependent 3′-UTR shortening has been identified as a hallmark of cellular proliferation. Hence, quiescent/dormant stem cells are characterized by long 3′-UTRs, whereas proliferative stem/progenitor cells exhibit 3′-UTR shortening. Here, the latest studies analyzing the role of APA in regulating stem cell state, self-renewal, differentiation, and metabolism are reviewed. The new role of APA in controlling stem cell fate opens novel potential therapeutic avenues in the field of regenerative medicine

Differential Alternative Polyadenylation Landscapes Mediate Hematopoietic Stem Cell Activation and Regulate Glutamine Metabolism

Alternative polyadenylation (APA) is emerging as an important regulatory mechanism of RNA and protein isoform expression by controlling 3′ untranslated region (3′-UTR) composition. The relevance of APA in stem cell hierarchies remains elusive. Here, we first demonstrate the requirement of the APA regulator Pabpn1 for hematopoietic stem cell (HSC) function. We then determine the genome-wide APA landscape (APAome) of HSCs and progenitors by performing low-input 3′ sequencing paired with bioinformatic pipelines. This reveals transcriptome-wide dynamic APA patterns and an overall shortening of 3′-UTRs during differentiation and upon homeostatic or stress-induced transition from quiescence to proliferation. Specifically, we show that APA regulates activation-induced Glutaminase (Gls) isoform switching by Nudt21. This adaptation of the glutamine metabolism by increasing the GAC:KGA isoform ratio fuels versatile metabolic pathways necessary for HSC self-renewal and proper stress response. Our study establishes APA as a critical regulatory layer orchestrating HSC self-renewal, behavior, and commitment

The long non-coding RNA Meg3 is dispensable for hematopoietic stem cells

The long non-coding RNA (lncRNA) Maternally Expressed Gene 3 (Meg3) is encoded within the imprinted Dlk1-Meg3 gene locus and is only maternally expressed. Meg3 has been shown to play an important role in the regulation of cellular proliferation and functions as a tumor suppressor in numerous tissues. Meg3 is highly expressed in mouse adult hematopoietic stem cells (HSCs) and strongly down-regulated in early progenitors. To address its functional role in HSCs, we used MxCre to conditionally delete Meg3 in the adult bone marrow of Meg3mat-flox/pat-wt mice. We performed extensive in vitro and in vivo analyses of mice carrying a Meg3 deficient blood system, but neither observed impaired hematopoiesis during homeostatic conditions nor upon serial transplantation. Furthermore, we analyzed VavCre Meg3mat-flox/pat-wty/sup> mice, in which Meg3 was deleted in the embryonic hematopoietic system and unexpectedly this did neither generate any hematopoietic defects. In response to interferon-mediated stimulation, Meg3 deficient adult HSCs responded highly similar compared to controls. Taken together, we report the finding, that the highly expressed imprinted lncRNA Meg3 is dispensable for the function of HSCs during homeostasis and in response to stress mediators as well as for serial reconstitution of the blood system in vivo

Prostate brachytherapy seed migration to the heart seen on cardiovascular computed tomographic angiography

AbstractBrachytherapy consists of placing radioactive sources into or adjacent to tumors, to deliver conformal radiation treatment. The technique is used for treatment of primary malignancies and for salvage in recurrent disease. Permanent prostate brachytherapy seeds are small metal implants containing radioactive sources of I-125, Pd-103, or Cs-131 encased in a titanium shell. They can embolize through the venous system to the lungs or heart and subsequently be detected by cardiovascular computed tomography. Cardiovascular imagers should be aware of the appearance of migrated seeds, as their presence in the chest is generally benign, so that unnecessary worry and testing are avoided. We report a case of a patient who underwent brachytherapy for prostate cancer and developed a therapeutic seeds embolus to the right ventricle

Multilayer omics analysis reveals a non-classical retinoic acid signaling axis that regulates hematopoietic stem cell identity

Hematopoietic stem cells (HSCs) rely on complex regulatory networks to preserve stemness. Due to the scarcity of HSCs, technical challenges have limited our insights into the interplay between metabolites, transcription, and the epigenome. In this study, we generated low-input metabolomics, transcriptomics, chromatin accessibility, and chromatin immunoprecipitation data, revealing distinctmetabolic hubs that are enriched in HSCs and their downstream multipotent progenitors. Mechanistically, we uncover a non-classical retinoic acid (RA) signaling axis that regulates HSC function. We show that HSCs rely on Cyp26b1, an enzyme conventionally considered to limit RA effects in the cell. In contrast to the traditional view, we demonstrate that Cyp26b1 is indispensable for production of the active metabolite 4-oxo-RA. Further, RA receptor beta (Rarb) is required for complete transmission of 4-oxo-RA-mediated signaling to maintain stem cells. Our findings emphasize that a single metabolite controls stem cell fate by instructing epigenetic and transcriptional attributes