bims-micpro 2024-02-11 papers

iScience. 2024 Feb 16. 27(2): 108972

No country for old methods: New tools for studying microproteins.

Fabiola Valdivia-Francia, Ataman Sendoel.

Microproteins encoded by small open reading frames (sORFs) have emerged as a fascinating frontier in genomics. Traditionally overlooked due to their small size, recent technological advancements such as ribosome profiling, mass spectrometry-based strategies and advanced computational approaches have led to the annotation of more than 7000 sORFs in the human genome. Despite the vast progress, only a tiny portion of these microproteins have been characterized and an important challenge in the field lies in identifying functionally relevant microproteins and understanding their role in different cellular contexts. In this review, we explore the recent advancements in sORF research, focusing on the new methodologies and computational approaches that have facilitated their identification and functional characterization. Leveraging these new tools hold great promise for dissecting the diverse cellular roles of microproteins and will ultimately pave the way for understanding their role in the pathogenesis of diseases and identifying new therapeutic targets.

Keywords: Biological sciences; Biotechnology; Genetics; Molecular biology

DOI: https://doi.org/10.1016/j.isci.2024.108972

Am J Physiol Heart Circ Physiol. 2024 Feb 09.

Deletion of DWORF does not affect cardiac function in ageing and in PLN-R14del cardiomyopathy.

Nienke M Stege, Vivian Oliveira Nunes Teixeira, Sietske N Zijlstra, Anna M Feringa, Rudolf A de Boer, Herman H W Silljé.

The phospholamban (PLN) pathogenic gene variant p.Arg14del causes cardiomyopathy, which is characterized by perinuclear PLN protein clustering and can lead to severe heart failure (HF). Elevated expression of Dwarf open reading frame (DWORF), a protein counteracting the function of PLN in the sarcoplasmic reticulum (SR), can delay disease progression in a PLN-R14del mouse model. Here, we evaluated whether deletion of DWORF (DWORF-/-) would have an opposite effect and accelerate age-dependent disease progression in wild-type (WT) mice and mice with a pathogenic PLN-R14del allele (R14Δ/+). We show that DWORF-/- mice maintained a normal left-ventricular ejection fraction (LVEF) during ageing and no difference with WT control mice could be observed up to 20 months of age. R14Δ/+ mice maintained a normal cardiac function until 12 months of age, but at 18 months of age LVEF was significantly reduced as compared with WT mice. Absence of DWORF did not accelerate the R14Δ/+-induced reduction in LVEF, nor enhance the increases in gene expression of markers related to cardiac remodeling and fibrosis and did not exacerbate cardiac fibrosis caused by the R14Δ/+ mutation. Together, these results demonstrate that absence of DWORF does not accelerate nor exacerbate PLN-R14del cardiomyopathy in mice harboring the pathogenic R14del allele. In addition, our data indicate that DWORF appears to be dispensable for cardiac function during ageing.

Keywords: DWORF knockout; cardiomyopathy; heart failure; p.Arg14del; phospholamban

DOI: https://doi.org/10.1152/ajpheart.00741.2023

Sci Adv. 2024 Feb 09. 10(6): eadg8816

Pri peptides temporally coordinate transcriptional programs during epidermal differentiation.

Maylis Gallois, Delphine Menoret, Simon Marques-Prieto, Audrey Montigny, Philippe Valenti, Bernard Moussian, Serge Plaza, François Payre, Hélène Chanut-Delalande.

To achieve a highly differentiated state, cells undergo multiple transcriptional processes whose coordination and timing are not well understood. In Drosophila embryonic epidermal cells, polished-rice (Pri) smORF peptides act as temporal mediators of ecdysone to activate a transcriptional program leading to cell shape remodeling. Here, we show that the ecdysone/Pri axis concomitantly represses the transcription of a large subset of cuticle genes to ensure proper differentiation of the insect exoskeleton. The repression relies on the transcription factor Ken and persists for several days throughout early larval stages, during which a soft cuticle allows larval crawling. The onset of these cuticle genes normally awaits the end of larval stages when the rigid pupal case assembles, and their premature expression triggers abnormal sclerotization of the larval cuticle. These results uncovered a temporal switch to set up distinct structures of cuticles adapted to the animal lifestyle and which might be involved in the evolutionary history of insects.

DOI: https://doi.org/10.1126/sciadv.adg8816

Int J Mol Sci. 2024 Jan 26. pii: 1539. [Epub ahead of print]25(3):

Non-Mature miRNA-Encoded Micropeptide miPEP166c Stimulates Anthocyanin and Proanthocyanidin Synthesis in Grape Berry Cells.

Mariana Vale, Hélder Badim, Hernâni Gerós, Artur Conde.

The phenylpropanoid and flavonoid pathways exhibit intricate regulation, not only influenced by environmental factors and a complex network of transcription factors but also by post-transcriptional regulation, such as silencing by microRNAs and miRNA-encoded micropeptides (miPEPs). VviMYBC2-L1 serves as a transcriptional repressor for flavonoids, playing a crucial role in coordinating the synthesis of anthocyanin and proanthocyanidin. It works in tandem with their respective transcriptional activators, VviMYBA1/2 and VviMYBPA1, to maintain an equilibrium of flavonoids. We have discovered a miPEP encoded by miR166c that appears to target VviMYBC2-L1. We conducted experiments to test the hypothesis that silencing this transcriptional repressor through miPEP166c would stimulate the synthesis of anthocyanins and proanthocyanidins. Our transcriptional analyses by qPCR revealed that the application of exogenous miPEP166c to Gamay Fréaux grape berry cells resulted in a significant upregulation in flavonoid transcriptional activators (VviMYBA1/2 and VviMYBPA1) and structural flavonoid genes (VviLDOX and VviDFR), as well as genes involved in the synthesis of proanthocyanidins (VviLAR1 and VviANR) and anthocyanins (VviUFGT1). These findings were supported by the increased enzyme activities of the key enzymes UFGT, LAR, and ANR, which were 2-fold, 14-fold, and 3-fold higher, respectively, in the miPEP166c-treated cells. Ultimately, these changes led to an elevated total content of anthocyanins and proanthocyanidins.

Keywords: anthocyanins; grape berry cells; non-mature miRNA-encoded micropeptides (miPEPs); proanthocyanidins; secondary metabolism

DOI: https://doi.org/10.3390/ijms25031539