Evidence for discrete modes of YAP1 signaling via mRNA splice isoforms in development and diseases

Vrbský, Jan; Vinarský, Vladimír; Perestrelo, Ana Rubina; Cruz, Jorge Oliver-De La; Martino, Fabiana De; Pompeiano, Antonio; Izzi, Valerio; Hlinomaz, Ota; Rotrekl, Vladimír; Sudol, Marius; Pagliari, Stefania; Forte, Giancarlo

doi:10.1016/j.ygeno.2021.03.009

Cited by 16 publications

(16 citation statements)

References 76 publications

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“…This splicing event is of particular relevance, since the exon encodes for the second WW domain, a domain known to directly control the protein interaction with TEAD transcription factor and thus its DNA binding activity 49 . This switch towards the expression of YAP1 isoforms with two WW domains (YAP1-2) has been recently described by our research group in human pathological hearts 56 and confirmed in other two independently published RNA-seq datasets.…”

Section: Discussionsupporting

confidence: 84%

The mechanical regulation of RNA binding protein hnRNPC in the failing heart

Martino

Perestrelo

Hejret

et al. 2021

Preprint

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Cardiac pathologies are characterized by intense remodeling of the extracellular matrix (ECM) that eventually leads to heart failure. Cardiomyocytes respond to the ensuing biomechanical stress by re-expressing fetal contractile proteins via transcriptional and post-transcriptional processes, like alternative splicing (AS). Here, we demonstrate that the heterogeneous nuclear ribonucleoprotein C (hnRNPC) is upregulated and relocates to the sarcomeric Z-disk upon ECM pathological remodeling. We show that this is an active site of localized translation, where the ribonucleoprotein associates to the translation machinery. Alterations in hnRNPC expression and localization can be mechanically determined and affect the AS of numerous mRNAs involved in mechanotransduction and cardiovascular diseases, like Hippo pathway effector YAP1. We propose that cardiac ECM remodeling serves as a switch in RNA metabolism by impacting an associated regulatory protein of the spliceosome apparatus. These findings offer new insights on the mechanism of mRNAs homeostasis mechanoregulation in pathological conditions.

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Section: Discussionsupporting

confidence: 84%

The mechanical regulation of RNA binding protein hnRNPC in the failing heart

Martino

Perestrelo

Hejret

et al. 2021

Preprint

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“…AICS-0037-172, Camden, New Jersey, USA). All iPSC cells were cultured and maintained in feeder-free conditions as previously described 103,104 on Growth Factor Reduced Matrigel®-coated plates, (1:100 in DMEM/F12, Corning) in complete Essential 8™ Medium (E8, Thermo Fisher Scientific) containing penicillin/streptomycin (P/S) (0.5%, VWR), incubated at 37°C, 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…Cells dissociated with Accutase on Day 15 of differentiation, and with MACS Multi-tissue dissociation kit 3 (Miltenyi Biotec Ca No. 130-110-204) at day 30 and 50, along with corresponding 2D controls were analysed by Beckman Coulter MoFlow Astrios Cell Sorter (Beckman Coulter Life Sciences) as described previously 96,104 , with CD90-APC, TNNT2-FITC antibodies, and their corresponding unstained controls( Supplementary table 3). Cell populations were quantified by using FlowJo software V10 (Tree Star).…”

Section: Fluorescent Activated Cell Sorting (Facs)mentioning

confidence: 99%

Generation and Maturation of Human iPSC-derived Cardiac Organoids in Long Term Culture

Ergir

Cruz

Fernandes

et al. 2022

Preprint

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Cardiovascular diseases remain the leading cause of death worldwide; hence there is an increasing focus on developing physiologically relevant in vitro cardiovascular tissue models suitable for studying personalized medicine and pre-clinical tests. Despite recent advances, models that reproduce both tissue complexity and maturation are still limited. We have established a scaffold-free protocol to generate multicellular, beating and self-organized human cardiac organoids (hCO) in vitro from hiPSCs that can be cultured for long term. This is achieved by differentiation of hiPSC in 2D monolayer culture towards cardiovascular lineage, followed by further aggregation on low-attachment culture dishes in 3D. The generated human cardiac organoids (hCOs) containing multiple cell types that physiologically compose the heart, gradually self-organize and beat without external stimuli for more than 50 days. We have shown that 3D hCOs display improved cardiac specification, survival and maturation as compared to standard monolayer cardiac differentiation. We also confirmed the functionality of hCOs by their response to cardioactive drugs in long term culture. Furthermore, we demonstrated that hCOs can be used to study chemotherapy-induced cardiotoxicity. This study could help to develop more physiologically-relevant cardiac tissue models, and represent a powerful platform for future translational research in cardiovascular biology.

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“…The properties of YAP are diversified by multiple mRNA splice variants. Eight YAP protein isoforms have been characterized—the main differences are the presence of one or two WW domains, and the presence of an intact or disrupted leucine zipper domain, which mediates interaction with TAZ and pro-oncogenic phosphatase SHP2 [ 16 , 17 , 18 ]. The retention of the leucine zipper was shown to be influenced by oncogenic KRAS regulation of splicing factor SRSF3 [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…These differences afforded the isoforms distinct interacting partners and transcriptional activities in regulating cell proliferation, differentiation and oncogenic potential. YAP isoforms are differentially expressed based on cell type, as well as levels of pluripotency and differentiation [ 17 ]. TAZ possesses one WW domain [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

The Multiple Interactions of RUNX with the Hippo–YAP Pathway

Chuang

Ito

2021

Cells

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The Hippo–YAP signaling pathway serves roles in cell proliferation, stem cell renewal/maintenance, differentiation and apoptosis. Many of its functions are central to early development, adult tissue repair/regeneration and not surprisingly, tumorigenesis and metastasis. The Hippo pathway represses the activity of YAP and paralog TAZ by modulating cell proliferation and promoting differentiation to maintain tissue homeostasis and proper organ size. Similarly, master regulators of development RUNX transcription factors have been shown to play critical roles in proliferation, differentiation, apoptosis and cell fate determination. In this review, we discuss the multiple interactions of RUNX with the Hippo–YAP pathway, their shared collaborators in Wnt, TGFβ, MYC and RB pathways, and their overlapping functions in development and tumorigenesis.

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Evidence for discrete modes of YAP1 signaling via mRNA splice isoforms in development and diseases

Cited by 16 publications

References 76 publications

The mechanical regulation of RNA binding protein hnRNPC in the failing heart

The mechanical regulation of RNA binding protein hnRNPC in the failing heart

Generation and Maturation of Human iPSC-derived Cardiac Organoids in Long Term Culture

The Multiple Interactions of RUNX with the Hippo–YAP Pathway

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