Filamin Research Articles

Integrated application of Iso-seq and RNA-seq provides insights into unsynchronized growth in red swamp crayfish (Procambarus clarkii)

Red swamp crayfish is one of the most important freshwater shrimps with high economic value in China. The crayfish shows obvious sexual dimorphism in growth and secondary sex characteristics, however, the mechanisms underlying the growth of muscle tissue in the crayfish still remain unclear. Both high-throughput RNA-Seq and Iso-seq strategies were applied to reveal the molecular basis of the growth difference between fast-growing and slow-growing crayfish. After splicing and assembling, 63,350 genes with an average length of 2151 bp and N50 of 2568 bp were obtained. A total of 122 growth-related differentially expressed genes (DEGs) were identified, of which 87 genes were significantly up-regulated and 35 were down-regulated. Using quantitative PCR it was confirmed that the expressions of tps, inpp5l, flna, flnc, tpnc3 and other genes was higher in the fast-growing individuals. Subsequently, 144 genes differentially expressed between males and females were identified. 130 of them, 84 up-regulated and 46 down-regulated, were identified in the fast-growing group, while only 14 genes, 3 up-regulated and 11 down-regulated, were identified in the slow-growing group. The KEGG pathway enrichment analysis indicated that the identified DEGs were mainly involved in metabolic pathways, including arachidonic acid metabolism, glutathione metabolism, alanine, aspartate and glutamate metabolism. This study provides a basis for understanding the molecular mechanism of the sexual growth dimorphism and its application for future genetic breeding in red swamp crayfish.

Filamin A Is Required for NK Cell Cytotoxicity at the Expense of Cytokine Production via Synaptic Filamentous Actin Modulation.

Natural killer (NK) cells are innate cytotoxic lymphocytes that efficiently eliminate malignant and virus-infected cells without prior activation via the directed and focused release of lytic granule contents for target cell lysis. This cytolytic process is tightly regulated at discrete checkpoint stages to ensure the selective killing of diseased target cells and is highly dependent on the coordinated regulation of cytoskeletal components. The actin-binding protein filamin crosslinks cortical actin filaments into orthogonal networks and links actin filament webs to cellular membranes to modulate cell migration, adhesion, and signaling. However, its role in the regulation of NK cell functions remains poorly understood. Here, we show that filamin A (FLNa), a filamin isoform with preferential expression in leukocytes, is recruited to the NK cell lytic synapse and is required for NK cell cytotoxicity through the modulation of conjugate formation with target cells, synaptic filamentous actin (F-actin) accumulation, and cytotoxic degranulation, but not granule polarization. Interestingly, we also find that the loss of FLNa augments the target cell-induced expression of IFN-γ and TNF-α by NK cells, correlating with enhanced activation signals such as Ca2+ mobilization, ERK, and NF-κB, and a delayed down-modulation of the NKG2D receptor. Thus, our results identify FLNa as a new regulator of NK cell effector functions during their decision to kill target cells through a balanced regulation of NK cell cytotoxicity vs cytokine production. Moreover, this study implicates the cross-linking/bundling of F-actin mediated by FLNa as a necessary process coordinating optimal NK effector functions.

Filamin A increases aggressiveness of human neuroblastoma.

BackgroundThe actin-binding protein filamin A (FLNA) regulates oncogenic signal transduction important for tumor growth, but the role of FLNA in the progression of neuroblastoma (NB) has not been explored.MethodsWe analyzed FLNA mRNA expression in the R2 NB-database and FLNA protein expression in human NB tumors. We then silenced FLNA expression in human SKNBE2 and IMR32 NB cells by lentiviral vector encoding shRNA FLNA and assayed the cells for proliferation, migration, colony, spheroid formation, and apoptosis. SKNBE2 xenografts expressing or lacking FLNA in BALB/c nude mice were analyzed by both routine histopathology and immunohistochemistry.ResultsWe observed shorter patient survival with higher expression of FLNA mRNA than patients with lower FLNA mRNA expression, and high-risk NB tumors expressed higher FLNA levels. Overexpression of FLNA increased proliferation of SH-SY5 NB cells. NB cell lines transfected with siRNA FLNA proliferated and migrated less, expressed lower levels of phosphorylated AKT and ERK1/2, formed smaller colonies and spheroids, as well as increased apoptosis. After inoculation of SKNBE2 cells infected with lentivirus expressing shRNA FLNA, size of NB tumors and number of proliferating cells were decreased. Furthermore, we identified STAT3 as an interacting partner of FLNA. Silencing FLNA mRNA reduced levels of NF-κB, STAT3 and MYCN, and increased levels of p53 and cleaved caspase 3.ConclusionInhibition of FLNA impaired NB cell signaling and function and reduced NB tumor size in vivo, suggesting that drugs targeting either FLNA or its interaction with STAT3 may be useful in the treatment of NB.

Filamin A and parafibromin expression in parathyroid carcinoma.

Parathyroid carcinoma (PC), atypical parathyroid tumours (APT) and parathyroid adenoma (PA), all present with hypercalcemia. Diminished calcium-sensing receptor (CaSR) expression is reported in PC but is rare in benign tumours. Filamin A (FLNA) binds to the CaSR and activates the mitogen-activated protein kinase (MAPK) signalling pathway. FLNA is related to tumour aggressiveness in several cancers, but its role in parathyroid neoplasia is unknown. We examined FLNA, CaSR and parafibromin expression in PCs (n = 32), APTs (n = 44) and PAs (n = 77) and investigated their potential as diagnostic and/or prognostic markers. Tissue microarray slides were immunohistochemically stained with antibodies for FLNA, CaSR and parafibromin. Staining results were correlated with detailed clinical data. All tumours stained positively for CaSR, with two tumours (one PC and one APT) showing diminished expression. Carcinomas were characterized by increased cytoplasmic FLNA expression compared to APTs and PAs (P = 0.004). FLNA expression was not correlated with Ki-67 proliferation index or loss of parafibromin expression. Cytoplasmic FLNA expression was also associated with higher serum calcium, PTH concentrations and male sex (P = 0.014, P = 0.017 and P = 0.049 respectively). Using a combined marker score, we found that parathyroid tumours with low FLNA expression and positive parafibromin staining were extremely likely to be benign (P < 0.001). Cytoplasmic and membranous FLNA expression is increased in parathyroid carcinomas compared to benign tumours. A combined FLNA and parafibromin expression score shows potential as a prognostic predictor of indolent behaviour in parathyroid neoplasms.

Two Complementary Signaling Pathways Depict Eukaryotic Chemotaxis: A Mechanochemical Coupling Model.

Many eukaryotic cells, including neutrophils and Dictyostelium cells, are able to undergo correlated random migration in the absence of directional cues while reacting to shallow gradients of chemoattractants with exquisite precision. Although progress has been made with regard to molecular identities, it remains elusive how molecular mechanics are integrated with cell mechanics to initiate and manipulate cell motility. Here, we propose a two dimensional (2D) cell migration model wherein a multilayered dynamic seesaw mechanism is accompanied by a mechanical strain-based inhibition mechanism. In biology, these two mechanisms can be mapped onto the biochemical feedback between phosphoinositides (PIs) and Rho GTPase and the mechanical interplay between filamin A (FLNa) and FilGAP. Cell migration and the accompanying morphological changes are demonstrated in numerical simulations using a particle-spring model, and the diffusion in the cell membrane are simulations using a one dimensional (1D) finite differences method (FDM). The fine balance established between endogenous signaling and a mechanically governed inactivation scheme ensures the endogenous cycle of self-organizing pseudopods, accounting for the correlated random migration. Furthermore, this model cell manifests directional and adaptable responses to shallow graded signaling, depending on the overwhelming effect of the graded stimuli guidance on strain-based inhibition. Finally, the model cell becomes trapped within an obstacle-ridden spatial region, manifesting a shuttle run for local explorations and can chemotactically “escape”, illustrating again the balance required in the complementary signaling pathways.

Abstract 9122: Polyvalvular Heart Disease in Children Associated With FilaminA Mutations

Introduction: FilaminA ( FLNA ), an X-linked gene encoding an actin binding protein, is one of the only known causative genes for periventricular nodular heterotopia (PVNH) and mitral valve (MV) prolapse. FLNA mutations have been well associated with familial MV prolapse and polyvalvular disease in adults. There is limited data, however, on the type and distribution of valve disease in children with FLNA mutations. We aim to assess the frequency of polyvalvular disease in a predominantly pediatric cohort. Methods: We retrospectively enrolled subjects from a large registry at Boston Children’s Hospital of patients and families with PVNH and FLNA mutations with at least one transthoracic echo and clinical phenotyping of their cardiovascular and neurologic status. Additionally, data from published subjects with FLNA mutations and PVNH were included in the cohort. Imaging data about valvular heart disease were extracted for all subjects. Results: 165 patients with FLNA mutations formed our cohort (128 F, median age 9 yrs, range 0-71 yrs), with 53% ≤ 21 yrs. Valve disease was the most common type of isolated structural disease, presenting in 58% (62/110) of FLNA patients with congenital heart disease. Of these patients, 45% (28/62, 10 M) had polyvalvular disease and 36% (22/62, 8 M) underwent cardiac surgery. MV prolapse or dysplasia was present in 60% (37/62) of patients. Aortic valve abnormalities were equally common, also occurring in 60% (37/62) of patients (e.g. bicuspid aortic valves and aortic valve prolapse). Notably, tricuspid valve dysplasia did not occur independently (n=0), and always presented with involvement of other cardiac valves. In patients with polyvalvular disease, mitral and aortic valves were most commonly involved together, occurring in 23% (14/62) of patients. Males with FLNA mutations were more likely to have polyvalvular disease with more severe clinical phenotypes. Conclusions: In this largest cohort of predominantly children with FLNA mutations, FLNA patients frequently have polyvalvular disease on echocardiography. When polyvalvular disease is detected especially involving the tricuspid valve, pediatric cardiologists should consider genetic testing for FLNA mutations as a potential contributor of disease.

Targeting Filamin A alleviates ovariectomy-induced bone loss in mice via the WNT/β-catenin signaling pathway

Osteoporosis (OP) is a worldwide prevalent chronic metabolic bone disease, causing by a disruption of the balance between bone resorption and formation. Estrogen deficiency and aging are the main causes for disturbances in bone remodeling activity and bone loss, however, the mechanisms underlying bone remodeling regulation require clarification if novel targets for OP treatment are to be identified. In this investigation, we showed that filamin A (FLNA) accumulated in osteoblasts (OBs) and osteoclasts (OC) in bone from human OP samples, and mice with age-related and postmenopausal OP. FLNA negatively modulated in vitro osteogenic differentiation and positively promoted RANKL-induced osteoclastic differentiation. Mechanistically, FLNA interacted with low-density lipoprotein receptor-related proteins 6 (LRP6) to inhibit β-catenin expression, and enhanced nuclear factor of activated T cell c1 (NFATc1)-dependent osteoclastogenic gene expression to inhibit osteogenesis, and promote osteoclastogenesis. Inhibiting FLNA with calpeptin activated WNT/β-catenin signaling, resulting in prominent protective effects of bone loss in ovariectomy (OVX)-induced postmenopausal OP mice. Our findings revealed that FLNA not only participated in OP pathogenesis, but could be a new target to stimulate bone formation and inhibit bone resorption. Targeting FLNA with calpeptin may be a promising therapeutic approach for postmenopausal OP in the future.

A fertilin-derived peptide improves in vitro maturation and ploidy of human oocytes

To analyze the effect of a cyclic fertilin-derived peptide (cFEE) on invitro maturation of human oocytes. Randomized study. Fertility center in an academic hospital. Not applicable. Human immature germinal vesicle-stage oocytes (n = 1,629) donated for research according to French bioethics laws were randomly allocated to groups treated with 1 or 100 μM of cFEE or to a control group. They were incubated at 37 °C in 6% CO2 and 5% O2, and their maturation was assessed using time-lapse microscopy over 24 hours. Invitro maturated metaphase II oocytes were analyzed for chromosomal content using microarray comparative genomic hybridization, and their transcriptomes were analyzed using Affymetrix Clariom D microarrays. The percentage of oocytes undergoing maturation invitro was observed. Aneuploidy and euploidy were assessed for all chromosomes, and differential gene expression was analyzed in oocytes treated with cFEE compared with the control to obtain insights into its mechanism of action. cFEE significantly increased the percentage of oocytes that matured invitro and improved euploidy in meiosis II oocytes by the up-regulation of FMN1 and FLNA genes, both of which encode proteins involved in spindle structure. cFEE improves human oocyte maturation invitro and reduces aneuploidy. It may prove useful for treating oocytes before fertilization in assisted reproductive technology and for invitro maturation in fertility preservation programs to improve oocyte quality and the chances for infertile couples to conceive.

Application of lung volume reduction surgery for a child with filamin A (FLNA) mutations

Diffuse lung disease in early childhood due to mutations in the filamin A gene has been recently reported. Clinical outcomes vary among individuals indicating variability in phenotype but a substantial proportion of reported cases in early life have ended up in death or lung transplantation. We recently encountered a school-aged child in whom the diagnosis of a filamin A mutation was delayed and the natural history of emphysematous lung disease was altered by serial lung volume reduction surgeries. She eventually underwent a bilateral lung transplant and we report the natural history of her disease and treatments applied herein.

Association between β arrestin 2 and filamin A gene variations with medical treatment response in acromegaly patients.

Acromegaly is a disease that occurs as a result of excessive growth hormone caused by pituitary adenomas. Some acromegaly patients show resistance to somatostatin analog (SSA) treatment. Filamin-A (FLNA) and β-arrestins are thought to play a role in the response to SSAs. We aimed to investigate the relationship between FLNA-rs782079491 and β-arrestin-2-rs34230287 single-nucleotide polymorphisms and disease risk, as well as treatment response in patients with acromegaly in the Turkish population. The genotypes of 110 acromegaly patients and 99 controls were determined by realtime PCR. The genotype distributions were compared with clinical data on the disease. There was no association between the β-arrestin-2 gene polymorphism and the response to SSA treatment in acromegaly patients. For responder patients to SSAs, the β-arrestin-2-rs34230287 CT+TT genotype was associated with higher microadenoma as compared with the CC genotype (p = 0.017). The FLNA polymorphism was not observed in the study group. We showed that there was no association between the polymorphic genotypes of FLNA and β-arrestin-2 genes with acromegaly disease and SSAs response in the Turkish population. However, there was a relationship between β-arrestin-2 and some of the clinical characteristics. Furthermore, the CC genotype and the C allele are risk factors associated with tumor growth rate in acromegaly patients.

Downregulation of Filamin a Expression in the Aorta Is Correlated With Aortic Dissection.

Filamins (FLNs) are actin cross-linking proteins, and as scaffolding proteins, FLNs are closely associated with the stabilization of the cytoskeleton. Nevertheless, the biological importance of FLNs in aortic dissection (AD) has not been well-elucidated. In this study, we first reanalyzed datasets downloaded from the Gene Expression Omnibus (GEO) database, and we found that in addition to the extracellular matrix, the actin cytoskeleton is a key structure associated with AD. Given that FLNs are involved in remodeling the cytoskeleton to affect cellular functions, we measured their expression levels in the aortas of patients with Stanford type A AD (TAAD). Our results showed that the mRNA and protein levels of FLNA were consistently decreased in dissected aortas of both humans and mice, while the FLNB protein level was upregulated despite decreased FLNB mRNA levels, and comparable expression levels of FLNC were observed between groups. Furthermore, the immunohistochemistry results demonstrated that FLNA was highly expressed in smooth muscle cells (SMCs) of aorta in non-AD samples, and downregulated in the medial layer of the dissected aortas of humans and mice. Moreover, we revealed that FOS and JUN, forming a dimeric transcription factor called AP-1 (activating protein-1), were positively correlated with the expression of FLNA in aorta. Either overexpression of FOS or JUN alone, or overexpression of FOS and JUN together, facilitated the expression of FLNA in primary cultured human aortic SMCs. In the present study, we not only detected the expression pattern of FLNs in aortas of humans and mice with or without AD, but we also found that the expression of FLNA in the AD samples was significantly reduced and that AP-1 might regulate the expression of FLNA. Our findings will contribute to the elucidation of the pathological mechanisms of AD and provide potential therapeutic targets for AD.

Exon skip-inducing variants in FLNA in an attenuated form of frontometaphyseal dysplasia.

Pathogenic variation in the X-linked gene FLNA causes a wide range of human developmental phenotypes. Loss-of-function is usually male embryonic-lethal, and most commonly results in a neuronal migration disorder in affected females. Gain-of-function variants cause a spectrum of skeletal dysplasias that present with variable additional, often distinctive, soft-tissue anomalies in males and females. Here we present two, unrelated, male individuals with novel, intronic variants in FLNA that are predicted to be pathogenic. Their phenotypes are reminiscent of the gain-of-function spectrum without the skeletal manifestations. Most strikingly, they manifest urethral anomalies, cardiac malformations, and keloid scarring, all commonly encountered features of frontometaphyseal dysplasia. Both variants prevent inclusion of exon 40 into the FLNA transcript, predicting the in-frame deletion of 42 amino acids, however the abundance of FLNA protein was equivalent to that observed in healthy individuals. Loss of these 42 amino acids removes sites that mediate key FLNA functions, including binding of some ligands and phosphorylation. This phenotype further expands the spectrum of the FLNA filaminopathies.

New variants in FLNA gene cause periventricular nodular heterotopia and epileptic seizure in three cases

To explore the genetic bases of 3 patients with periventricular nodular heterotopia and epileptic seizure. The clinical data of three patients presenting with periventricular nodular ectopic with epileptic seizure were analyzed. Whole exome sequencing (WES) was performed on the patients, and Sanger sequencing was used to validate the suspected variants. In three female patients, head MRI showed nodular gray matter ectopic in the bilateral ventricle. WES identified the heterozygous c.2720del T(p.Leu907Argfs*39) variant of FLNA gene in case 1 and her mother (case 2), and heterozygous c.1387_1390del GTGC(p.Val463Profs*34) of FLNA gene in case 3. According to the American College of Medical Genetics and Genomics standards and guidelines, the c.2720delT(p.Leu907Argfs*39) and c.1387_1390del GTGC (p.Val463Profs*34) variants of FLNA gene were predicted to be pathogenic (PVS1+PM2+PP1) and likely pathogenic(PVS1+PM2), respectively. The c.2720delT(p.Leu907Argfs*39) and c.1387_1390del GTGC(p.Val463Profs*34) variants of FLNA gene may be the genetic cause of the three patients.

Application of high-throughput sequencing for hereditary thrombocytopenia in southwestern China.

BackgroundThe aim of this study was to design and analyze the applicability of a 21‐gene high‐throughput sequencing (HTS) panel in the molecular diagnosis of patients with hereditary thrombocytopenia (HT).MethodsA custom target enrichment library was designed to capture 21 genes known to be associated with HTs. Twenty‐four patients with an HT phenotype were studied using this technology.ResultsOne pathogenic variant on the MYH9 gene and one likely pathogenic variant on the ABCG8 gene previously known to cause HTs were identified. Additionally, 3 previously reported variants affecting WAS, ADAMTS13, and GP1BA were detected, and 9 novel variants affecting FLNA, ITGB3, NBEAL2, MYH9, VWF, and ANKRD26 genes were identified. The 12 variants were classified to be of uncertain significance.ConclusionOur results demonstrate that HTS is an accurate and reliable method of pre‐screening patients for variants in known HT‐causing genes. With the advantage of distinguishing HT from immune thrombocytopenia, HTS could play a key role in improving the clinical management of patients.

Probing mechanobiological role of filamin A in migration and invasion of human U87 glioblastoma cells using submicron soft pillars

Filamin A (FLNa) belongs to an actin-binding protein family in binding and cross-linking actin filaments into a three-dimensional structure. However, little attention has been given to its mechanobiological role in cancer cells. Here, we quantitatively investigated the role of FLNa by analyzing the following parameters in negative control (NC) and FLNa-knockdown (KD) U87 glioma cells using submicron pillars (900 nm diameter and 2 μm height): traction force (TF), rigidity sensing ability, cell aspect ratio, migration speed, and invasiveness. During the initial phase of cell adhesion (< 1 h), FLNa-KD cells polarized more slowly than did NC cells, which can be explained by the loss of rigidity sensing in FLNa-KD cells. The higher motility of FLNa-KD cells relative to NC cells can be explained by the high TF exerted by FLNa-KD cells when compared to NC cells, while the higher invasiveness of FLNa-KD cells relative to NC cells can be explained by a greater number of filopodia in FLNa-KD cells than in NC cells. Our results suggest that FLNa plays important roles in suppressing motility and invasiveness of U87 cells.

Diseases associated with mutations in the filamin A gene (FLNA)

The article presents literature review of the diseases associated with mutations in the FLNA gene encoding filamin A, which is a cytoskeleton protein with polymorphic functions. The mutations of this gene lead to the damage of the central nervous system (periventricular nodular heterotopy), respiratory organs (emphysema, interstitial lung disease), heart (congenital heart defects and minor heart abnormalities); the listed diseases can be diagnosed at different ages. The information presented in this review can be useful for clinical geneticists, specialists in rare (orphan) diseases, pediatricians, neonatologists, neurologists, epileptologists, pulmonologists, surgeons, cardiologists for timely diagnosis and improvement of medical care for patients requiring a multidisciplinary approach.

Surgical Management of Craniomaxillofacial Features in the Otopalatodigital Spectrum Disorders

Otopalatodigital syndrome spectrum disorders are caused by Filamin A (FLNA) gene mutations. Otopalatodigital syndrome spectrum disorders are a group of rare congenital skeletal dysplasia, with specific craniomaxillofacial features including otopalatodigital syndrome type 1 and type 2, Melnick-Needles syndrome, frontometaphyseal dysplasia, terminal osseous dysplasia with pigmentary defects. The authors describe cases of a young girl with Melnick-Needles syndrome and a young boy with frontometaphyseal dysplasia treated in the Oral and Maxillofacial Surgery Department. Both patients had FLNA gene mutation confirmed with molecular genetic analysis. The authors proposed a 4 step treatment of the malformations with good outcomes both aesthetically and functionally, without complication.

Transcript Expression, Intron Retention, and RNA Editing Are Conserved in Human Platelets over a 4 Year Period

The use of circulating, anucleate platelet RNA signatures has been proposed as a new “liquid biopsy platform” for precision diagnostics. Changes within the platelet transcriptome during disease have also been used to identify the molecular basis of altered platelet phenotypes. Nevertheless, the durability of the platelet transcriptome in health is unknown. To determine the inter- and intra-individual durability of the human platelet transcriptome, we performed next-generation RNA-sequencing (RNA-seq) on purified platelets isolated from the same healthy individuals repeatedly over time (up to 4 years). We analyzed individual transcript expression (e.g. mRNAs) as well as the conservation of Adenosine to Inosine (A to I) RNA editing, and intron retention within and among individuals over time.We initially examined the platelet transcriptome in 31 healthy individuals at visit 1 (time 0) and again 4 months later. Intra-individual durability over this 4 month period among both protein coding and non-coding transcripts was very high (Spearman correlation coefficient [rho] > 0.975), while comparisons between subjects (inter-individual) was significantly lower. The percentage of transcripts with low variability (CV<0.20) over 4 months was significantly higher within subjects (e.g. self-pairs) than among subjects (e.g. random-pairs) (78% vs. 20%, p<0.05). To determine the long-term durability of the platelet transcriptome, we performed RNA-seq in healthy subjects (n=7) studied repeatedly over 4 years. Consistent with short-term findings, we found that intra-individual durability of the human platelet transcriptome remained remarkably high over the 4 year study period. Differentially expressed transcripts specific for gender and age were also highly correlated over 4 years.The protein end products of RNA expression are dictated by RNA features beyond absolute transcript expression. For example, intron retention alters the product and quantity of synthesized protein. Therefore, we assessed the extent and durability of intron retention in human platelets. The extent of intron retention, as measured by individual intron/total exon ratios, was highly durable within the same individual over time. We focused on the mitochondrial superoxide dismutase gene (SOD2), which mediates ROS generation and programmed cell death. Interestingly, retention of intron 5 of SOD2 was common in platelets (35% to 100% retention) and the extent of SOD2 intron retention was highly conserved over time within the same individual (rho 0.88, Figure 1A and 1B). A to I RNA editing also exhibited high durability among self-pairs. Post-transcriptional A to I RNA editing regulates host inflammatory responses to dsRNA, and can alter protein coding regions (I is read as G by polymerases and ribosomes). We examined A to I RNA editing in a protein coding region (Q->R coding change) of Filamin A (FLNA), a cytoskeletal regulator known to undergo RNA editing. FLNA was variably edited among individuals, (18-50% of transcripts) but remarkably durable within the same individuals over time (rho=0.82, Figure 1C and 1D).This is the first prospective, longitudinal study to demonstrate that in health, the human platelet transcriptome is highly durable over a 4-year period. Both protein-coding and non-coding mRNAs exhibited remarkable durability and precise signatures related to gender and age. We also identified for the first time that intron retention and RNA-editing, features of RNA expression that may modulate the platelet proteome, are remarkably conserved in the same individuals over time. These findings support the concept of the human platelet transcriptome as a diagnostic tool for precision medicine. We also suggest the intriguing possibility of using platelet RNA-seq as a reliable window to understand the architecture of human gene expression. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Filamin A Regulates Cardiovascular Remodeling.

Filamin A (FLNA) is a large actin-binding cytoskeletal protein that is important for cell motility by stabilizing actin networks and integrating them with cell membranes. Interestingly, a C-terminal fragment of FLNA can be cleaved off by calpain to stimulate adaptive angiogenesis by transporting multiple transcription factors into the nucleus. Recently, increasing evidence suggests that FLNA participates in the pathogenesis of cardiovascular and respiratory diseases, in which the interaction of FLNA with transcription factors and/or cell signaling molecules dictate the function of vascular cells. Localized FLNA mutations associate with cardiovascular malformations in humans. A lack of FLNA in experimental animal models disrupts cell migration during embryogenesis and causes anomalies, including heart and vessels, similar to human malformations. More recently, it was shown that FLNA mediates the progression of myocardial infarction and atherosclerosis. Thus, these latest findings identify FLNA as an important novel mediator of cardiovascular development and remodeling, and thus a potential target for therapy. In this update, we summarized the literature on filamin biology with regard to cardiovascular cell function.

LXN deficiency regulates cytoskeleton remodelling by promoting proteolytic cleavage of Filamin A in vascular endothelial cells.

Endothelial cells (ECs) respond to blood shear stress by changing their morphology is important for maintaining vascular homeostasis. Studies have documented a relationship between endothelial cell shape and the stress flow, and however, the mechanism underlying this cytoskeletal rearrangement due to shear stress remains uncertain. In this paper, we demonstrate that laminar shear stress (LSS) significantly reduces latexin (LXN) expression in ECs. By using siRNA and cell imaging, we demonstrated that LXN knockdown results in the morphologic change and F‐actin remodelling just like what LSS does in ECs. We further demonstrate that LXN interacts with Filamin A (FLNA) and regulates FLNA proteolytic cleavage and nuclei translocation. By constructing LXN‐/‐ mice and ApoE‐/‐LXN‐/‐ double knockout mice, we evaluated the effect of LXN knockout on aortic endothelium damage in mice. We found that LXN deficiency significantly improves vascular permeability, vasodilation and atherosclerosis in mice. Our findings provide confident evidence, for the first time, that LXN is a novel regulator for morphological maintenance of ECs, and LXN deficiency has a protective effect on vascular homeostasis. This provides new strategies and drug targets for the treatment of vascular diseases.