BEND3 safeguards pluripotency by repressing differentiation-associated genes.

BEN domain-containing proteins are emerging rapidly as an important class of factors involved in modulating gene expression, yet the molecular basis of how they regulate chromatin function and transcription remains to be established. BEND3 is a quadruple BEN domain-containing protein that associates with heterochromatin and functions as a transcriptional repressor. We find that BEND3 is highly expressed in pluripotent cells, and the induction of differentiation results in the down-regulation of BEND3. The removal of BEND3 from pluripotent cells results in cells exhibiting upregulation of the differentiation-inducing gene expression signature. We find that BEND3 binds to the promoters of differentiation-associated factors and key cell cycle regulators, including CDKN1A, encoding the cell cycle inhibitor p21, and represses the expression of differentiation-associated genes by enhancing H3K27me3 decoration at these promoters. Our results support a model in which transcription repression mediated by BEND3 is essential for normal development and to prevent differentiation.

LncRNA-mediated regulation of SOX9 expression in basal subtype breast cancer cells.

Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer (BC) subtypes with a poor prognosis and high recurrence rate. Recent studies have identified vital roles played by several lncRNAs (long noncoding RNAs) in BC pathobiology. Cell type-specific expression of lncRNAs and their potential role in regulating the expression of oncogenic and tumor suppressor genes have made them promising cancer drug targets. By performing a transcriptome screen in an isogenic TNBC/basal subtype BC progression cell line model, we recently reported ∼1800 lncRNAs that display aberrant expression during breast cancer progression. Mechanistic studies on one such nuclear-retained lncRNA, linc02095, reveal that it promotes breast cancer proliferation by facilitating the expression of oncogenic transcription factor, SOX9. Both linc02095 and SOX9 display coregulated expression in BC patients as well in basal subtype BC cell lines. Knockdown of linc02095 results in decreased BC cell proliferation, whereas its overexpression promotes cells proliferation. Linc02095-depleted cells display reduced expression of SOX9 concomitant with reduced RNA polymerase II occupancy at the SOX9 gene body as well as defective SOX9 mRNA export, implying that linc02095 positively regulates SOX9 transcription and mRNA export. Finally, we identify a positive feedback loop in BC cells that controls the expression of both linc02095 and SOX9 Thus, our results unearth tumor-promoting activities of a nuclear lncRNA linc02095 by facilitating the expression of key oncogenic transcription factor in BC.

Antagonism between splicing and microprocessor complex dictates the serum-induced processing of lnc-MIRHG for efficient cell cycle reentry.

Cellular quiescence and cell cycle reentry regulate vital biological processes such as cellular development and tissue homeostasis and are controlled by precise regulation of gene expression. The roles of long noncoding RNAs (lncRNAs) during these processes remain to be elucidated. By performing genome-wide transcriptome analyses, we identify differential expression of several hundreds of lncRNAs, including a significant number of the less-characterized class of microRNA-host-gene (MIRHG) lncRNAs or lnc-MIRHGs, during cellular quiescence and cell cycle reentry in human diploid fibroblasts. We observe that MIR222HG lncRNA displays serum-stimulated RNA processing due to enhanced splicing of the host nascent pri-MIR222HG transcript. The pre-mRNA splicing factor SRSF1 negatively regulates the microprocessor-catalyzed cleavage of pri-miR-222, thereby increasing the cellular pool of the mature MIR222HG Association of SRSF1 to pri-MIR222HG, including to a mini-exon, which partially overlaps with the primary miR-222 precursor, promotes serum-stimulated splicing over microRNA processing of MIR222HG Further, we observe that the increased levels of spliced MIR222HG in serum-stimulated cells promote the cell cycle reentry post quiescence in a microRNA-independent manner. MIR222HG interacts with DNM3OS, another lncRNA whose expression is elevated upon serum-stimulation, and promotes cell cycle reentry. The double-stranded RNA binding protein ILF3/2 complex facilitates MIR222HG:DNM3OS RNP complex assembly, thereby promoting DNM3OS RNA stability. Our study identifies a novel mechanism whereby competition between the splicing and microprocessor machinery modulates the serum-induced RNA processing of MIR222HG, which dictates cell cycle reentry.

Nuclear Long Noncoding RNAs: Key Regulators of Gene Expression.

A significant portion of the human genome encodes genes that transcribe long nonprotein-coding RNAs (lncRNAs). A large number of lncRNAs localize in the nucleus, either enriched on the chromatin or localized to specific subnuclear compartments. Nuclear lncRNAs participate in several biological processes, including chromatin organization, and transcriptional and post-transcriptional gene expression, and also act as structural scaffolds of nuclear domains. Here, we highlight recent studies demonstrating the role of lncRNAs in regulating gene expression and nuclear organization in mammalian cells. In addition, we update current knowledge about the involvement of the most-abundant and conserved lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), in gene expression control.

MIR100 host gene-encoded lncRNAs regulate cell cycle by modulating the interaction between HuR and its target mRNAs.

Long non-coding RNAs (lncRNAs) regulate vital biological processes, including cell proliferation, differentiation and development. A subclass of lncRNAs is synthesized from microRNA (miRNA) host genes (MIRHGs) due to pre-miRNA processing, and are categorized as miRNA-host gene lncRNAs (lnc-miRHGs). Presently, the cellular function of most lnc-miRHGs is not well understood. We demonstrate a miRNA-independent role for a nuclear-enriched lnc-miRHG in cell cycle progression. MIR100HG produces spliced and stable lncRNAs that display elevated levels during the G1 phase of the cell cycle. Depletion of MIR100HG-encoded lncRNAs in human cells results in aberrant cell cycle progression without altering the levels of miRNA encoded within MIR100HG. Notably, MIR100HG interacts with HuR/ELAVL1 as well as with several HuR-target mRNAs. Further, MIR100HG-depleted cells show reduced interaction between HuR and three of its target mRNAs, indicating that MIR100HG facilitates interaction between HuR and target mRNAs. Our studies have unearthed novel roles played by a MIRHG-encoded lncRNA in regulating RNA binding protein activity, thereby underscoring the importance of determining the function of several hundreds of lnc-miRHGs that are present in human genome.

Research on a Cognitive Distraction Recognition Model for Intelligent Driving Systems Based on Real Vehicle Experiments.

The accurate and prompt recognition of a driver's cognitive distraction state is of great significance to intelligent driving systems (IDSs) and human-autonomous collaboration systems (HACSs). Once the driver's distraction status has been accurately identified, the IDS or HACS can actively intervene or take control of the vehicle, thereby avoiding the safety hazards caused by distracted driving. However, few studies have considered the time-frequency characteristics of the driving behavior and vehicle status during distracted driving for the establishment of a recognition model. This study seeks to exploit a recognition model of cognitive distraction driving according to the time-frequency analysis of the characteristic parameters. Therefore, an on-road experiment was implemented to measure the relative parameters under both normal and distracted driving via a test vehicle equipped with multiple sensors. Wavelet packet analysis was used to extract the time-frequency characteristics, and 21 pivotal features were determined as the input of the training model. Finally, a bidirectional long short-term memory network (Bi-LSTM) combined with an attention mechanism (Atten-BiLSTM) was proposed and trained. The results indicate that, compared with the support vector machine (SVM) model and the long short-term memory network (LSTM) model, the proposed model achieved the highest recognition accuracy (90.64%) for cognitive distraction under the time window setting of 5 s. The determination of time-frequency characteristic parameters and the more accurate recognition of cognitive distraction driving achieved in this work provide a foundation for human-centered intelligent vehicles.

Human-Like Obstacle Avoidance Trajectory Planning and Tracking Model for Autonomous Vehicles That Considers the River's Operation Characteristics.

Developing a human-like autonomous driving system has gained increasing amounts of attention from both technology companies and academic institutions, as it can improve the interpretability and acceptance of the autonomous system. Planning a safe and human-like obstacle avoidance trajectory is one of the critical issues for the development of autonomous vehicles (AVs). However, when designing automatic obstacle avoidance systems, few studies have focused on the obstacle avoidance characteristics of human drivers. This paper aims to develop an obstacle avoidance trajectory planning and trajectory tracking model for AVs that is consistent with the characteristics of human drivers' obstacle avoidance trajectory. Therefore, a modified artificial potential field (APF) model was established by adding a road boundary repulsive potential field and ameliorating the obstacle repulsive potential field based on the traditional APF model. The model predictive control (MPC) algorithm was combined with the APF model to make the planning model satisfy the kinematic constraints of the vehicle. In addition, a human driver's obstacle avoidance experiment was implemented based on a six-degree-of-freedom driving simulator equipped with multiple sensors to obtain the drivers' operation characteristics and provide a basis for parameter confirmation of the planning model. Then, a linear time-varying MPC algorithm was employed to construct the trajectory tracking model. Finally, a co-simulation model based on CarSim/Simulink was established for off-line simulation testing, and the results indicated that the proposed trajectory planning controller and the trajectory tracking controller were more human-like under the premise of ensuring the safety and comfort of the obstacle avoidance operation, providing a foundation for the development of AVs.

Human-Like Lane Change Decision Model for Autonomous Vehicles that Considers the Risk Perception of Drivers in Mixed Traffic.

Determining an appropriate time to execute a lane change is a critical issue for the development of Autonomous Vehicles (AVs).However, few studies have considered the rear and the front vehicle-driver's risk perception while developing a human-like lane-change decision model. This paper aims to develop a lane-change decision model for AVs and to identify a two level threshold that conforms to a driver's perception of the ability to safely change lanes with a rear vehicle approaching fast. Based on the signal detection theory and extreme moment trials on a real highway, two thresholds of safe lane change were determined with consideration of risk perception of the rear and the subject vehicle drivers, respectively. The rear vehicle's Minimum Safe Deceleration (MSD) during the lane change maneuver of the subject vehicle was selected as the lane change safety indicator, and was calculated using the proposed human-like lane-change decision model. The results showed that, compared with the driver in the front extreme moment trial, the driver in the rear extreme moment trial is more conservative during the lane change process. To meet the safety expectations of the subject and rear vehicle drivers, the primary and secondary safe thresholds were determined to be 0.85 m/s2 and 1.76 m/s2, respectively. The decision model can help make AVs safer and more polite during lane changes, as it not only improves acceptance of the intelligent driving system, but also further ensures the rear vehicle's driver's safety.

Research on a Pedestrian Crossing Intention Recognition Model Based on Natural Observation Data.

Accurate identification of pedestrian crossing intention is of great significance to the safe and efficient driving of future fully automated vehicles in the city. This paper focuses on pedestrian intention recognition on the basis of pedestrian detection and tracking. A large number of natural crossing sequence data of pedestrians and vehicles are first collected by a laser scanner and HD camera, then 1980 effective crossing samples of pedestrians are selected. Influencing parameter sets of pedestrian crossing intention are then obtained through statistical analysis. Finally, long short-term memory network with attention mechanism (AT-LSTM) model is proposed. Compared with the support vector machine (SVM) model, results show that when the pedestrian crossing intention is recognized 0 s prior to crossing, the recognition accuracy of the AT-LSTM model for pedestrian crossing intention is 96.15%, which is 6.07% higher than that of SVM model; when the pedestrian crossing intention is recognized 0.6 s prior, the recognition accuracy of AT-LSTM model is 90.68%, which is 4.85% higher than that of the SVM model. The determination of pedestrian crossing intention parameter set and the more accurate recognition of pedestrian intention provided in this work provide a foundation for future fully automated driving vehicles.

Quantitative analysis of multilayer organization of proteins and RNA in nuclear speckles at super resolution.

Nuclear speckles are self-assembled organelles composed of RNAs and proteins. They are proposed to act as structural domains that control distinct steps in gene expression, including transcription, splicing and mRNA export. Earlier studies identified differential localization of a few components within the speckles. It was speculated that the spatial organization of speckle components might contribute directly to the order of operations that coordinate distinct processes. Here, by performing multi-color structured illumination microscopy, we characterized the multilayer organization of speckles at a higher resolution. We found that SON and SC35 (also known as SRSF2) localize to the central region of the speckle, whereas MALAT1 and small nuclear (sn)RNAs are enriched at the speckle periphery. Coarse-grained simulations indicate that the non-random organization arises due to the interplay between favorable sequence-encoded intermolecular interactions of speckle-resident proteins and RNAs. Finally, we observe positive correlation between the total amount of RNA present within a speckle and the speckle size. These results imply that speckle size may be regulated to accommodate RNA accumulation and processing. Accumulation of RNA from various actively transcribed speckle-associated genes could contribute to the observed speckle size variations within a single cell.

p21-Activated kinase 2 (PAK2) inhibits TGF-ß signaling in Madin-Darby canine kidney (MDCK) epithelial cells by interfering with the receptor-Smad interaction.

TGF-ß (transforming growth factor ß) plays a variety of cellular functions mainly through the Smad pathway. Phosphorylation of the carboxyl SXS motif in R-Smads (Smad2 and Smad3) by the type I receptor TßRI is a key step for their activation. It has been reported that the serine/threonine kinase PAK2 (p21-activated kinase 2) can mediate TGF-ß signaling in mesenchymal cells. Here, we report that PAK2 restricts TGF-ß-induced Smad2/3 activation and transcriptional responsiveness in MDCK epithelial cells. Mechanistically, PAK2 associates with Smad2 and Smad3 in a kinase activity-dependent manner and blocks their activation. PAK2 phosphorylates Smad2 at Ser-417, which is adjacent to the L3 loop that contributes to the TßRI-R-Smad association. Consistently, substitution of Ser-417 with glutamic acid attenuates the interaction of Smad2 with TßRI. Together, our results indicate that PAK2 negatively modulate TGF-ß signaling by attenuating the receptor-Smad interaction and thus Smad activation.

Insight into regulation of adventitious root formation by arbuscular mycorrhizal fungus and exogenous auxin in tea plant (Camellia sinensis L.) cuttings.

Introduction: Adventitious root (AR) development, affected by various biotic and abiotic factors, is the most important procedure in tea plant (Camellia sinensis L.) cutting propagation. Establishing symbiotic relationships with most terrestrial plants, AMF (Arbuscular mycorrhizal fungus) can mediate the AR formation of several herbaceous and woody plants in previous studies. Methods: In this paper, effects of combined application of AMF and exogenous auxin on AR formation of cuttings from different tea plant varieties ('Pingyangtezao', 'Longjing 43' and 'Longjingchangye') were studied. Then we also performed RNA-Seq analysis with 'Pingyangtezao' cuttings aiming to find the possible auxin-related pathway of AM fungal regulation on AR formation. To accurately uncover the regulatory mechanism of AMF on AR formation of tea cuttings, rooting process were separated into four stages (S0, non-rooting; S1, AR protrusion; S2, AR formation and S3, AR elongation) at the same sampling time. Results and Discussion: Results showed that IBA treatment increased the mycorrhizal colonization rate, especially in 'Pingyangtezao' variety (from 37.58% to 46.29%). Both inoculating AMF and addition of IBA promoted the AR formation, and rooting of different tea plant varieties showed different dependence on auxin. AMF could alleviate the effect of auxin-related inhibitors (2,3,5-triiodobenzoic acid, L-α-(Aminooxy)-ß-phenylpropionic acid and α-(phenylethyl-2-oxo)-IAA) on rooting of tea cuttings, even though the colonization of AMF was hindered at various degrees. Transcriptomic analysis showed that different numbers of differentially expressed genes (DEGs) at various rooting stages of tea cuttings with the most at S2 stage (1360 DEGs), indicating the increasing regulation by AMF with the development of AR. Similar trend was found in auxin-related DEGs, and family genes of YUC, GH, PIN, LAX, SAUR, AUX, and ABP involved in the AM fungal regulation on AR formation of tea cuttings. Additionally, AMF strongly mediated auxin transport and signal transduction pathways in tea cuttings as showed by the results of correlation analysis. Overall, interaction of AMF and exogenous auxin in promoting rooting and the preliminary mechanism of AMF regulating AR formation of tea cuttings was deciphered in this paper, which may provide a basis for further deep mechanistic research and cutting propagation of tea production.

Arbuscular mycorrhizal fungus alleviates anthracnose disease in tea seedlings.

Tea has been gaining increasing popularity all over the world in recent years, and its yield and quality depend on the growth and development of tea plants [Camellia sinensis (L.) Kuntze] in various environments. Nowadays, biotic stress and extreme weather, such as high temperature, drought, waterlogging, pests, and diseases, bring about much pressure on the production of tea with high quality. Wherein anthracnose, which is the most common and serious disease of tea plants, has earned more and more attention, as its control mainly relies on chemical pesticides. Arbuscular mycorrhizal fungi (AMF), forming symbiosis with most terrestrial plants, participate in plant resistance against the anthracnose disease, which was found by previous studies in a few herbaceous plants. However, there are a few studies about arbuscular mycorrhizal (AM) fungal regulation of the resistance to the anthracnose pathogen in woody plants so far. In this paper, we investigated the effect of AMF on the development of anthracnose caused by Colletotrichum camelliae and tried to decipher the pertinent mechanism through transcriptome analysis. Results showed that inoculating AMF significantly reduced the damage of anthracnose on tea seedlings by reducing the lesion area by 35.29% compared to that of the control. The content of superoxide anion and activities of catalase and peroxidase significantly increased (P < 0.05) in mycorrhizal treatment in response to the pathogen with 1.23, 2.00, and 1.39 times higher, respectively, than those in the control. Pathways of plant hormone signal transduction, mitogen-activated protein kinase (MAPK) signaling, and phenylpropanoid biosynthesis might play roles in this regulation according to the transcriptomic results. Further redundancy analysis (RDA) and partial least squares structural equation modeling (PLS-SEM) analysis found that plant hormones, such as auxin and ethylene, and the antioxidant system (especially peroxidase) were of great importance in the AM fungal alleviation of anthracnose. Our results preliminarily indicated the mechanisms of enhanced resistance in mycorrhizal tea seedlings to the anthracnose pathogen and provided a theoretical foundation for the application of AMF as one of the biological control methods in tea plantations.

One locus with two roles: microRNA-independent functions of microRNA-host-gene locus-encoded long noncoding RNAs.

Long noncoding RNAs (lncRNAs) are RNA transcripts longer than 200 nucleotides that do not code for proteins. LncRNAs play crucial regulatory roles in several biological processes via diverse mechanisms and their aberrant expression is associated with various diseases. LncRNA genes are further subcategorized based on their relative organization in the genome. MicroRNA (miRNA)-host-gene-derived lncRNAs (lnc-MIRHGs) refer to lncRNAs whose genes also harbor miRNAs. There exists crosstalk between the processing of lnc-MIRHGs and the biogenesis of the encoded miRNAs. Although the functions of the encoded miRNAs are usually well understood, whether those lnc-MIRHGs play independent functions are not fully elucidated. Here, we review our current understanding of lnc-MIRHGs, including their biogenesis, function, and mechanism of action, with a focus on discussing the miRNA-independent functions of lnc-MIRHGs, including their involvement in cancer. Our current understanding of lnc-MIRHGs strongly indicates that this class of lncRNAs could play important roles in basic cellular events as well as in diseases. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs.

Arbuscular Mycorrhizal Fungus Alters Root System Architecture in Camellia sinensis L. as Revealed by RNA-Seq Analysis.

Arbuscular mycorrhizal fungus (AMF), forming symbiosis with most terrestrial plants, strongly modulates root system architecture (RSA), which is the main characteristic of root in soil, to improve plant growth and development. So far, the studies of AMF on tea plant seedlings are few and the relevant molecular mechanism is not deciphered. In this study, the 6-month-old cutting seedlings of tea plant cultivar "Wancha No.4" were inoculated with an AMF isolate, Rhizophagus intraradices BGC JX04B and harvested after 6 months of growth. The indexes of RSA and sugar contents in root were determined. The transcriptome data in root tips of mycorrhizal and non-mycorrhizal cutting seedlings were obtained by RNA-sequence (Seq) analysis. The results showed that AMF significantly decreased plant growth, but increased the sucrose content in root and the higher classes of lateral root (LR) formation (third and fourth LR). We identified 2047 differentially expressed genes (DEGs) based on the transcriptome data, and DEGs involved in metabolisms of phosphorus (42 DEGs), sugar (39), lipid (67), and plant hormones (39) were excavated out. Variation partitioning analysis showed all these four categories modulated the RSA. In phosphorus (P) metabolism, the phosphate transport and release (DEGs related to purple acid phosphatase) were promoted by AMF inoculation, while DEGs of sugar transport protein in sugar metabolism were downregulated. Lipid metabolism might not be responsible for root branching but for AMF propagation. With respect to phytohormones, DEGs of auxin (13), ethylene (14), and abscisic acid (5) were extensively affected by AMF inoculation, especially for auxin and ethylene. The further partial least squares structural equation modeling analysis indicated that pathways of P metabolism and auxin, as well as the direct way of AMF inoculation, were of the most important in AMF promoting root branching, while ethylene performed a negative role. Overall, our data revealed the alterations of genome-wide gene expression in tea plant roots after inoculation with AMF and provided a molecular basis for the regulatory mechanism of RSA (mainly root branching) changes induced by AMF.

Analysis of Pedestrian Street-Crossing Decision-Making Based on Vehicle Deceleration-Safety Gap.

Numerous traffic crashes occur every year on zebra crossings in China. Pedestrians are vulnerable road users who are usually injured severely or fatally during human-vehicle collisions. The development of an effective pedestrian street-crossing decision-making model is essential to improving pedestrian street-crossing safety. For this purpose, this paper carried out a naturalistic field experiment to collect a large number of vehicle and pedestrian motion data. Through interviewed with many pedestrians, it is found that they pay more attention to whether the driver can safely brake the vehicle before reaching the zebra crossing. Therefore, this work established a novel decision-making model based on the vehicle deceleration-safety gap (VD-SGM). The deceleration threshold of VD-SGM was determined based on signal detection theory (SDT). To verify the performance of VD-SGM proposed in this work, the model was compared with the Raff model. The results show that the VD-SGM performs better and the false alarm rate is lower. The VD-SGM proposed in this work is of great significance to improve pedestrians' safety. Meanwhile, the model can also increase the efficiency of autonomous vehicles.

What is the difference between perceived and actual risk of distracted driving? A field study on a real highway.

Distracted driving is a leading cause of traffic accidents. It is influenced by driver attitude toward secondary tasks; however, field-based studies on the effects of low-perceived-risk tasks on lateral driving have rarely been reported. A total of 17 experienced non-professional drivers were recruited to participate in two secondary tasks: a cognitive experiment (conversation) and a visual distraction experiment (observation of following vehicles), each representing low-perceived-risk secondary tasks. One-way analysis of variance (ANOVA) was conducted to evaluate the effects of low-perceived-risk tasks on lateral driving performance. ANOVA results indicated that compared with baseline (no task) lateral performance, lane-keeping ability was enhanced during cognitive distractions. In the visual distraction experiment, more than 50% of the distractions required 1-2 s. Lane deviation and its growth rate increased with the duration of distraction. Compared with cognitive distraction, lane deviation increased significantly with visual distraction, and lane-keeping performance was seriously impaired. For low-perceived-risk tasks, visual distractions impaired driving safety more seriously, compared with cognitive distractions, suggesting that drivers misjudge the risks associated with visual tasks. These results can contribute to the design of advanced driving-assistance systems and improve professional driver programs, potentially reducing the frequency of traffic accidents caused by distracted driving.

ORCA/LRWD1 Regulates Homologous Recombination at ALT-Telomeres by Modulating Heterochromatin Organization.

Telomeres are maintained by telomerase or in a subset of cancer cells by a homologous recombination (HR)-based mechanism, Alternative Lengthening of Telomeres (ALT). The mechanisms regulating telomere-homeostasis in ALT cells remain unclear. We report that a replication initiator protein, Origin Recognition Complex-Associated (ORCA/LRWD1), by localizing at the ALT-telomeres, modulates HR activity. ORCA's localization to the ALT-telomeres is facilitated by its interaction to SUMOylated shelterin components. The loss of ORCA in ALT-positive cells elevates the levels of two mediators of HR, RPA and RAD51, and consistent with this, we observe increased ALT-associated promyelocytic leukemia body formation and telomere sister chromatid exchange. ORCA binds to RPA and modulates the association of RPA to telomeres. Finally, the loss of ORCA causes global chromatin decondensation, including at the telomeres. Our results demonstrate that ORCA acts as an inhibitor of HR by modulating RPA binding to ssDNA and inducing chromatin compaction.

The S-phase-induced lncRNA SUNO1 promotes cell proliferation by controlling YAP1/Hippo signaling pathway.

Cell cycle is a cellular process that is subject to stringent control. In contrast to the wealth of knowledge of proteins controlling the cell cycle, very little is known about the molecular role of lncRNAs (long noncoding RNAs) in cell-cycle progression. By performing genome-wide transcriptome analyses in cell-cycle-synchronized cells, we observed cell-cycle phase-specific induction of >2000 lncRNAs. Further, we demonstrate that an S-phase-upregulated lncRNA, SUNO1, facilitates cell-cycle progression by promoting YAP1-mediated gene expression. SUNO1 facilitates the cell-cycle-specific transcription of WTIP, a positive regulator of YAP1, by promoting the co-activator, DDX5-mediated stabilization of RNA polymerase II on chromatin. Finally, elevated SUNO1 levels are associated with poor cancer prognosis and tumorigenicity, implying its pro-survival role. Thus, we demonstrate the role of a S-phase up-regulated lncRNA in cell-cycle progression via modulating the expression of genes controlling cell proliferation.

A small protein encoded by a putative lncRNA regulates apoptosis and tumorigenicity in human colorectal cancer cells.

Long noncoding RNAs (lncRNAs) are often associated with polysomes, indicating coding potential. However, only a handful of endogenous proteins encoded by putative lncRNAs have been identified and assigned a function. Here, we report the discovery of a putative gastrointestinal-tract-specific lncRNA (LINC00675) that is regulated by the pioneer transcription factor FOXA1 and encodes a conserved small protein of 79 amino acids which we termed FORCP (FOXA1-Regulated Conserved Small Protein). FORCP transcript is undetectable in most cell types but is abundant in well-differentiated colorectal cancer (CRC) cells where it functions to inhibit proliferation, clonogenicity, and tumorigenesis. The epitope-tagged and endogenous FORCP protein predominantly localizes to the endoplasmic reticulum (ER). In response to ER stress, FORCP depletion results in decreased apoptosis. Our findings on the initial characterization of FORCP demonstrate that FORCP is a novel, conserved small protein encoded by a mis-annotated lncRNA that regulates apoptosis and tumorigenicity in well-differentiated CRC cells.