No abstract

No abstract

Mirror self-recognition is a hallmark of higher intelligence in humans. Most children recognize themselves in the mirror by 2 years of age. In contrast to human and some great apes, monkeys have consistently failed the standard mark test for mirror self-recognition in all previous studies. Here, we show that rhesus monkeys could acquire mirror-induced self-directed behaviors resembling mirror self-recognition following training with visual-somatosensory association. Monkeys were trained on a monkey chair in front of a mirror to touch a light spot on their faces produced by a laser light that elicited an irritant sensation. After 2-5 weeks of training, monkeys had learned to touch a face area marked by a non-irritant light spot or odorless dye in front of a mirror and by a virtual face mark on the mirroring video image on a video screen. Furthermore, in the home cage, five out of seven trained monkeys showed typical mirror-induced self-directed behaviors, such as touching the mark on the face or ear and then looking at and/or smelling their fingers, as well as spontaneously using the mirror to explore normally unseen body parts. Four control monkeys of a similar age that went through mirror habituation but had no training of visual-somatosensory association did not pass any mark tests and did not exhibit mirror-induced self-directed behaviors. These results shed light on the origin of mirror self-recognition and suggest a new approach to studying its neural mechanism.

BackgroundThe hierarchical organization of eukaryotic chromatin plays a central role in gene regulation, by controlling the extent to which the transcription machinery can access DNA. The histone variants H3.3 and H2A.Z have recently been identified as key regulatory players in this process, but the underlying molecular mechanisms by which they permit or restrict gene expression remain unclear. Here, we investigated the regulatory function of H3.3 and H2A.Z on chromatin dynamics and Polycomb-mediated gene silencing.ResultsOur ChIP-seq analysis reveals that in mouse embryonic stem (mES) cells, H3K27me3 enrichment correlates strongly with H2A.Z. We further demonstrate that H2A.Z promotes PRC2 activity on H3K27 methylation through facilitating chromatin compaction both in vitro and in mES cells. In contrast, PRC2 activity is counteracted by H3.3 through impairing chromatin compaction. However, a subset of H3.3 may positively regulate PRC2-dependent H3K27 methylation via coordinating depositions of H2A.Z to developmental and signaling genes in mES cells. Using all-trans retinoic acid (tRA)-induced gene as a model, we show that the dynamic deposition of H2A.Z and H3.3 coordinately regulates the PRC2-dependent H3K27 methylation by modulating local chromatin structure at the promoter region during the process of turning genes off.ConclusionsOur study provides key insights into the mechanism of how histone variants H3.3 and H2A.Z function coordinately to finely tune the PRC2 enzymatic activity during gene silencing, through promoting or impairing chromosome compaction respectively.Electronic supplementary materialThe online version of this article (10.1186/s12915-018-0568-6) contains supplementary material, which is available to authorized users.

Mirror self-recognition (MSR) is generally considered to be an intrinsic cognitive ability found only in humans and a few species of great apes. Rhesus monkeys do not spontaneously show MSR, but they have the ability to use a mirror as an instrument to find hidden objects. The mechanism underlying the transition from simple mirror use to MSR remains unclear. Here we show that rhesus monkeys could show MSR after learning precise visualproprioceptive association for mirror images. We trained headfixed monkeys on a chair in front of a mirror to touch with spatiotemporal precision a laser pointer light spot on an adjacent board that could only be seen in the mirror. After several weeks of training, when the same laser pointer light was projected to the monkey's face, a location not used in training, all three trained monkeys successfully touched the face area marked by the light spot in front of a mirror. All trained monkeys passed the standard face mark test for MSR both on the monkey chair and in their home cage. Importantly, distinct from untrained control monkeys, the trained monkeys showed typical mirror-induced self-directed behaviors in their home cage, such as using the mirror to explore normally unseen body parts. Thus, bodily self-consciousness may be a cognitive ability present in many more species than previously thought, and acquisition of precise visual-proprioceptive association for the images in the mirror is critical for revealing the MSR ability of the animal.mirror self-recognition | rhesus monkey | bodily self-consciousness | visual-proprioceptive association | instrumental mirror use S elf-awareness reflects a form of higher intelligence that could be revealed by mirror self-recognition (MSR) in humans. Testing MSR has become the main approach in studying selfrecognition in animals, and only a few species (1-8) have passed the test. In the standard face mark test for demonstrating MSR, an odorless nonirritant dye is placed on the face of the subject (without the subject's awareness) that can only be seen in the mirror. Humans and several species of great apes could pass the test by touching the dye mark after seeing themselves in the mirror. However, it remains unclear whether failing the MSR test is a result of the lack of an animal's self-recognition ability or the inadequacy of the mirror test to reveal this ability (9). Previous studies on several species of monkeys have shown that although monkeys could not pass the mark test, they were capable of using the mirror as an instrument to find hidden objects with or without training (10-15). This has led to the view that instrumental mirror use and MSR represent two distinct levels of cognitive abilities. In our previous study, we found that some rhesus monkeys could pass various forms of the mark test after visual-somatosensory training, indicating the monkey's ability to learn MSR. This led to the present study of the mechanism underlying the transition from the simple instrumental use of the mirror to MSR in rhesus monkeys. We found that mirr...

Intratumor heterogeneity (ITH) of bladder cancer (BLCA) facilitates therapy resistance and immune evasion to affect clinical prognosis directly. However, the molecular and cellular mechanism generating ITH in BLCA remains elusive. Here we show that a TM4SF1-positive cancer subpopulation (TPCS) drives ITH diversification in BLCA. By extensive profiling of the epigenome and transcriptome of BLCA from 79 donors across all stages, we elucidated the evolution trajectories of luminal and basal BLCA. TPCS emerges from the basal trajectory and shows extensive transcriptional plasticity with a distinct epigenomic landscape. Clinically, TPCS were enriched in advanced stage patients and associated with poor prognosis. Our results showed how cancer adapts to its environment by adopting a stem cell-like epigenomic landscape.

Long non-coding RNA metastasis associated with lung adenocarcinoma transcript 1 (MALAT1) contributes to chemotherapy resistance in some cancers, but the role of MALAT1 in sunitinib (SU) chemoresistance of carcinoma (RCC) is still unknown. In this study, MALAT1 expression in SUresistance tumor tissues and cells was tested by qRT-PCR. Then, CCK-8, Annexin V-FITC/PI, transwell, and Western blotting assays were used to evaluate cell viability and IC50, apoptosis, cell invasion, and resistance of SU-resistance RCC cells after transfected with small interfering RNA against MALAT1. Further, RNA pull-down and luciferase reporter assay were applied to investigate the underlying mechanism of MALAT1 in SU resistance. The results showed that MALAT1 expression was dramatically upregulated in SU-resistance RCC tissues and cell lines. Knockdown of MALAT1 inhibited proliferation, invasion, and SU chemoresistance, but induced apoptosis in RCC cells. The results of RNA pull-down and luciferase reporter assay indicated that MALAT1 could interact with miR-362-3p and miR-362-3p interact with RasGAP SH3-domain-Binding Protein 1 (G3BP1). Moreover, G3BP1 also played a role in SU chemoresistance of RCC cells, and MALAT1 could perform as a miR-362-3p sponge to modulate G3BP1 expression. Rescue experiments suggested that downregulation of miR-362-3p and overexpression of G3BP1 can reverse the SU chemosensitivity of MALAT1 knockdown in RCC cells. In conclusion, depletion of LncRNA MALAT1 inhibited SU chemoresistance through modulating G3BP1 via sponging miR-362-3p in RCC cells, suggesting that targeting MALAT1 may be a potential therapeutic strategy for SU-resistance RCC.

No abstract