Cancer stem cells (CSCs), a minor subpopulation of tumor bulks with self-renewal and seeding capacity to generate new tumors, posit a significant challenge to develop effective and long-lasting anti-cancer therapies. The emergence of drug resistance appears upon failure of chemo-/radiation therapy to eradicate the CSCs, thereby leading to CSC-mediated clinical relapse. Accumulating evidence suggests that transcription factor SOX2, a master regulator of embryonic and induced pluripotent stem cells, drives cancer stemness, fuels tumor initiation, and contributes to tumor aggressiveness through major drug resistance mechanisms like epithelial-to-mesenchymal transition, ATP-binding cassette drug transporters, anti-apoptotic and/or pro-survival signaling, lineage plasticity, and evasion of immune surveillance. Gaining a better insight and comprehensive interrogation into the mechanistic basis of SOX2-mediated generation of CSCs and treatment failure might therefore lead to new therapeutic targets involving CSC-specific anti-cancer strategies.

Three-dimensional chromatin structures undergo dynamic reorganization during mammalian spermatogenesis; however, their impacts on gene regulation remain unclear. Here, we focused on understanding the structure-function regulation of meiotic chromosomes by Hi-C and other omics techniques in mouse spermatogenesis across five stages. Beyond confirming recent reports regarding changes in compartmentalization and reorganization of topologically associating domains (TADs), we further demonstrated that chromatin loops are present prior to and after, but not at, the pachytene stage. By integrating Hi-C and RNA-seq data, we showed that the switching of A/B compartments between spermatogenic stages is tightly associated with meiosis-specific mRNAs and piRNAs expression. Moreover, our ATAC-seq data indicated that chromatin accessibility per se is not responsible for the TAD and loop diminishment at pachytene. Additionally, our ChIP-seq data demonstrated that CTCF and cohesin remain bound at TAD boundary regions throughout meiosis, suggesting that dynamic reorganization of TADs does not require CTCF and cohesin clearance.

Chronic pain causes both physical suffering and comorbid mental symptoms such as anhedonia. However, the neural circuits and molecular mechanisms underlying these maladaptive behaviors remain elusive. Here using a mouse model, we report a pathway from vesicular glutamate transporter 3 neurons in the dorsal raphe nucleus to dopamine neurons in the ventral tegmental area (VGluT3^DRN→DA^VTA) wherein population-level activity in response to innocuous mechanical stimuli and sucrose consumption is inhibited by chronic neuropathic pain. Mechanistically, neuropathic pain dampens VGluT3^DRN → DA^VTA glutamatergic transmission and DA^VTA neural excitability. VGluT3^DRN → DA^VTA activation alleviates neuropathic pain and comorbid anhedonia-like behavior (CAB) by releasing glutamate, which subsequently promotes DA release in the nucleus accumbens medial shell (NAcMed) and produces analgesic and anti-anhedonia effects via D2 and D1 receptors, respectively. In addition, VGluT3^DRN → DA^VTA inhibition produces pain-like reflexive hypersensitivity and anhedonia-like behavior in intact mice. These findings reveal a crucial role for VGluT3^DRN → DA^VTA → D2/D1^NAcMed pathway in establishing and modulating chronic pain and CAB.

In recent years, researches focusing on PIWI-interacting RNAs (piRNAs) have increased rapidly. It has been revealed that piRNAs have strong association with a wide range of diseases; thus, it becomes very important to understand piRNAs’ role(s) in disease diagnosis, prognosis and assessment of treatment response. We searched more than 2500 articles using keywords, such as `PIWI-interacting RNAs’ and `piRNAs’, and further scrutinized the articles to collect piRNAs-disease association data. These data are highly complex and heterogeneous due to various types of piRNA idnetifiers (IDs) and different reference genome versions. We put considerable efforts into removing redundancy and anomalies and thus homogenized the data. Finally, we developed the piRDisease database, which incorporates experimentally supported data for piRNAs’ relationship with wide range of diseases. The piRDisease (piRDisease v1.0) is a novel, comprehensive and exclusive database resource, which provides 7939 manually curated associations of experimentally supported 4796 piRNAs involved in 28 diseases. piRDisease facilitates users by providing detailed information of the piRNA in respective disease, explored by experimental support, brief description, sequence and location information. Considering piRNAs’ role(s) in wide range of diseases, it is anticipated that huge amount of data would be produced in the near future. We thus offer a submitting page, on which users or researches can contribute in to update our piRDisease database.