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The versatility of cellular response arises from the communication, or crosstalk, of signaling pathways in a complex network of signaling and transcriptional regulatory interactions. Understanding the various mechanisms underlying crosstalk on a global scale requires untargeted computational approaches. We present a network-based statistical approach, MuXTalk, that uses high-dimensional edges called multilinks to model the unique ways in which signaling and regulatory interactions can interface. We demonstrate that the signaling-regulatory interface is located primarily in the intermediary region between signaling pathways where crosstalk occurs, and that multilinks can differentiate between distinct signaling-transcriptional mechanisms. Using statistically over-represented multilinks as proxies of crosstalk, we infer crosstalk among 60 signaling pathways, expanding currently available crosstalk databases by more than five-fold. MuXTalk surpasses existing methods in terms of model performance metrics, identifies additions to manual curation efforts, and pinpoints potential mediators of crosstalk. Moreover, it accommodates the inherent context-dependence of crosstalk, allowing future applications to cell type- and disease-specific crosstalk. Show less

The versatility of cellular response arises from the communication, or crosstalk, of signaling pathways in a complex network of signaling and transcriptional regulatory interactions. Understanding the various mechanisms underlying crosstalk on a global scale requires untargeted computational approaches. We present a network-based statistical approach, MuXTalk, that uses high-dimensional edges called multilinks to model the unique ways in which signaling and regulatory interactions can interface. We demonstrate that the signaling-regulatory interface is located Show less

Hydrogen peroxide (H2 O2 ) is an important reactive oxygen species that plays a major role in redox signaling. Although H2 O2 is known to regulate gene expression and affect multiple cellular processes, the characteristics and mechanisms of such transcriptional regulation remain to be defined. In this study, we utilized transcriptome sequencing to determine the global changes of mRNA and lncRNA transcripts induced by H2 O2 in human pancreatic normal epithelial (HPNE) and pancreatic cancer (PANC-1) cells. Promoter analysis using PROMO and TRRUST revealed that mRNAs and lncRNAs largely shared the same sets of transcription factors in response to ROS stress. Interestingly, promoters of the upregulated genes were similar to those of the downregulated transcripts, suggesting that the H2 O2 -responding promoters are conserved but they alone do not determine the levels of transcriptional outputs. We also found that H2 O2 induced significant changes in molecules involved in the pathways of RNA metabolism, processing, and transport. Detailed analyses further revealed a significant difference between pancreatic cancer and noncancer cells in their response to H2 O2 stress, especially in the transcription of genes involved in cell-cycle regulation and DNA repair. Our study provides new insights into RNA transcriptional regulation upon ROS stress in cancer and normal cells. Transcription of mRNA and lncRNA. Antioxidants 2022, 11, 495. https:// Show less

In eukaryotes, three RNA polymerases (RNAPs) play essential roles in the synthesis of various types of RNA: namely, RNAPI for rRNA; RNAPII for mRNA and most snRNAs; and RNAPIII for tRNA and other small RNAs. All three RNAPs possess a short flexible tail derived from their common subunit RPB6. However, the function of this shared N-terminal tail (NTT) is not clear. Here we show that NTT interacts with the PH domain (PH-D) of the p62 subunit of the general transcription/repair factor TFIIH, and present the structures of RPB6 unbound and bound to PH-D by nuclear magnetic resonance (NMR). Using available cryo-EM structures, we modelled the activated elongation complex of RNAPII bound to TFIIH. We also provide evidence that the recruitment of TFIIH to transcription sites through the p62-RPB6 interaction is a common mechanism for transcription-coupled nucleotide excision repair (TC-NER) of RNAPI- and RNAPII-transcribed genes. Moreover, point mutations in the RPB6 NTT cause a significant reduction in transcription of RNAPI-, RNAPII- and RNAPIII-transcribed genes. These and other results show that the p62-RPB6 interaction plays multiple roles in transcription, TC-NER, and cell proliferation, suggesting that TFIIH is engaged in all RNAP systems. Show less

AIMS: Gastro-resistant dimethyl fumarate (DMF) is an oral therapeutic indicated for the treatment of relapsing multiple sclerosis. Recent data suggest that a primary pharmacodynamic response to DMF treatment is activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway; however, the gene targets modulated downstream of NRF2 that contribute to DMF-dependent effects are poorly understood. RESULTS: Using wild-type and NRF2 knockout mice, we characterized DMF transcriptional responses throughout the brain and periphery to understand DMF effects in vivo and to explore the necessity of NRF2 in this process. Our findings identified tissue-specific expression of NRF2 target genes as well as NRF2-dependent and -independent gene regulation after DMF administration. Furthermore, using gene ontology, we identified common biological pathways that may be regulated by DMF and contribute to in vivo functional effects. INNOVATION: Together, these data suggest that DMF modulates transcription through multiple pathways, which has implications for the cytoprotective, immunomodulatory, and clinical properties of DMF. CONCLUSION: These findings provide further understanding of the DMF mechanism of action and propose potential therapeutic targets that warrant further investigation for treating neurodegenerative diseases. Antioxid. Redox Signal. 24, 1058-1071. Show less