TAD hierarchy restricts poised LTR activation and loss of TAD hierarchy promotes LTR co-option in cancer.

Transposable elements (TEs) are abundant in the human genome, and they provide the sources for genetic and functional diversity. The regulation of TEs expression and their functional consequences in physiological conditions and cancer development remain to be fully elucidated. Previous studies suggested TEs are repressed by DNA methylation and chromatin modifications. The effect of 3D chromatin topology on TE regulation remains elusive. Here, by integrating transcriptome and 3D genome architecture studies, we showed that haploinsufficient loss of NIPBL selectively activates alternative promoters at the long terminal repeats (LTRs) of the TE subclasses. This activation occurs through the reorganization of topologically associating domain (TAD) hierarchical structures and recruitment of proximal enhancers. These observations indicate that TAD hierarchy restricts transcriptional activation of LTRs that already possess open chromatin features. In cancer, perturbation of the hierarchical chromatin topology can lead to co-option of LTRs as functional alternative promoters in a context-dependent manner and drive aberrant transcriptional activation of novel oncogenes and other divergent transcripts. These data uncovered a new layer of regulatory mechanism of TE expression beyond DNA and chromatin modification in human genome. They also posit the TAD hierarchy dysregulation as a novel mechanism for alternative promoter-mediated oncogene activation and transcriptional diversity in cancer, which may be exploited therapeutically.

Systematic review of the barriers and facilitators to dietary modification in people living with type 2 diabetes and pre-diabetes from South Asian ethnic populations.

AIMS: Lifestyle and dietary modification are effective in the prevention and management of Type 2 diabetes Mellitus (T2DM). However, South Asian (SA) populations living in Western countries have low adherence rates to healthcare advice and experience poor diabetes control and clinical outcomes compared with the general population. This systematic review aimed to summarise the barriers and facilitators of dietary modification within people from South Asian (SA) ethnicity with T2DM or pre-diabetes. METHODS: A systematic search of PubMed, Web of Science and Scopus generated 3739 articles, of which seven were included. Qualitative and quantitative data were inputted utilising COVIDENCE. Qualitative data were analysed by thematic analysis. RESULTS: Thematic analysis identified three facilitators: (1) cultural sensitivity, (2) health education and (3) support networks. Barriers include (1) healthcare inequity, (2) cultural insensitivity, (3) social pressures, (4) misconceptions and (5) time constraints. Good access to health care and motivation were the most common facilitators discussed. Misconceptions on T2DM management and cultural insensitivity contributed to the majority of barriers discussed. CONCLUSIONS: Culturally tailored interventions could improve adherence to diet modification in people with T2DM from SA ethnicity. Interventions involving the application of social media to challenge intergenerational stigmas and misinformation, distributing culturally appropriate resources and providing diets tailored to the SA palate could help.

PRC2-Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1-Targeted Therapy via Enhanced Viral Mimicry.

Polycomb repressive complex 2 (PRC2) has oncogenic and tumor-suppressive roles in cancer. There is clinical success of targeting this complex in PRC2-dependent cancers, but an unmet therapeutic need exists in PRC2-loss cancer. PRC2-inactivating mutations are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with poor prognosis and no effective targeted therapy. Through RNAi screening in MPNST, we found that PRC2 inactivation increases sensitivity to genetic or small-molecule inhibition of DNA methyltransferase 1 (DNMT1), which results in enhanced cytotoxicity and antitumor response. Mechanistically, PRC2 inactivation amplifies DNMT inhibitor-mediated expression of retrotransposons, subsequent viral mimicry response, and robust cell death in part through a protein kinase R (PKR)-dependent double-stranded RNA sensor. Collectively, our observations posit DNA methylation as a safeguard against antitumorigenic cell-fate decisions in PRC2-loss cancer to promote cancer pathogenesis, which can be therapeutically exploited by DNMT1-targeted therapy. SIGNIFICANCE: PRC2 inactivation drives oncogenesis in various cancers, but therapeutically targeting PRC2 loss has remained challenging. Here we show that PRC2-inactivating mutations set up a tumor context-specific liability for therapeutic intervention via DNMT1 inhibitors, which leads to innate immune signaling mediated by sensing of derepressed retrotransposons and accompanied by enhanced cytotoxicity. See related commentary by Guil and Esteller, p. 2020. This article is highlighted in the In This Issue feature, p. 2007.

HSMotifDiscover: identification of motifs in sequences composed of non-single-letter elements.

SUMMARY: The functional sub-string(s) of a biopolymer sequence defines the specificity of its interaction with other biomolecules and is often referred to as motifs. Computational algorithms and software have been broadly developed for finding such motifs in sequences in which the individual elements are single characters, such as those in DNA and protein sequences. However, there are more complex scenarios where the motifs exist in non-single-letter contexts, e.g. preferred patterns of chemical modifications on proteins, DNAs, RNAs or polysaccharides. To search for those motifs, we describe a new method that converts the modified sequence elements to representative single-letter codes and then uses a modified Gibbs-sampling algorithm to define the position specific scoring matrix representing the motif(s). As a proof of principle, we describe the implementation and application of an R package for discovering heparan sulfate (HS) motifs in glycan sequences, which are important in regulating protein-protein interactions. This software can be valuable for analyzing high-throughput glycoprotein binding data using microarrays with HS oligosaccharides or other biological polymers. AVAILABILITY AND IMPLEMENTATION: HSMotifDiscover is freely available as an open source R package released under an MIT license at https://github.com/bioinfoDZ/HSMotifDiscover and also available in the form of an app at https://hsmotifdiscover.shinyapps.io/HSMotifDiscover_ShinyApp/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Mce2R/Rv0586 of Mycobacterium tuberculosis is the functional homologue of FadRE. coli.

Lipid metabolism is critical to Mycobacterium tuberculosis survival and infection. Unlike Escherichia coli, which has a single FadR, the M. tuberculosis genome encodes five proteins of the FadR sub-family. While the role of E. coli FadR as a regulator of fatty acid metabolism is well known, the definitive functions of M. tuberculosis FadR proteins are still under investigation. An interesting question about the M. tuberculosis FadRs remains open: which one of these proteins is the functional homologue of E. coli FadR? To address this, we have applied two different approaches. The first one was the bioinformatics approach and the second one was the classical molecular genetic approach involving complementation studies. Surprisingly, the results of these two approaches did not agree. Among the five M. tuberculosis FadRs, Rv0494 shared the highest sequence similarity with FadRE. coli and Rv0586 was the second best match. However, only Rv0586, but not Rv0494, could complement E. coli ∆fadR, indicating that Rv0586 is the M. tuberculosis functional homologue of FadRE. coli. Further studies showed that both regulators, Rv0494 and Rv0586, show similar responsiveness to LCFA, and have conserved critical residues for DNA binding. However, analysis of the operator site indicated that the inter-palindromic distance required for DNA binding differs for the two regulators. The differences in the binding site selection helped in the success of Rv0586 binding to fadB upstream over Rv0494 and may have played a critical role in complementing E. coli ∆fadR. Further, for the first time, we report the lipid-responsive nature of Rv0586.

Identification of Plasmodium falciparum apicoplast-targeted tRNA-guanine transglycosylase and its potential inhibitors using comparative genomics, molecular modelling, docking and simulation studies.

tRNA modifications play an important role in the proper folding of tRNA and thereby determine its functionality as an adaptor molecule. Notwithstanding the centrality of this basic process in translation, a major gap in the genomics of Plasmodium falciparum is unambiguous identification of enzymes catalysing the various tRNA modifications. In this study, tRNA-modifying enzymes of P. falciparum were annotated using homology-based approach. Based on the presence of these identified enzymes, the modifications were compared with those of prokaryotic and eukaryotic organisms. Through sequence comparison and phylogenetic analysis, we have identified P. falciparum apicoplast tRNA-guanine 34 transglycosylase (TGT, EC: 2.4.2.29), which shows evidence of its prokaryotic origin. The docking analysis of the modelled TGT structures revealed that binding of quinazolinone derivatives is more favourable with P. falciparum apicoplast TGT as compared to human TGT. Molecular dynamic simulation and molecular mechanics/generalized Born surface area analysis of the complex confirmed the greater binding affinity of the ligand in the binding pocket of P. falciparum TGT protein. Further, evolutionary patterning analysis identified the amino acids of P. falciparum apicoplast TGT that are under purifying selection pressure and hence can be good inhibitor-targeting sites. Based on these computational studies, we suggest that P. falciparum apicoplast tRNA-guanine 34 transglycosylase can be a promising drug target.