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Background: Centromere function is highly conserved across eukaryotes, but the underlying centromeric DNA sequences vary dramatically between species. Centromeres often contain a high proportion of repetitive DNA, such as tandem repeats and/or transposable elements (TEs). Einkorn wheat centromeres lack tandem repeat arrays and are instead composed mostly of the two long terminal repeat (LTR) retrotransposon families RLG_Cereba and RLG_Quinta which specifically insert in centromeres. However, it is poorly understood how these two TE families relate to each other and if and how they contribute to centromere function and evolution. Results: Based on conservation of diagnostic motifs (LTRs, integrase and primer binding site and polypurine-tract), we propose that RLG_Cereba and RLG_Quinta are a pair of autonomous and non-autonomous partners, in which the autonomous RLG_Cereba contributes all the proteins required for transposition, while the non-autonomous RLG_Quinta contributes GAG protein. Phylogenetic analysis of predicted GAG proteins showed that the RLG_Cereba lineage was present for at least 100 million years in monocotyledon plants. In contrast, RLG_Quinta evolved from RLG_Cereba between 28 and 35 million years ago in the common ancestor of oat and wheat. Interestingly, the integrase of RLG_Cereba is fused to a so-called CR-domain, which is hypothesized to guide the integrase to the functional centromere. Indeed, ChIP-seq data and TE population analysis show only the youngest subfamilies of RLG_Cereba and RLG_Quinta are found in the active centromeres. Importantly, the LTRs of RLG_Quinta and RLG_Cereba are strongly associated with the presence of the centromere-specific CENH3 histone variant. We hypothesize that the LTRs of RLG_Cereba and RLG_Quinta contribute to wheat centromere integrity by phasing and/or placing CENH3 nucleosomes, thus favoring their persistence in the competitive centromere-niche. Conclusion: Our data show that RLG_Cereba cross-mobilizes the non-autonomous RLG_Quinta retrotransposons. New copies of both families are specifically integrated into functional centromeres presumably through direct binding of the integrase CR domain to CENH3 histone variants. The LTRs of newly inserted RLG_Cereba and RLG_Quinta elements, in turn, recruit and/or phase new CENH3 deposition. This mutualistic interplay between the two TE families and the plant host dynamically maintains wheat centromeres. [ABSTRACT FROM AUTHOR]

Myelin regeneration (remyelination) is essential to prevent neurodegeneration in demyelinating diseases such as Multiple Sclerosis, however, its efficiency declines with age. Regulatory T cells (Treg) recently emerged as critical players in tissue regeneration, including remyelination. However, the effect of ageing on Treg-mediated regenerative processes is poorly understood. Here, we show that expansion of aged Treg does not rescue age-associated remyelination impairment due to an intrinsically diminished capacity of aged Treg to promote oligodendrocyte differentiation and myelination in male and female mice. This decline in regenerative Treg functions can be rescued by a young environment. We identified Melanoma Cell Adhesion Molecule 1 (MCAM1) and Integrin alpha 2 (ITGA2) as candidates of Treg-mediated oligodendrocyte differentiation that decrease with age. Our findings demonstrate that ageing limits the neuroregenerative capacity of Treg, likely limiting their remyelinating therapeutic potential in aged patients, and describe two mechanisms implicated in Treg-driven remyelination that may be targetable to overcome this limitation.Factors limiting CNS remyelination with age are poorly understood. Here the authors show that aged Treg lose capacity to support CNS remyelination in mice, which can be restored in a young environment. [ABSTRACT FROM AUTHOR]

Patients with class I V600EBRAF-mutant (MT) colorectal cancer (CRC) have a poor prognosis and their response to combined anti-BRAF/EGFR inhibition remains limited. There is clearly an unmet need in further understanding the biology of V600EBRAFMT CRC. We have used differential gene expression of BRAFWT and MT CRC cells to identify pathways underpinning BRAFMT CRC. We tested a panel of molecularly/genetically subtyped CRC cells for their sensitivity to the Unfolded Protein Response (UPR) activator BOLD-100. To identify novel combination strategies for BOLD-100, we performed RNA sequencing and high-throughput drug screening. Pathway enrichment analysis identified that the UPR and DNA repair pathways were significantly enriched in BRAFMT CRC. We found that oncogenic BRAF plays a crucial role in mediating response to BOLD-100. Using a systems biology approach, we identified V600EBRAFMT-dependent activation of the replication stress response kinase ATR as a key mediator of resistance to BOLD-100. Further analysis identified acute increases in BRAFMT-dependent-reactive oxygen species (ROS) levels following treatment with BOLD-100 that was demonstrated to promote ATR/CHK1 activation and apoptosis. Furthermore, activation of ROS/ATR/CHK1 following BOLD-100 was found to be mediated through the AHR transcription factor and CYP1A1. Importantly, pharmacological blockade of this resistance pathway with ATR inhibitors synergistically increased BOLD-100-induced apoptosis and growth inhibition in BRAFMT models. These results unveil possible novel therapeutic opportunity for BRAFMT CRC. Implications: BOLD-100 induces BRAFMT-dependent replication stress, and targeted strategies against replication stress (eg. by using ATR inhibitors) in combination with BOLD-100 may serve as a potential novel therapeutic strategy for clinically aggressive BRAFMT CRC.