Base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG) is essential for removal of aberrantly methylated DNA bases. Genome instability and accumulation of aberrant bases accompany multiple diseases, including cancer and neurological disorders. While BER is well studied on naked DNA, it remains unclear how BER efficiently operates on chromatin. Here, we show that AAG binds to chromatin and forms complex with RNA polymerase (pol) II. This occurs through direct interaction with Elongator and results in transcriptional co-regulation. Importantly, at co-regulated genes, aberrantly methylated bases accumulate towards the 3′end in regions enriched for BER enzymes AAG and APE1, Elongator and active RNA pol II. Active transcription and functional Elongator are further crucial to ensure efficient BER, by promoting AAG and APE1 chromatin recruitment. Our findings provide insights into genome stability maintenance in actively transcribing chromatin and reveal roles of aberrantly methylated bases in regulation of gene expression.

MicroRNAs (miRNAs) are small non‐coding RNAs that have emerged as central regulators of gene expression and powerful biomarkers of disease. Much is yet unknown about their role in psoriasis pathology. To globally characterize the miRNAome of psoriatic skin, skin biopsies were collected from psoriatic cases (n = 75) and non‐psoriatic controls (n = 46) and RNA sequenced. Count data were meta‐analysed with a previously published dataset (cases,n = 24, controls,n = 20), increasing the number of psoriatic cases fourfold from previously published studies. Differential gene expression analyses were performed comparing lesional psoriatic (PP), non‐lesional psoriatic (PN) and control (NN) skin. Further, functional enrichment and cell‐specific analyses were performed. Across all contrasts, we identified 439 significantly differentially expressed miRNAs (DEMs), of which 85 were novel for psoriasis and 11 were related to disease severity. Meta‐analyses identified 20 DEMs between PN and NN, suggesting an inherent change in the constitution of all skin in psoriasis. By integrating the miRNA transcriptome with mRNA target interactions, we identified several functionally enriched terms, including “thyroid hormone signalling,” “insulin resistance” and various infectious diseases. Cell‐specific expression analyses revealed that the upregulated DEMs were enriched in epithelial and immune cells. This study provides the most comprehensive overview of the miRNAome in psoriatic skin to date and identifies a miRNA signature related to psoriasis severity. Our results may represent molecular links between psoriasis and related comorbidities and have outlined potential directions for future functional studies to identify biomarkers and treatment targets.

The omega‐3 fatty acid docosahexaenoic acid (DHA) is known as an anticancer agent. Colorectal cancer (CRC) cells exhibit different sensitivity toward DHA, but the mechanisms involved are still unclear. Gene expression profiling of 10 CRC cell lines demonstrated a correlation between the level of DHA sensitivity and different biological stress responses, such as endoplasmic reticulum (ER) stress, oxidative stress, and autophagy. The basal level of autophagy and MAP1LC3B‐II protein correlated with DHA sensitivity in the cell lines studied. DHA induced oxidative stress, ER stress, and autophagy in DHA‐sensitive DLD‐1 cells, while the less sensitive LS411N cells were affected to a much lesser extent. Co‐treatment with DHA and the autophagy inducer rapamycin reduced DHA sensitivity in DLD‐1 and HCT‐8 cells, while co‐treatment with DHA and the autophagy inhibitors chloroquine and 3‐methyladenine increased the DHA sensitivity in LS411N and LS513 cells. Differentially expressed genes correlating with DHA sensitivity and the level of autophagy demonstrated an overlap in biological pathways involved. Results indicate the basal level of autophagy and MAP1LC3B‐II protein as potential biomarkers for DHA sensitivity in CRC cells.Databases: Protocol and data for gene expression experiments have been submitted to ArrayExpress with accession number E‐MTAB‐5750.

Psoriasis is a chronic cutaneous inflammatory disease. The immunopathogenesis is a complex interplay between T cells, dendritic cells and the epidermis in which T cells and dendritic cells maintain skin inflammation. Anti-tumour necrosis factor (anti-TNF)-α agents have been approved for therapeutic use across a range of inflammatory disorders including psoriasis, but the anti-inflammatory mechanisms of anti-TNF-α in lesional psoriatic skin are not fully understood. We investigated early events in skin from psoriasis patients after treatment with anti-TNF-α antibodies by use of bioinformatics tools. We used the Human Gene 1.0 ST Array to analyse gene expression in punch biopsies taken from psoriatic patients before and also 4 and 14 days after initiation of treatment with the anti-TNF-α agent adalimumab. The gene expression was analysed by gene set enrichment analysis using the Functional Annotation Tool from DAVID Bioinformatics Resources. The most enriched pathway was visualised by the Pathview Package on Kyoto Encyclopedia of Genes and Genomes (KEGG) graphs. The analysis revealed new very early events in psoriasis after adalimumab treatment. Some of these events have been described after longer periods of anti-TNF-α treatment when clinical and histological changes appear, suggesting that effects of anti-TNF-α treatment on gene expression appear very early before clinical and histological changes. Combining microarray data on biopsies from psoriasis patients with pathway analysis allowed us to integrate in vitro findings into the identification of mechanisms that may be important in vivo. Furthermore, these results may reflect primary effect of anti-TNF-α treatment in contrast to studies of gene expression changes following clinical and histological changes, which may reflect secondary changes correlated to the healing of the skin.

The medial entorhinal cortex (MEC) is important in spatial navigation and memory formation and its layers have distinct neuronal subtypes, connectivity, spatial properties, and disease susceptibility. As little is known about the molecular basis for the development of these laminar differences, we analyzed microRNA (miRNA) and messenger RNA (mRNA) expression differences between rat MEC layer II and layers III–VI during postnatal development. We identified layer and age-specific regulation of gene expression by miRNAs, which included processes related to neuron specialization and locomotor behavior. Further analyses by retrograde labeling and expression profiling of layer II stellate neurons and in situ hybridization revealed that the miRNA most up-regulated in layer II, miR-143, was enriched in stellate neurons, whereas the miRNA most up-regulated in deep layers, miR-219-5p, was expressed in ependymal cells, oligodendrocytes and glia. Bioinformatics analyses of predicted mRNA targets with negatively correlated expression patterns to miR-143 found that miR-143 likely regulates the Lmo4 gene, which is known to influence hippocampal-based spatial learning.