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Background: Lung cancer is the leading cause of cancer death worldwide. It has been reported that genetic and epigenetic factors play a crucial role in the onset and evolution of lung cancer. Previous reports have shown that essential transcription factors in embryonic development contribute to this pathology. Runt-related transcription factor (RUNX) proteins belong to a family of master regulators of embryonic developmental programs. Specifically, RUNX2 is the master transcription factor (TF) of osteoblastic differentiation, and it can be involved in pathological conditions such as prostate, thyroid, and lung cancer by regulating apoptosis and mesenchymal-epithelial transition processes. In this paper, we identified TALAM1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) as a genetic target of the RUNX2 TF in lung cancer and then performed functional validation of the main findings., Methods: We performed ChIP-seq analysis of tumor samples from a patient diagnosed with lung adenocarcinoma to evaluate the target genes of the RUNX2 TF. In addition, we performed shRNA-mediated knockdown of RUNX2 in this lung adenocarcinoma cell line to confirm the regulatory role of RUNX2 in TALAM1 expression., Results: We observed RUNX2 overexpression in cell lines and primary cultured lung cancer cells. Interestingly, we found that lncRNA TALAM1 was a target of RUNX2 and that RUNX2 exerted a negative regulatory effect on TALAM1 transcription.

In cancer cells, the long non-coding RNA (lncRNA) MALAT1 has arisen as a key partner for the Polycomb Repressive Complex 2 (PRC2), an epigenetic modifier. However, it is unknown whether this partnership occurs genome-wide at the chromatin level, as most of the studies focus on single genes that are usually repressed. Due to the genomic binding properties of both macromolecules, we wondered whether there are binding sites shared by PRC2 and MALAT1. Using public genome-binding datasets for PRC2 and MALAT1 derived from independent ChIP- and CHART-seq experiments performed with the breast cancer cell line MCF7, we searched for regions containing PRC2 and MALAT1 overlapping peaks. Peak calls for each molecule were performed using MACS2 and then overlapping peaks were identified by bedtools intersect. Using this approach, we identified 1293 genomic sites where PRC2 and MALAT1 concur. Interestingly, 54.75% of those sites are within gene promoter regions (<3000 bases from the TSS). These analyses were also linked with the transcription profiles of MCF7 cells, obtained from public RNA-seq data. Hence, it is suggested that MALAT1 and PRC2 can concomitantly bind to promoters of actively-transcribed genes in MCF7 cells. Gene ontology analyses revealed an enrichment of genes related to categories including cancer malignancy and epigenetic regulation. Thus, by re-visiting occupancy and transcriptomic data, we identified a key gene subset controlled by the collaboration of MALAT1 and PRC2.

Healthy brain functioning in mammals requires a continuous fine-tuning of gene expression. Accumulating evidence over the last three decades demonstrates that epigenetic mechanisms and dynamic changes in chromatin organization are critical components during the control of gene transcription in neural cells. Recent genome-wide analyses show that the regulation of brain genes requires the contribution of both promoter and long-distance enhancer elements, which must functionally interact with upregulated gene expression in response to physiological cues. Hence, a deep comprehension of the mechanisms mediating these enhancer-promoter interactions (EPIs) is critical if we are to understand the processes associated with learning, memory and recall. Moreover, the onset and progression of several neurodegenerative diseases and neurological alterations are found to be strongly associated with changes in the components that support and/or modulate the dynamics of these EPIs. Here, we overview relevant discoveries in the field supporting the role of the chromatin organization and of specific epigenetic mechanisms during the control of gene transcription in neural cells from healthy mice subjected to the fear conditioning paradigm, a relevant model to study memory ensemble. Additionally, special consideration is dedicated to revising recent results generated by investigators working with animal models and human postmortem brain tissue to address how changes in the epigenome and chromatin architecture contribute to transcriptional dysregulation in Alzheimer's disease, a widely studied neurodegenerative disease. We also discuss recent developments of potential new therapeutic strategies involving epigenetic editing and small chromatin-modifying molecules (or epidrugs).

The bioinformatic pipeline previously developed in our research laboratory is used to identify potential general and specific deregulated tumor genes and transcription factors related to the establishment and progression of tumoral diseases, now comparing lung cancer with other two types of cancer. Twenty microarray datasets were selected and analyzed separately to identify hub differentiated expressed genes and compared to identify all the deregulated genes and transcription factors in common between the three types of cancer and those unique to lung cancer. The winning DEGs analysis allowed to identify an important number of TFs deregulated in the majority of microarray datasets, which can become key biomarkers of general tumors and specific to lung cancer. A coexpression network was constructed for every dataset with all deregulated genes associated with lung cancer, according to DAVID's tool enrichment analysis, and transcription factors capable of regulating them, according to oPOSSUM´s tool. Several genes and transcription factors are coexpressed in the networks, suggesting that they could be related to the establishment or progression of the tumoral pathology in any tissue and specifically in the lung. The comparison of the coexpression networks of lung cancer and other types of cancer allowed the identification of common connectivity patterns with deregulated genes and transcription factors correlated to important tumoral processes and signaling pathways that have not been studied yet to experimentally validate their role in lung cancer. The Kaplan-Meier estimator determined the association of thirteen deregulated top winning transcription factors with the survival of lung cancer patients. The coregulatory analysis identified two top winning transcription factors networks related to the regulatory control of gene expression in lung and breast cancer. Our transcriptomic analysis suggests that cancer has an important coregulatory network of transcription factors related to the acquisition of the hallmarks of cancer. Moreover, lung cancer has a group of genes and transcription factors unique to pulmonary tissue that are coexpressed during tumorigenesis and must be studied experimentally to fully understand their role in the pathogenesis within its very complex transcriptomic scenario. Therefore, the downstream bioinformatic analysis developed was able to identify a coregulatory metafirm of cancer in general and specific to lung cancer taking into account the great heterogeneity of the tumoral process at cellular and population levels.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) and can be treated with glucocorticoids (GC), although some patients are unresponsive to this therapy. The transcription factor LRH-1/ NR5A2 is critical to intestinal cortisol production (intestinal steroidogenesis), being reduced in UC patients. However, the relationship between LRH-1 expression and distribution with altered corticosteroid responses is unknown. To address this, we categorized UC patients by their steroid response. Here, we found that steroid-dependent and refractory patients presented reduced glucocorticoid receptor (GR)-mediated intestinal steroidogenesis compared to healthy individuals and responder patients, possibly related to increased colonic mucosa GR isoform beta (GRβ) content and cytoplasmic LRH-1 levels in epithelial and lamina propria cells. Interestingly, an intestinal epithelium-specific GR-induced knockout (GR iKO ) dextran sodium sulfate (DSS)-colitis mice model presented decreased epithelial LRH-1 expression, whilst it increased in the lamina propria compared to DSS-treated control mice. Mechanistically, GR directly induced NR5A2 gene expression in CCD841CoN cells and human colonic organoids. Furthermore, GR bound to two glucocorticoid-response elements within the NR5A2 promoter in dexamethasone-stimulated CCD841CoN cells. We conclude that GR contributes to intestinal steroidogenesis by inducing LRH-1 in epithelial cells, suggesting LRH-1 as a potential marker for glucocorticoid-impaired response in UC. However, further studies with a larger patient cohort will be necessary to confirm role of LRH-1 as a therapeutic biomarker.

Ezh2 is a catalytic subunit of the polycomb repressive complex 2 (PRC2) which mediates epigenetic gene silencing through depositing the mark histone H3 lysine 27 trimethylation (H3K27me3) at target genomic sequences. Previous studies have demonstrated that Enhancer of Zeste Homolog 2 (Ezh2) was differentially expressed during maturation of hippocampal neurons; in immature neurons, Ezh2 was abundantly expressed, whereas in mature neurons the expression Ezh2 was significantly reduced. Here, we report that Ezh2 is downregulated by microRNAs (miRs) that are expressed during the hippocampal maturation process. We show that, in mature hippocampal neurons, lethal-7 (let-7) and microRNA-124 (miR-124) are robustly expressed and can target cognate motifs at the 3'-UTR of the Ezh2 gene sequence to downregulate Ezh2 expression. Together, these data demonstrate that the PRC2 repressive activity during hippocampal maturation is controlled through a post-transcriptional mechanism that mediates Ezh2 downregulation in mature neurons.