Genomic Imprinting: Insights into Diverse Epigenetic Regulatory Mechanisms.

Background: Genomic imprinting is a well-known phenomenon in which certain genes are expressed in a sex-of-the-parent-specific manner, resulting in mono-allelic expression.

Summary: Over the years, the diversity of mechanisms observed in imprinted gene clusters has provided a valuable model system for exploring the complexities of epigenetics, which can be extended to other cellular and disease models. This review examines these different mechanisms throughout early embryonic development and offers insights into the interactions among key players such as DNA methylation, histone modifications, and non-coding RNAs, as well as their regulatory impact on gene expression.

Combination of EZH2 and ATM inhibition in BAP1-deficient mesothelioma.

Background: More than half of mesothelioma tumours show alterations in the tumour suppressor gene BAP1. BAP1-deficient mesothelioma is shown to be sensitive to EZH2 inhibition in preclinical settings but only showed modest efficacy in clinical trial. Adding a second inhibitor could potentially elevate EZH2i treatment efficacy while preventing acquired resistance at the same time.

Combined Inhibition of EZH2 and FGFR is Synergistic in BAP1-deficient Malignant Mesothelioma.

Unlabelled: Malignant mesothelioma is a highly aggressive tumor with a survival of only 4-18 months after diagnosis. Treatment options for this disease are limited. Immune checkpoint blockade using ipilimumab and nivolumab has recently been approved as a frontline therapy, but this led to only a small improvement in overall patient survival.

Bioactive molecules from fungal endophytes and their applications in pharmaceutical industries: challenges and future scope.

Medicinal plants are an important source of bioactive compounds and have been used to isolate various bioactive compounds having industrial applications. The demand for plants derived bioactive molecules is increasing gradually. However, the extensive use of these plants to extract bioactive molecules has threatened many plant species.

Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma.

More than half of patients with malignant mesothelioma show alterations in the BAP1 tumor-suppressor gene. Being a member of the Polycomb repressive deubiquitinating (PR-DUB) complex, BAP1 loss results in an altered epigenome, which may create new vulnerabilities that remain largely unknown. Here, we performed a CRISPR-Cas9 kinome screen in mesothelioma cells that identified two kinases in the mevalonate/cholesterol biosynthesis pathway.

Long Non-Coding RNAs: Tools for Understanding and Targeting Cancer Pathways.

The regulatory nature of long non-coding RNAs (lncRNAs) has been well established in various processes of cellular growth, development, and differentiation. Therefore, it is vital to examine their contribution to cancer development. There are ample examples of lncRNAs whose cellular levels are significantly associated with clinical outcomes.

Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice.

We have generated mouse models of malignant mesothelioma (MM) based upon disruption of the Bap1, Nf2, and Cdkn2ab tumor suppressor loci in various combinations as also frequently observed in human MM. Inactivation of all three loci in the mesothelial lining of the thoracic cavity leads to a highly aggressive MM that recapitulates the histological features and gene expression profile observed in human patients. The tumors also show a similar inflammatory phenotype.

EZH2 Is Overexpressed in -like Breast Tumors and Predictive for Sensitivity to High-Dose Platinum-Based Chemotherapy.

Purpose: BRCA1-deficient breast cancers carry a specific DNA copy-number signature ("") and are hypersensitive to DNA double-strand break (DSB) inducing compounds. Here, we explored whether (i) EZH2 is overexpressed in human -deficient breast tumors and might predict sensitivity to DSB-inducing drugs; (ii) EZH2 inhibition potentiates cisplatin efficacy in -deficient murine mammary tumors.

Experimental Design: EZH2 expression was analyzed in 497 breast cancers using IHC or RNA sequencing.

Long noncoding RNAs and neuroblastoma.

Neuroblastoma is a disease that affects infants and despite intense multimodal therapy, high-risk patients have low survival rates (<50%). In recent years long noncoding RNAs (lncRNAs) have become the cutting edge of cancer research with inroads made in understanding their roles in multiple cancer types, including prostate and breast cancers. The roles of lncRNAs in neuroblastoma have just begun to be elucidated.

The risk-associated long noncoding RNA NBAT-1 controls neuroblastoma progression by regulating cell proliferation and neuronal differentiation.

Neuroblastoma is an embryonal tumor of the sympathetic nervous system and the most common extracranial tumor of childhood. By sequencing transcriptomes of low- and high-risk neuroblastomas, we detected differentially expressed annotated and nonannotated long noncoding RNAs (lncRNAs). We identified a lncRNA neuroblastoma associated transcript-1 (NBAT-1) as a biomarker significantly predicting clinical outcome of neuroblastoma.

Temporal separation of replication and transcription during S-phase progression.

Transcriptional events during S-phase are critical for cell cycle progression. Here, by using a nascent RNA capture assay coupled with high-throughput sequencing, we determined the temporal patterns of transcriptional events that occur during S-phase. We show that genes involved in critical S-phase-specific biological processes such as nucleosome assembly and DNA repair have temporal transcription patterns across S-phase that are not evident from total RNA levels.

Long noncoding RNA-mediated maintenance of DNA methylation and transcriptional gene silencing.

Establishment of silencing by noncoding RNAs (ncRNAs) via targeting of chromatin remodelers is relatively well investigated; however, their role in the maintenance of silencing is poorly understood. Here, we explored the functional role of the long ncRNA Kcnq1ot1 in the maintenance of transcriptional gene silencing in the one mega-base Kcnq1 imprinted domain in a transgenic mouse model. By conditionally deleting the Kcnq1ot1 ncRNA at different stages of mouse development, we suggest that Kcnq1ot1 ncRNA is required for the maintenance of the silencing of ubiquitously imprinted genes (UIGs) at all developmental stages.

Kcnq1ot1 noncoding RNA mediates transcriptional gene silencing by interacting with Dnmt1.

A long noncoding RNA, Kcnq1ot1, regulates the expression of both ubiquitously and tissue-specific imprinted genes within the Kcnq1 domain. However, the functional sequences of the Kcnq1ot1 RNA that mediate lineage-specific imprinting are unknown. Here, we have generated a knockout mouse with a deletion encompassing an 890-bp silencing domain (Delta890) downstream of the Kcnq1ot1 promoter.

Regulation of the mammalian epigenome by long noncoding RNAs.

Genomic analyses have demonstrated that although less than 2% of the mammalian genome encodes proteins, at least two thirds is transcribed. Many nontranslated RNAs have now been characterized, and several long transcripts, ranging from 0.5 to over 100 kb, have been shown to regulate gene expression by modifying chromatin structure.