CHD6 promotes broad nucleosome eviction for transcriptional activation in prostate cancer cells

Methylation-dependent and -independent roles of EZH2 synergize in CDCA8 activation in prostate cancer

A PRC2-independent function for EZH2 in regulating rRNA 2′-O methylation and IRES-dependent translation

Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy

MACMIC Reveals A Dual Role of CTCF in Epigenetic Regulation of Cell Identity Genes

Antihistamine Drug Ebastine Inhibits Cancer Growth by Targeting Polycomb Group Protein EZH2

Machine learning uncovers cell identity regulator by histone code

MIF as a biomarker and therapeutic target for overcoming resistance to proteasome inhibitors in human myeloma

AbstractMultiple myeloma (MM) remains largely incurable despite significant advances in biotherapy and chemotherapy. The development of drug resistance is a major problem in MM management. Macrophage migration inhibitory factor (MIF) expression was significantly higher in purified MM cells from relapsed patients than those with sustained response, and MM patients with high MIF had significantly shorter progression-free survival (PFS) and overall survival (OS). MM cell lines also express high levels of MIF, and knocking out MIF made them more sensitive to proteasome inhibitor (PI)-induced apoptosis not observed with other chemotherapy drugs. Mechanistic studies showed that MIF protects MM cells from PI-induced apoptosis by maintaining mitochondrial function via suppression of superoxide production in response to PIs. Specifically, MIF, in the form of a homotrimer, acts as a chaperone for superoxide dismutase 1 (SOD1) to suppress PI-induced SOD1 misfolding and to maintain SOD1 activity. MIF inhibitor 4-iodo-6-phenylpyrimidine and homotrimer disrupter ebselen, which do not kill MM cells, enhanced PI-induced SOD1 misfolding and loss of function, resulting in significantly more cell death in both cell lines and primary MM cells. More importantly, inhibiting MIF activity in vivo displayed synergistic antitumor activity with PIs and resensitized PI-resistant MM cells to treatment. In support of these findings, gene-profiling data showed a significantly negative correlation between MIF and SOD1 expression and response to PI treatment in patients with MM. This study shows that MIF plays a crucial role in MM sensitivity to PIs and suggests that targeting MIF may be a promising strategy to (re)sensitize MM to the treatment.

TADsplimer reveals splits and mergers of topologically associating domains for epigenetic regulation of transcription

AbstractWe present TADsplimer, the first computational tool to systematically detect topologically associating domain (TAD) splits and mergers across the genome between Hi-C samples. TADsplimer recaptures splits and mergers of TADs with high accuracy in simulation analyses and defines hundreds of TAD splits and mergers between pairs of different cell types, such as endothelial cells and fibroblasts. Our work reveals a key role for TAD remodeling in epigenetic regulation of transcription and delivers the first tool for the community to perform dynamic analysis of TAD splits and mergers in numerous biological and disease models.

Broad genic repression domains signify enhanced silencing of oncogenes

Abstract Cancers result from a set of genetic and epigenetic alterations. Most known oncogenes were identified by gain-of-function mutations in cancer, yet little is known about their epigenetic features. Through integrative analysis of 11,596 epigenomic profiles and mutations from >8200 tumor-normal pairs, we discover broad genic repression domains (BGRD) on chromatin as an epigenetic signature for oncogenes. A BGRD is a widespread enrichment domain of the repressive histone modification H3K27me3 and is further enriched with multiple other repressive marks including H3K9me3, H3K9me2, and H3K27me2. Further, BGRD displays widespread enrichment of repressed cis-regulatory elements. Shortening of BGRDs is linked to derepression of transcription. BGRDs at oncogenes tend to be conserved across normal cell types. Putative tumor-promoting genes and lncRNAs defined using BGRDs are experimentally verified as required for cancer phenotypes. Therefore, BGRDs play key roles in epigenetic regulation of cancer and provide a direction for mutation-independent discovery of oncogenes.

Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer

BMI1 is directly regulated by androgen receptor to promote castration-resistance in prostate cancer

Roles of the HOXA10 gene during castrate-resistant prostate cancer progression

Homeobox A10 (HOXA10) is an important transcription factor that regulates the development of the prostate gland. However, it remains unknown whether it modulates prostate cancer (PCa) progression into castrate-resistant stages. In this study, we have applied RNA in situ hybridization assays to demonstrate that downregulation of HOXA10 expression is associated with castrate-resistant PCa. These findings are supported by public RNA-seq data showing that reduced HOXA10 expression is correlated with poor patient survival. We show that HOXA10 suppresses PCa cell proliferation, anchorage colony formation and xenograft growth independent to androgens. Using AmpliSeq transcriptome sequencing, we have found that gene groups associated with lipid metabolism and androgen receptor (AR) signaling are enriched in the HOXA10 transcriptome. Furthermore, we demonstrate that HOXA10 suppresses the transcription of the fatty acid synthase (FASN) gene by forming a protein complex with AR and prevents AR recruitment to the FASN gene promoter. These results lead us to conclude that downregulation of HOXA10 gene expression may enhance lipogenesis to promote PCa cell growth and tumor progression to castrate-resistant stage.

PGAP-X: extension on pan-genome analysis pipeline

BMI1 regulates androgen receptor in prostate cancer independently of the polycomb repressive complex 1

MLL4 Is Required to Maintain Broad H3K4me3 Peaks and Super-Enhancers at Tumor Suppressor Genes

Temporal Transcriptomic and Proteomic Landscapes of Deteriorating Pancreatic Islets in Type 2 Diabetic Rats

Human absorbable microRNA prediction based on an ensemble manifold ranking model

The Overlooked Fact: Fundamental Need for Spike-In Control for Virtually All Genome-Wide Analyses

Genome-wide analyses of changes in gene expression, transcription factor occupancy on DNA, histone modification patterns on chromatin, genomic copy number variation, and nucleosome positioning have become popular in many modern laboratories, yielding a wealth of information during health and disease states. However, most of these studies have overlooked an inherent normalization problem that must be corrected with spike-in controls. Here we describe the reason why spike-in controls are so important and explain how to appropriately design and use spike-in controls for normalization. We also suggest ways to retrospectively renormalize data sets that were wrongly interpreted due to omission of spike-in controls.

WikiCell: A Unified Resource Platform for Human Transcriptomics Research

PMirP: A pre-microRNA prediction method based on structure–sequence hybrid features