In yeast and humans, previous experiences can lead to epigenetic transcriptional memory: repressed genes that exhibit mitotically heritable changes in chromatin structure and promoter recruitment of poised RNA polymerase II preinitiation complex (RNAPII PIC), which enhances future reactivation. Here, we show that INO1 memory in yeast is initiated by binding of the Sfl1 transcription factor to the cis-acting Memory Recruitment Sequence, targeting INO1 to the nuclear periphery. Memory requires a remodeled form of the Set1/COMPASS methyltransferase lacking Spp1, which dimethylates histone H3 lysine 4 (H3K4me2). H3K4me2 recruits the SET3C complex, which plays an essential role in maintaining this mark. Finally, while active INO1 is associated with Cdk8- Mediator, during memory, Cdk8+ Mediator recruits poised RNAPII PIC lacking the Kin28 CTD kinase. Aspects of this mechanism are generalizable to yeast and conserved in human cells. Thus, COMPASS and Mediator are repurposed to promote epigenetic transcriptional poising by a highly conserved mechanism.DOI: http://dx.doi.org/10.7554/eLife.16691.001

SUMMARY Nucleosome organization influences gene activity by controlling DNA accessibility to transcription machinery. Here, we develop a chemical biology approach to determine mammalian nucleosome positions genome-wide. We uncovered surprising features of nucleosome organization in mouse embryonic stem cells. In contrast to the prevailing model, we observe that for nearly all mouse genes a class of fragile nucleosomes occupies previously designated nucleosome-depleted regions around transcription start sites and transcription termination sites. We show that nucleosomes occupy DNA targets for a subset of DNA-binding proteins, including CTCF and pluripotency factors. Furthermore, we provide evidence that promoter-proximal nucleosomes, with the +1 nucleosome in particular, contribute to the pausing of RNA polymerase II. Lastly, we find a characteristic preference for nucleosomes at exon-intron junctions. Taken together, we establish an accurate method for defining the nucleosome landscape, and provide a valuable resource for studying nucleosome-mediated gene regulation in mammalian cells.

In spite of the clinical importance of prostate cancer (PCa) bone metastasis, the precise mechanisms for the directed migration of malignant cells remain unclear. In the present study, the expression of CXCR6 in human PCa and benign prostatic hyperplasia samples, and the expression of CXCL16 in human osseous tissues were determined by immunohistochemistry. It was found that the level of CXCR6 protein expression was elevated in human malignant prostate tumors, and CXCL16 was expressed positively by human osteocytes in vivo. The in vitro experiments further confirmed that the PCa cell lines PC3 and LNCap expressed CXCR6 at both the mRNA and protein levels, and exogenous CXCL16 has the potential to stimulate the invasion of PC3 and LNCap. To further elucidate the role of the CXCL16-CXCR6 axis in PCa progression, we compared the expression of CXCR6 and CXCR4 in human PCa tissues and the effects of CXCL16 and CXCL12 on the in vitro invasion of PC3 and LNCap cells. P rostate cancer is a common neoplasm and the second leading cause of cancer death in American men, and its morbidity has also increased in recent years in China.(1,2) Despite advances in early diagnosis and therapeutics of PCa, metastasis to bone is one of the most severe complications and major causes of mortality of PCa.(3,4) Many factors have been implicated in the process of metastasis, but the precise mechanisms for the directed migration and invasion of malignant cells into selective organs at both the cellular and molecular levels remain unclear.Recent studies indicate that tumor cell migration and metastasis are not random processes; rather, chemokines and chemokine receptors may play important roles in determining the metastatic destination of tumor cells.(5,6) For PCa, most investigations focused on the CXCL12-CXCR4 signaling pathway; (7)(8)(9) however, little is known about the relationship between PCa specific metastasis and other chemokines or chemokine receptors.CXCR6, initially described under the names Bonzo, STRL33 and TYMSTR, is a newly characterized chemokine receptor that until now was described to be expressed selectively by subsets of memory/effector T cells, (10) NK cells, (11) NK T cells,and plasma cells.(13) CXCL16, the sole ligand of CXCR6, is a unique CXC chemokine that exists both in a transmembrane form and a soluble form. (14,15) The interaction between CXCL16 and CXCR6 has been shown to mediate multiple biological activities, including selective trafficking of lymphocyte subsets, cell adhesion, cell survival, chronic inflammation, and antitumor immunity. (16)(17)(18)(19)(20) In particular, human bone marrow plasma cells express CXCR6 selectively, and tissues known to be enriched with plasma cells as well as cultured human bone marrow stromal cells express CXCL16 constitutively, (13) implying the importance of the CXCL16-CXCR6 axis in efficient recruitment to target tissues. Furthermore, it has been found that first-trimester human cytotrophoblasts coexpress CXCL16 and CXCR6 as well as secreted CXCL16, which induces their inva...

RNA degradation affects RNA-seq quality when profiling transcriptional activities in cells. Here, we show that transcript degradation is both gene- and sample-specific and is a common and significant factor that may bias the results in RNA-seq analysis. Most existing global normalization approaches are ineffective to correct for degradation bias. We propose a novel pipeline named DegNorm to adjust the read counts for transcript degradation heterogeneity on a gene-by-gene basis while simultaneously controlling for the sequencing depth. The robust and effective performance of this method is demonstrated in an extensive set of simulated and real RNA-seq data. Electronic supplementary material The online version of this article (10.1186/s13059-019-1682-7) contains supplementary material, which is available to authorized users.

Long non‐coding RNA MIR503 host gene (MIR503HG) is located on chromosome Xq26.3, and has been found to be deregulated in many types of human malignancy and function as tumour suppressor or promoter based on cancer types. The role of MIR503HG in breast cancer was still unknown. In our study, we found MIR503HG expression was significantly decreased in triple‐negative breast cancer tissues and cell lines. Furthermore, we observed low MIR503HG expression was correlated with late clinical stage, lymph node metastasis and distant metastasis. In the survival analysis, we observed that triple‐negative breast cancer patients with low MIR503HG expression had a statistically significant worse prognosis compared with those with high MIR503HG expression, and low MIR503HG expression was a poor independent prognostic factor for overall survival in triple‐negative breast cancer patients. The study in vitro suggested MIR503HG inhibits cell migration and invasion via miR‐103/OLFM4 axis in triple negative breast cancer. In conclusion, MIR503HG functions as a tumour suppressive long non‐coding RNA in triple negative breast cancer.