一周快讯：本周表观文献精选（2018.5.12）

Chromatin analysis in human early development reveals epigenetic transition during ZGA

Jingyi Wu, Jiawei Xu, Yingpu Sun

原文链接：

https://www.nature.com/articles/s41586-018-0080-8

原文摘要：

Upon fertilization, drastic chromatin reorganization occurs during preimplantation development1. However, the global chromatin landscape and its molecular dynamics in this period remain largely unexplored in humans. Here we investigate chromatin states in human preimplantation development using an improved assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq)2. We find widespread accessible chromatin regions in early human embryos that overlap extensively with putative cis-regulatory sequences and transposable elements. Integrative analyses show both conservation and divergence in regulatory circuitry between human and mouse early development, and between human pluripotency in vivo and human embryonic stem cells. In addition, we find widespread open chromatin regions before zygotic genome activation (ZGA). The accessible chromatin loci are readily found at CpG-rich promoters. Unexpectedly, many others reside in distal regions that overlap with DNA hypomethylated domains in human oocytes and are enriched for transcription factor-binding sites. A large portion of these regions then become inaccessible after ZGA in a transcription-dependent manner. Notably, such extensive chromatin reorganization during ZGA is conserved in mice and correlates with the reprogramming of the non-canonical histone mark H3K4me3, which is uniquely linked to genome silencing3,4,5. Taken together, these data not only reveal a conserved principle that underlies the chromatin transition during mammalian ZGA, but also help to advance our understanding of epigenetic reprogramming during human early development and in vitro fertilization.

Loss-of-function of IFT88 determines metabolic phenotypes in thyroid cancer

Junguee Lee, Shinae Yi, Minho Won, Young Shin Song, Hyon-Seung Yi, Young Joo Park, Ki Cheol Park, Jung Tae Kim, Joon Young Chang, Min Joung Lee, Hae Joung Sul, Ji Eun Choi, Koon Soon Kim, Jukka Kero, Joon Kim & Minho Shong

原文链接：

https://www.nature.com/articles/s41388-018-0211-6

原文摘要：

Primary cilia are microtubule-based, dynamic organelles characterized by continuous assembly and disassembly. The intraflagellar transport (IFT) machinery, including IFT88 in cilia, is involved in the maintenance of bidirectional motility along the axonemes, which is required for ciliogenesis and functional competence. Cancer cells are frequently associated with loss of primary cilia and IFT functions. However, there is little information on the role of IFT88 or primary cilia in the metabolic remodeling of cancer cells. Therefore, we investigated the cellular and metabolic effects of the loss-of-function (LOF) mutations of IFT88/primary cilia in thyroid cancer cells. IFT88-deficient 8505C thyroid cancer cells were generated using the CRISPR/Cas9 system, and RNA-sequencing analysis was performed. LOF of the IFT88 gene resulted in a marked defect in ciliogenesis and mitochondrial oxidative function. Gene expression patterns in IFT88-deficient thyroid cancer cells favored glycolysis and lipid biosynthesis. However, LOF of IFT88/primary cilia did not promote thyroid cancer cell proliferation, migration, and invasion. The results suggest that IFT88/primary cilia play a role in metabolic reprogramming in thyroid cancer cells.

GALNT5 uaRNA promotes gastric cancer progression through its interaction with HSP90

Hui Guo, Lianmei Zhao, Bianhua Shi, Jiayu Bao, Dexian Zheng, Baoguo Zhou & Juan Shi

原文链接：

https://www.nature.com/articles/s41388-018-0266-4

原文摘要：

Recently, long noncoding RNAs (lncRNAs) have been reported to play a pivotal role in the occurrence and progression of cancer because of their unique characteristics and have therefore become an active area of cancer research. The object of this study was to screen lncRNAs that are dysregulated in gastric cancer and to investigate their potential functions. Global expression of lncRNAs in gastric cancer and adjacent normal tissues of patients was profiled using a microarray assay. We identified an lncRNA (GALNT5 uaRNA, UTR-associated RNA) that is derived from the 3′-UTR of GALNT5. This lncRNA was transcribed independently of the coding region of GALNT5 and was determined to be markedly upregulated in human gastric carcinoma relative to their corresponding normal gastric tissues by quantitative RT-PCR (qRT-PCR) analysis of tissues from 122 gastric carcinoma patients. The expression of GALNT5 uaRNA was significantly correlated with the TNM stage and with lymph node metastasis. Further results demonstrated that GALNT5 uaRNA facilitated the proliferation and migration of gastric cancer cells in vitro and promoted tumor growth in a mouse model of human gastric cancer. Our results also indicated that GALNT5 uaRNA might function in gastric cancer by binding with HSP90. Further studies indicated that the 5′-end stem-loop motifs of GALNT5 uaRNA promoted the binding of HSP90 and its client proteins, and thus inhibited ubiquitination of the clients. These results expanded our understanding of GALNT5 uaRNA as a new avenue for therapeutic intervention against gastric cancer progression.

ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade

Jianfeng Shen, Zhenlin Ju, Wei Zhao, Lulu Wang, Yang Peng, Zhongqi Ge, Zachary D. Nagel, Jun Zou, Chen Wang, Prabodh Kapoor, Xiangyi Ma, Ding Ma, Jiyong Liang, Shumei Song, Jinsong Liu, Leona D. Samson, Jaffer A. Ajani, Guo-Min Li, Han Liang, Xuetong Shen, Gordon B. Mills & Guang Peng

原文链接：

https://www.nature.com/articles/s41591-018-0012-z

原文摘要：

ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer1,2. The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression3, which makes ARID1A a poor therapeutic target. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A-mutant tumors. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis. ARID1A deficiency correlated with microsatellite instability genomic signature and a predominant C>T mutation pattern and increased mutation load across multiple human cancer types. Tumors formed by an ARID1A-deficient ovarian cancer cell line in syngeneic mice displayed increased mutation load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression. Notably, treatment with anti-PD-L1 antibody reduced tumor burden and prolonged survival of mice bearing ARID1A-deficient but not ARID1A-wild-type ovarian tumors. Together, these results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy.

CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought

Mary E. Klein, Marta Kovatcheva, Lara E. Davis, William D. Tap, Andrew Koff

原文链接：

https://www.cell.com/cancer-cell/fulltext/S1535-6108(18)30128-4

原文摘要：

CDK4/6 inhibitors are among a new generation of therapeutics. Building upon the striking success of the combination of CDK4/6 inhibitors and the hormone receptor antagonist letrozole in breast cancer, many other combinations have recently entered clinical trials in multiple diseases. To achieve maximal benefit with CDK4/6 inhibitors it will be critical to understand the cellular mechanisms by which they act. Here we highlight the mechanisms by which CDK4/6 inhibitors can exert their anti-tumor activities beyond simply enforcing cytostatic growth arrest, and discuss how this knowledge may inform new combinations, improve outcomes, and modify dosing schedules in the future.

RNA Helicase DDX1 Converts RNA G-Quadruplex Structures into R-Loops to Promote IgH Class Switch Recombination

Claudia Ribeiro de Almeida, Somdutta Dhir, Ashish Dhir, Amin E. Moghaddam, Quentin Sattentau, Anton Meinhart, Nicholas J. Proudfoot

原文链接：

https://www.cell.com/molecular-cell/fulltext/S1097-2765(18)30269-7

原文摘要：

Class switch recombination (CSR) at the immunoglobulin heavy-chain (IgH) locus is associated with the formation of R-loop structures over switch (S) regions. While these often occur co-transcriptionally between nascent RNA and template DNA, we now show that they also form as part of a post-transcriptional mechanism targeting AID to IgH S-regions. This depends on the RNA helicase DDX1 that is also required for CSR in vivo. DDX1 binds to G-quadruplex (G4) structures present in intronic switch transcripts and converts them into S-region R-loops. This in turn targets the cytidine deaminase enzyme AID to S-regions so promoting CSR. Notably R-loop levels over S-regions are diminished by chemical stabilization of G4 RNA or by the expression of a DDX1 ATPase-deficient mutant that acts as a dominant-negative protein to reduce CSR efficiency. In effect, we provide evidence for how S-region transcripts interconvert between G4 and R-loop structures to promote CSR in the IgH locus.