一周快讯：本周表观文献精选（2019.8.31）

Cell Discovery：

ATG5 cancer mutations and alternative mRNA splicing reveal a conjugation switch that regulates ATG12–ATG5-ATG16L1 complex assembly and autophagy

Daric J. Wible, Hsueh-Ping Chao, Dean G. Tang & Shawn B. Bratton

原文链接：

https://www.nature.com/articles/s41421-019-0110-1

原文摘要：

Autophagy is critical for maintaining cellular homeostasis during times of stress, and is thought to play important roles in both tumorigenesis and tumor cell survival. Formation of autophagosomes, which mediate delivery of cytoplasmic cargo to lysosomes, requires multiple autophagy-related (ATG) protein complexes, including the ATG12–ATG5-ATG16L1 complex. Herein, we report that a molecular ATG5 “conjugation switch”, comprised of competing ATG12 and ubiquitin conjugation reactions, integrates ATG12–ATG5-ATG16L1 complex assembly with protein quality control of its otherwise highly unstable subunits. This conjugation switch is tightly regulated by ATG16L1, which binds to free ATG5 and mutually protects both proteins from ubiquitin conjugation and proteasomal degradation, thereby instead promoting the irreversible conjugation of ATG12 to ATG5. The resulting ATG12–ATG5 conjugate, in turn, displays enhanced affinity for ATG16L1 and thus fully stabilizes the ATG12–ATG5-ATG16L1 complex. Most importantly, we find in multiple tumor types that ATG5 somatic mutations and alternative mRNA splicing specifically disrupt the ATG16L1-binding pocket in ATG5 and impair the essential ATG5-ATG16L1 interactions that are initially required for ATG12–ATG5 conjugation. Finally, we provide evidence that ATG16L2, which is overexpressed in several cancers relative to ATG16L1, hijacks the conjugation switch by competing with ATG16L1 for binding to ATG5. While ATG16L2 stabilizes ATG5 and enables ATG12–ATG5 conjugation, this endogenous dominant-negative inhibitor simultaneously displaces ATG16L1, resulting in its proteasomal degradation and a block in autophagy. Thus, collectively, our findings provide novel insights into ATG12–ATG5-ATG16L1 complex assembly and reveal multiple mechanisms wherein dysregulation of the ATG5 conjugation switch inhibits autophagy.

Nature communications：

Distinct methylation levels of mature microRNAs in gastrointestinal cancers

Masamitsu Konno, Jun Koseki, Ayumu Asai, Akira Yamagata, Teppei Shimamura, Daisuke Motooka, Daisuke Okuzaki, Koichi Kawamoto, Tsunekazu Mizushima, Hidetoshi Eguchi, Shuji Takiguchi, Taroh Satoh, Koshi Mimori, Takahiro Ochiya, Yuichiro Doki, Ken Ofusa, Masaki Mori & Hideshi Ishii

原文链接：

https://www.nature.com/articles/s41467-019-11826-1

原文摘要：

The biological significance of micro (mi)RNAs has traditionally been evaluated according to their RNA expression levels based on the assumption that miRNAs recognize and regulate their targets in an unvarying fashion. Here we show that a fraction of mature miRNAs including miR-17-5p, -21-5p, and -200c-3p and let-7a-5p harbor methyl marks that potentially alter their stability and target recognition. Importantly, methylation of these miRNAs was significantly increased in cancer tissues as compared to paired normal tissues. Furthermore, miR-17-5p methylation level in serum samples distinguished early pancreatic cancer patients from healthy controls with extremely high sensitivity and specificity. These findings provide a basis for diagnostic strategies for early-stage cancer and add a dimension to our understanding of miRNA biology.

Nature communications：

Changes in gene expression predictably shift and switch genetic interactions

Xianghua Li, Jasna Lalic, Pablo Baeza-Centurion, Riddhiman Dhar & Ben Lehner

原文链接：

https://www.nature.com/articles/s41467-019-11735-3

原文摘要：

Non-additive interactions between mutations occur extensively and also change across conditions, making genetic prediction a difficult challenge. To better understand the plasticity of genetic interactions (epistasis), we combine mutations in a single protein performing a single function (a transcriptional repressor inhibiting a target gene). Even in this minimal system, genetic interactions switch from positive (suppressive) to negative (enhancing) as the expression of the gene changes. These seemingly complicated changes can be predicted using a mathematical model that propagates the effects of mutations on protein folding to the cellular phenotype. More generally, changes in gene expression should be expected to alter the effects of mutations and how they interact whenever the relationship between expression and a phenotype is nonlinear, which is the case for most genes. These results have important implications for understanding genotype-phenotype maps and illustrate how changes in genetic interactions can often—but not always—be predicted by hierarchical mechanistic models.

Nature communications：

EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity

Zhixiong Sun, Xiguang Xu, Jianlin He, Alexander Murray, Ming-an Sun, Xiaoran Wei, Xia Wang, Emmarose McCoig, Evan Xie, Xi Jiang, Liwu Li, Jinsong Zhu, Jianjun Chen, Alexei Morozov, Alicia M. Pickrell, Michelle H. Theus & Hehuang Xie

原文链接：

https://www.nature.com/articles/s41467-019-11905-3

原文摘要：

Life experience can leave lasting marks, such as epigenetic changes, in the brain. How life experience is translated into storable epigenetic information remains largely unknown. With unbiased data-driven approaches, we predicted that Egr1, a transcription factor important for memory formation, plays an essential role in brain epigenetic programming. We performed EGR1 ChIP-seq and validated thousands of EGR1 binding sites with methylation patterns established during postnatal brain development. More specifically, these EGR1 binding sites become hypomethylated in mature neurons but remain heavily methylated in glia. We further demonstrated that EGR1 recruits a DNA demethylase TET1 to remove the methylation marks and activate downstream genes. The frontal cortices from the knockout mice lacking Egr1 or Tet1 share strikingly similar profiles in both gene expression and DNA methylation. In summary, our study reveals EGR1 programs the brain methylome together with TET1 providing new insight into how life experience may shape the brain methylome.

Nature communications：

Emerging epigenomic landscapes of pancreatic cancer in the era of precision medicine

Gwen Lomberk, Nelson Dusetti, Juan Iovanna & Raul Urrutia

原文链接：

https://www.nature.com/articles/s41467-019-11812-7

原文摘要：

Genetic studies have advanced our understanding of pancreatic cancer at a mechanistic and translational level. Genetic concepts and tools are increasingly starting to be applied to clinical practice, in particular for precision medicine efforts. However, epigenomics is rapidly emerging as a promising conceptual and methodological paradigm for advancing the knowledge of this disease. More importantly, recent studies have uncovered potentially actionable pathways, which support the prediction that future trials for pancreatic cancer will involve the vigorous testing of epigenomic therapeutics. Thus, epigenomics promises to generate a significant amount of new knowledge of both biological and medical importance.