Jul 06, 2012

Leading Edge

In This Issue

In This Issue
PAGE 122

Previews

Maternal-Fetal Immune Tolerance, Block by Block
• Michael Gobert,
• Juan J. Lafaille
How difficult is to go from egg to implanted embryo? The evolution of placentation in eutherian mammals created enormous challenges, in particular to the maternal immune system, as the fetus expresses paternal antigens that are capable of triggering immune rejection. Samstein et al. reveal a role for inducible regulatory T cells in the enforcement of maternal-fetal immune tolerance.

U1 snRNA Rewrites the “Script”
• Evan C. Merkhofer,
• Tracy L. Johnson
Expression of eukaryotic mRNAs requires the collaboration of a host of RNA processing factors acting upon the transcript. Berg et al. describe how a pre-mRNA splicing factor modulates the activity of the polyadenylation machinery to regulate mRNA length, with important implications for isoform expression in activated neuronal and immune cells.

Review

Cancer Epigenetics: From Mechanism to Therapy
• Mark A. Dawson,
• Tony Kouzarides
The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15 years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biological processes that are fundamental to the genesis of cancer. Here, we present the basic principles behind these epigenetic pathways and highlight the evidence suggesting that their misregulation can culminate in cancer. This information, along with the promising clinical and preclinical results seen with epigenetic drugs against chromatin regulators, signifies that it is time to embrace the central role of epigenetics in cancer.

Articles

Extrathymic Generation of Regulatory T Cells in Placental Mammals Mitigates Maternal-Fetal Conflict
• Robert M. Samstein,
• Steven Z. Josefowicz,
• Aaron Arvey,
• Piper M. Treuting,
• Alexander Y. Rudensky
Molecular phylogeny reveals that an enhancer for the transcription factor Foxp3, which is essential for the differentiation of a subset of regulatory T cells, is present only in placental mammals. These T cells are important for maternal tolerance of the fetus, presenting a potential explanation for the emergence of a mechanism of extrathymic differentiation of T regulatory cells during evolution.

Telomeric 3′ Overhangs Derive from Resection by Exo1 and Apollo and Fill-In by POT1b-Associated CST
• Peng Wu,
• Hiroyuki Takai,
• Titia de Lange
The 3′ overhangs that help maintain and protect telomeres in mammalian cells are generated by nuclease resection of the 5′ end followed by fill-in synthesis. The telomeres synthesized by leading- and lagging-strand DNA replication are processed differently, and in both cases interactions with the shelterin complex preclude excessive resection and telomere shortening.

U1 snRNP Determines mRNA Length and Regulates Isoform Expression
• Michael G. Berg,
• Larry N. Singh,
• Ihab Younis,
• Qiang Liu,
• Anna Maria Pinto,
• Daisuke Kaida,
• Zhenxi Zhang,
• Sungchan Cho,
• Scott Sherrill-Mix,
• Lili Wan,
• Gideon Dreyfuss
In addition to its role in pre-mRNA splicing, U1 snRNP also regulates transcript length by preventing premature cleavage and polyadenylation at cryptic polyadenylation sites. Decreasing U1 levels leads to progressively shorter transcripts, and in neurons, where activation can selectively elevate mRNA levels relative to U1, this regulatory mechanism influences the transition between expressed protein isoforms of proteins involved in synaptogenesis.

piRNAs Initiate an Epigenetic Memory of Nonself RNA in the C. elegans Germline
• Masaki Shirayama,
• Meetu Seth,
• Heng-Chi Lee,
• Weifeng Gu,
• Takao Ishidate,
• Darryl Conte Jr.,
• Craig C. Mello
Evidence for a provocative theory that places piRNAs at the center of a “self” versus “nonself” sensor, with some piRNAs functioning to silence foreign DNA and others as part of a mechanism that protects endogenous germline-expressed genes from aberrant silencing.

C. elegans piRNAs Mediate the Genome-wide Surveillance of Germline Transcripts
• Heng-Chi Lee,
• Weifeng Gu,
• Masaki Shirayama,
• Elaine Youngman,
• Darryl Conte Jr.,
• Craig C. Mello
piRNA-mediated silencing persists for dozens of generations in worms, and a hand-off from piRNA-binding proteins to the nuclear WAGO Argonaute transcriptional silencing pathway means that the initial trigger does not need to be present to maintain the transgenerational effect.

piRNAs Can Trigger a Multigenerational Epigenetic Memory in the Germline of C. elegans
• Alyson Ashe,
• Alexandra Sapetschnig,
• Eva-Maria Weick,
• Jacinth Mitchell,
• Marloes P. Bagijn,
• Amy C. Cording,
• Anna-Lisa Doebley,
• Leonard D. Goldstein,
• Nicolas J. Lehrbach,
• Jérémie Le Pen,
• Greta Pintacuda,
• Aisa Sakaguchi,
• Peter Sarkies,
• Shawn Ahmed,
• Eric A. Miska
Multigenerational inheritance and piRNAs converge on same silencing pathway, in which both nuclear WAGOs and chromatin factors are required. The piRNA trigger can be lost, but the nuclear silencing pathway maintains the silencing for more than 20 generations.

The Structure of Human Argonaute-2 in Complex with miR-20a
• Elad Elkayam,
• Claus-D. Kuhn,
• Ante Tocilj,
• Astrid D. Haase,
• Emily M. Greene,
• Gregory J. Hannon,
• Leemor Joshua-Tor
The crystal structure of human Argonaute-2, the “slicer” in RNA interference, loaded with a miRNA with roles in development and cancer provides a framework to understand the functions of this essential enzyme.

A Translation-Like Cycle Is a Quality Control Checkpoint for Maturing 40S Ribosome Subunits
• Bethany S. Strunk,
• Megan N. Novak,
• Crystal L. Young,
• Katrin Karbstein
Discovery of a translation-like cycle that involves the assembly and disassembly of inactive 80S-like ribosomes lacking mRNA and tRNA identifies a quality control step where cells test the functionality of immature 40S subunits before the final stages of ribosome maturation are allowed to proceed.

Coordination of Kinase and Phosphatase Activities by Lem4 Enables Nuclear Envelope Reassembly during Mitosis
• Claudio Asencio,
• Iain F. Davidson,
• Rachel Santarella-Mellwig,
• Thi Bach Nga Ly-Hartig,
• Moritz Mall,
• Matthew R. Wallenfang,
• Iain W. Mattaj,
• Mátyás Gorjánácz
Phosphorylation of the protein BAF, an essential factor in nuclear envelope reformation, reduces its affinity for chromatin and its association with proteins that reside in the inner nuclear membrane. Identification of the protein Lem4 reveals the mechanism that regulates BAF dephosphorylation and controls postmitotic nuclear envelope formation.

Identification of Stem Cell Populations in Sweat Glands and Ducts Reveals Roles in Homeostasis and Wound Repair
• Catherine P. Lu,
• Lisa Polak,
• Ana Sofia Rocha,
• H. Amalia Pasolli,
• Shann-Ching Chen,
• Neha Sharma,
• Cedric Blanpain,
• Elaine Fuchs
Distinct stem cell populations in the sweat gland exhibit different regenerative potential and responses to injury. Progenitors produce de novo sweat glands when engrafted into the breast, revealing fundamental differences between the stem cells that give rise to the sweat and mammary glands and the responsiveness of glandular stem cells to their microenvironment.

Proteasomal Degradation Resolves Competition between Cell Polarization and Cellular Wound Healing
• Keiko Kono,
• Yasushi Saeki,
• Satoshi Yoshida,
• Keiji Tanaka,
• David Pellman
The same cytoskeletal and signaling molecules play a role in both cell polarity and cellular wound repair. In yeast cells, damage to the membrane triggers proteasomal degradation of polarity factors, allowing the redistribution of cytoskeletal and signaling proteins from the bud to the wound site, thus preventing competition between polarity and wound repair.

A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis
• Swarnali Acharyya,
• Thordur Oskarsson,
• Sakari Vanharanta,
• Srinivas Malladi,
• Juliet Kim,
• Patrick G. Morris,
• Katia Manova-Todorova,
• Margaret Leversha,
• Nancy Hogg,
• Venkatraman E. Seshan,
• Larry Norton,
• Edi Brogi,
• Joan Massagué
A paracrine cascade that triggers the production of survival factors by surrounding stromal cells, enabling the survival of metastatic cancer cells, is also elicited by chemotherapeutic agents and is central to chemoresistance. Blocking this chemokine axis may improve the efficacy of chemotherapy and reduce metastatic burden in breast cancer.

Acetylation-Dependent Regulation of Skp2 Function
• Hiroyuki Inuzuka,
• Daming Gao,
• Lydia W.S. Finley,
• Wen Yang,
• Lixin Wan,
• Hidefumi Fukushima,
• Y. Rebecca Chin,
• Bo Zhai,
• Shavali Shaik,
• Alan W. Lau,
• Zhiwei Wang,
• Steven P. Gygi,
• Keiko Nakayama,
• Julie Teruya-Feldstein,
• Alex Toker,
• Marcia C. Haigis,
• Pier Paolo Pandolfi,
• Wenyi Wei
Acetylation of the E3 ubiquitin ligase Skp2 leads to its cytoplasmic retention. This enhances the ubiquitin-mediated destruction of the adhesion molecule E-cadherin, thereby promoting cell migration during tumorigenesis.

Follicular Dendritic Cells Emerge from Ubiquitous Perivascular Precursors
• Nike Julia Krautler,
• Veronika Kana,
• Jan Kranich,
• Yinghua Tian,
• Dushan Perera,
• Doreen Lemm,
• Petra Schwarz,
• Annika Armulik,
• Jeffrey L. Browning,
• Michelle Tallquist,
• Thorsten Buch,
• José B. Oliveira-Martins,
• Caihong Zhu,
• Mario Hermann,
• Ulrich Wagner,
• Robert Brink,
• Mathias Heikenwalder,
• Adriano Aguzzi
Follicular dendritic cells (FDC) provide a cellular scaffold for lymphoid follicles, which facilitate the encounter between immune cells and antigens. The identification of a specific population of blood-vessel associated cells as precursors of FDC may explain the rapid, de novo generation of lymphoid follicles anywhere in the body during an inflammatory response.

Activity-Dependent Transport of the Transcriptional Coactivator CRTC1 from Synapse to Nucleus
• Toh Hean Ch'ng,
• Besim Uzgil,
• Peter Lin,
• Nuraly K. Avliyakulov,
• Thomas J. O'Dell,
• Kelsey C. Martin
How do calcium and cAMP differentially influence the dynamic gene expression required for neuronal plasticity and long-term memory formation? Local synaptic activity triggers calcium-dependent nuclear transport of CRCT1, whereas cAMP regulates CRCT1's nuclear persistence, suggesting that this transcriptional coactivator integrates both synaptic and neuromodulatory stimuli.

Adaptive Mutations that Prevent Crosstalk Enable the Expansion of Paralogous Signaling Protein Families
• Emily J. Capra,
• Barrett S. Perchuk,
• Jeffrey M. Skerker,
• Michael T. Laub
Following gene duplication, selective pressure to avoid signaling crosstalk drives gene divergence, promoting a burst of mutations in specificity determining residues.

Erratum

The Structure of Human Argonaute-2 in Complex with miR-20a
• Elad Elkayam,
• Claus-D. Kuhn,
• Ante Tocilj,
• Astrid D. Haase,
• Emily M. Greene,
• Gregory J. Hannon,
• Leemor Joshua-Tor
(Cell 150, 100–110; July 6, 2012)

SnapShot

SnapShot: Adipocyte Life Cycle
• Yuwei Jiang,
• A-Young Jo,
• Jonathan M. Graff