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A risk worth taking

Čt, 04/08/2021 - 19:41

QSER1 protects DNA methylation valleys from de novo methylation

Čt, 04/08/2021 - 19:41

DNA methylation is essential to mammalian development, and dysregulation can cause serious pathological conditions. Key enzymes responsible for deposition and removal of DNA methylation are known, but how they cooperate to regulate the methylation landscape remains a central question. Using a knockin DNA methylation reporter, we performed a genome-wide CRISPR-Cas9 screen in human embryonic stem cells to discover DNA methylation regulators. The top screen hit was an uncharacterized gene, QSER1, which proved to be a key guardian of bivalent promoters and poised enhancers of developmental genes, especially those residing in DNA methylation valleys (or canyons). We further demonstrate genetic and biochemical interactions of QSER1 and TET1, supporting their cooperation to safeguard transcriptional and developmental programs from DNMT3-mediated de novo methylation.

Comment on "Tumor-initiating cells establish an IL-33-TGF-{beta} niche signaling loop to promote cancer progression"

Čt, 04/08/2021 - 19:41

Taniguchi et al. (Research Articles, 17 July 2020, p. 269) claim that the cytokine interleukin-33 induces accumulation of tumor-associated macrophages expressing the immunoglobulin E receptor FcRI. Although these findings hold great therapeutic promise, we provide evidence that the anti-FcRI antibody used in this study is not specific for FcRI on macrophages, which raises concerns about the validity of some of the conclusions.

Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England

Čt, 04/08/2021 - 19:41

A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, VOC 202012/01 (lineage B.1.1.7), emerged in southeast England in September 2020 and is rapidly spreading toward fixation. Using a variety of statistical and dynamic modeling approaches, we estimate that this variant has a 43 to 90% (range of 95% credible intervals, 38 to 130%) higher reproduction number than preexisting variants. A fitted two-strain dynamic transmission model shows that VOC 202012/01 will lead to large resurgences of COVID-19 cases. Without stringent control measures, including limited closure of educational institutions and a greatly accelerated vaccine rollout, COVID-19 hospitalizations and deaths across England in the first 6 months of 2021 were projected to exceed those in 2020. VOC 202012/01 has spread globally and exhibits a similar transmission increase (59 to 74%) in Denmark, Switzerland, and the United States.

Imaging cell lineage with a synthetic digital recording system

Čt, 04/08/2021 - 19:41

During multicellular development, spatial position and lineage history play powerful roles in controlling cell fate decisions. Using a serine integrase–based recording system, we engineered cells to record lineage information in a format that can be read out in situ. The system, termed integrase-editable memory by engineered mutagenesis with optical in situ readout (intMEMOIR), allowed in situ reconstruction of lineage relationships in cultured mouse cells and flies. intMEMOIR uses an array of independent three-state genetic memory elements that can recombine stochastically and irreversibly, allowing up to 59,049 distinct digital states. It reconstructed lineage trees in stem cells and enabled simultaneous analysis of single-cell clonal history, spatial position, and gene expression in Drosophila brain sections. These results establish a foundation for microscopy-readable lineage recording and analysis in diverse systems.

Response to Comment on "Tumor-initiating cells establish an IL-33-TGF-{beta} niche signaling loop to promote cancer progression"

Čt, 04/08/2021 - 19:41

Kamphuis et al. argue that macrophages accumulated in the proximity of tumor-initiating cells do not express the high-affinity immunoglobulin E receptor FcRIα. Although we cannot exclude the possibility of nonspecific binding of anti-FcRIα antibody (clone MAR-1), we provide evidence that macrophages in squamous cell carcinomas express FcRIα and that IL-33 induces FcRIα expression in bone marrow cell–derived macrophages.

Epigenetics, fragmentomics, and topology of cell-free DNA in liquid biopsies

Čt, 04/08/2021 - 19:41

Liquid biopsies that analyze cell-free DNA in blood plasma are used for noninvasive prenatal testing, oncology, and monitoring of organ transplant recipients. DNA molecules are released into the plasma from various bodily tissues. Physical and molecular features of cell-free DNA fragments and their distribution over the genome bear information about their tissues of origin. Moreover, patterns of DNA methylation of these molecules reflect those of their tissue sources. The nucleosomal organization and nuclease content of the tissue of origin affect the fragmentation profile of plasma DNA molecules, such as fragment size and end motifs. Besides double-stranded linear fragments, other topological forms of cell-free DNA also exist—namely circular and single-stranded molecules. Enhanced by these features, liquid biopsies hold promise for the noninvasive detection of tissue-specific pathologies with a range of clinical applications.

Mechanism and dynamics of fatty acid photodecarboxylase

Čt, 04/08/2021 - 19:41

Fatty acid photodecarboxylase (FAP) is a photoenzyme with potential green chemistry applications. By combining static, time-resolved, and cryotrapping spectroscopy and crystallography as well as computation, we characterized Chlorella variabilis FAP reaction intermediates on time scales from subpicoseconds to milliseconds. High-resolution crystal structures from synchrotron and free electron laser x-ray sources highlighted an unusual bent shape of the oxidized flavin chromophore. We demonstrate that decarboxylation occurs directly upon reduction of the excited flavin by the fatty acid substrate. Along with flavin reoxidation by the alkyl radical intermediate, a major fraction of the cleaved carbon dioxide unexpectedly transformed in 100 nanoseconds, most likely into bicarbonate. This reaction is orders of magnitude faster than in solution. Two strictly conserved residues, R451 and C432, are essential for substrate stabilization and functional charge transfer.

Structure and dynamics of the CGRP receptor in apo and peptide-bound forms

Čt, 04/08/2021 - 19:41

G protein–coupled receptors (GPCRs) are key regulators of information transmission between cells and organs. Despite this, we have only a limited understanding of the behavior of GPCRs in the apo state and the conformational changes upon agonist binding that lead to G protein recruitment and activation. We expressed and purified unmodified apo and peptide-bound calcitonin gene–related peptide (CGRP) receptors from insect cells to determine their cryo–electron microscopy (cryo-EM) structures, and we complemented these with analysis of protein conformational dynamics using hydrogen-deuterium exchange mass spectrometry and three-dimensional variance analysis of the cryo-EM data. Together with our previously published structure of the active, Gs-bound CGRP receptor complex, our work provides insight into the mechanisms of class B1 GPCR activation.

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