623 research outputs found
ZNF410 represses fetal globin by devoted control of CHD4/NuRD [preprint]
Major effectors of adult-stage fetal globin silencing include the transcription factors (TFs) BCL11A and ZBTB7A/LRF and the NuRD chromatin complex, although each has potential on-target liabilities for rational β-hemoglobinopathy therapeutic inhibition. Here through CRISPR screening we discover ZNF410 to be a novel fetal hemoglobin (HbF) repressing TF. ZNF410 does not bind directly to the γ-globin genes but rather its chromatin occupancy is solely concentrated at CHD4, encoding the NuRD nucleosome remodeler, itself required for HbF repression. CHD4 has two ZNF410-bound regulatory elements with 27 combined ZNF410 binding motifs constituting unparalleled genomic clusters. These elements completely account for ZNF410’s effects on γ-globin repression. Knockout of ZNF410 reduces CHD4 by 60%, enough to substantially de-repress HbF while avoiding the cellular toxicity of complete CHD4 loss. Mice with constitutive deficiency of the homolog Zfp410 are born at expected Mendelian ratios with unremarkable hematology. ZNF410 is dispensable for human hematopoietic engraftment potential and erythroid maturation unlike known HbF repressors. These studies identify a new rational target for HbF induction for the β-hemoglobin disorders with a wide therapeutic index. More broadly, ZNF410 represents a special class of gene regulator, a conserved transcription factor with singular devotion to regulation of a chromatin subcomplex
A new measurement of antineutrino oscillation with the full detector configuration at Daya Bay
We report a new measurement of electron antineutrino disappearance using the
fully-constructed Daya Bay Reactor Neutrino Experiment. The final two of eight
antineutrino detectors were installed in the summer of 2012. Including the 404
days of data collected from October 2012 to November 2013 resulted in a total
exposure of 6.910 GW-ton-days, a 3.6 times increase over
our previous results. Improvements in energy calibration limited variations
between detectors to 0.2%. Removal of six Am-C radioactive
calibration sources reduced the background by a factor of two for the detectors
in the experimental hall furthest from the reactors. Direct prediction of the
antineutrino signal in the far detectors based on the measurements in the near
detectors explicitly minimized the dependence of the measurement on models of
reactor antineutrino emission. The uncertainties in our estimates of
and were halved as a result of these
improvements. Analysis of the relative antineutrino rates and energy spectra
between detectors gave and eV in the three-neutrino
framework.Comment: Updated to match final published versio
New measurement of via neutron capture on hydrogen at Daya Bay
This article reports an improved independent measurement of neutrino mixing
angle at the Daya Bay Reactor Neutrino Experiment. Electron
antineutrinos were identified by inverse -decays with the emitted
neutron captured by hydrogen, yielding a data-set with principally distinct
uncertainties from that with neutrons captured by gadolinium. With the final
two of eight antineutrino detectors installed, this study used 621 days of data
including the previously reported 217-day data set with six detectors. The
dominant statistical uncertainty was reduced by 49%. Intensive studies of the
cosmogenic muon-induced Li and fast neutron backgrounds and the
neutron-capture energy selection efficiency, resulted in a reduction of the
systematic uncertainty by 26%. The deficit in the detected number of
antineutrinos at the far detectors relative to the expected number based on the
near detectors yielded in the
three-neutrino-oscillation framework. The combination of this result with the
gadolinium-capture result is also reported.Comment: 26 pages, 23 figure
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