David M. S. Johnson

An integrated software system for analyzing ChIP-chip and ChIP-seq data

We present CisGenome, a software system for analyzing genome-wide chromatin immunoprecipitation (ChIP) data. CisGenome is designed to meet all basic needs of ChIP data analyses, including visualization, data normalization, peak detection, false discovery rate computation, gene-peak association, and sequence and motif analysis. In addition to implementing previously published ChIP–microarray (ChIP-chip) analysis methods, the software contains statistical methods designed specifically for ChlP sequencing (ChIP-seq) data obtained by coupling ChIP with massively parallel sequencing. The modular design of CisGenome enables it to support interactive analyses through a graphic user interface as well as customized batch-mode computation for advanced data mining. A built-in browser allows visualization of array images, signals, gene structure, conservation, and DNA sequence and motif information. We demonstrate the use of these tools by a comparative analysis of ChIP-chip and ChIP-seq data for the transcription factor NRSF/REST, a study of ChIP-seq analysis with or without a negative control sample, and an analysis of a new motif in Nanog- and Sox2-binding regions.

Genome-Wide Analysis of Transcription Factor Binding Sites Based on ChIP-Seq Data

Molecular interactions between protein complexes and DNA mediate essential gene-regulatory functions. Uncovering such interactions by chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-Seq) has recently become the focus of intense interest. We here introduce quantitative enrichment of sequence tags (QuEST), a powerful statistical framework based on the kernel density estimation approach, which uses ChIP-Seq data to determine positions where protein complexes contact DNA. Using QuEST, we discovered several thousand binding sites for the human transcription factors SRF, GABP and NRSF at an average resolution of about 20 base pairs. MEME motif-discovery tool–based analyses of the QuEST-identified sequences revealed DNA binding by cofactors of SRF, providing evidence that cofactor binding specificity can be obtained from ChIP-Seq data. By combining QuEST analyses with Gene Ontology (GO) annotations and expression data, we illustrate how general functions of transcription factors can be inferred.

Multiaxis inertial sensing with long-time point source atom interferometry.

We show that light-pulse atom interferometry with atomic point sources and spatially resolved detection enables multiaxis (two rotation, one acceleration) precision inertial sensing at long interrogation times. Using this method, we demonstrate a light-pulse atom interferometer for 87Rb with 1.4 cm peak wave packet separation and a duration of 2T=2.3 s. The inferred acceleration sensitivity of each shot is 6.7×10(-12)g, which improves on previous limits by more than 2 orders of magnitude. We also measure Earths rotation rate with a precision of 200 nrad/s.

Functional Architecture and Evolution of Transcriptional Elements That Drive Gene Coexpression

Transcriptional coexpression of interacting gene products is required for complex molecular processes; however, the function and evolution of cis-regulatory elements that orchestrate coexpression remain largely unexplored. We mutagenized 19 regulatory elements that drive coexpression of Ciona muscle genes and obtained quantitative estimates of the cis-regulatory activity of the 77 motifs that comprise these elements. We found that individual motif activity ranges broadly within and among elements, and among different instantiations of the same motif type. The activity of orthologous motifs is strongly constrained, although motif arrangement, type, and activity vary greatly among the elements of different co-regulated genes. Thus, the syntactical rules governing this regulatory function are flexible but become highly constrained evolutionarily once they are established in a particular element.

Enhanced atom interferometer readout through the application of phase shear.

We present a method for determining the phase and contrast of a single shot of an atom interferometer. The application of a phase shear across the atom ensemble yields a spatially varying fringe pattern at each output port, which can be imaged directly. This method is broadly relevant to atom-interferometric precision measurement, as we demonstrate in a 10 m 87Rb atomic fountain by implementing an atom-interferometric gyrocompass with 10 mdeg precision.

Broadband optical serrodyne frequency shifting.

We demonstrate serrodyne frequency shifting of light from 200 MHz to 1.2 GHz with an efficiency of better than 60%. The frequency shift is imparted by an electro-optic phase modulator driven by a high-frequency high-fidelity sawtooth waveform that is passively generated by a commercially available nonlinear transmission line. We also implement a push-pull configuration using two serrodyne-driven phase modulators, allowing for continuous tuning between -1.6 GHz and +1.6 GHz. Compared with competing technologies, this technique is simple and robust, and it offers the largest available tuning range in this frequency band.

Precision angle sensor using an optical lever inside a Sagnac interferometer

We built an ultra-low-noise angle sensor by combining a folded optical lever and a Sagnac interferometer. The instrument has a measured noise floor of 1.3 prad/√Hz at 2.4 kHz. We achieve this record angle sensitivity using a proof-of-concept apparatus with a conservative N=11 bounces in the optical lever. This technique could be extended to reach subpicoradian/√Hz sensitivities with an optimized design.

Identification of Rho GTPases implicated in terminal differentiation of muscle cells in ascidia

Background information. Members of the Rho GTPase family mediate changes in the actin cytoskeleton and are also implicated in developmental processes, including myogenesis. Nevertheless, a comprehensive analysis of these proteins during myofibrillogenesis has never been performed in any organism.

A high-performance magnetic shield with large length-to-diameter ratio

We have demonstrated a 100-fold improvement in the magnetic field uniformity on the axis of a large aspect ratio, cylindrical, mumetal magnetic shield by reducing discontinuities in the material of the shield through the welding and re-annealing of a segmented shield. The three-layer shield reduces Earths magnetic field along an 8 m region to 420 μG (rms) in the axial direction, and 460 and 730 μG (rms) in the two transverse directions. Each cylindrical shield is a continuous welded tube which has been annealed after manufacture and degaussed in the apparatus. We present both experiments and finite element analysis that show the importance of uniform shield material for large aspect ratio shields, favoring a welded design over a segmented design. In addition, we present finite element results demonstrating the smoothing of spatial variations in the applied magnetic field by cylindrical magnetic shields. Such homogenization is a potentially useful feature for precision atom interferometric measurements.

Picosecond Optical Switching Using RF Nonlinear Transmission Lines

We propose a novel sub-ps optical switch composed of an interferometer in which the phase difference between the arms is controlled by a pair of electrooptic modulators (EOMs) driven by integrated nonlinear transmission lines (NLTLs). As a proof-of-concept we demonstrate 70 ps switching using discrete LiNbO3 traveling wave EOMs and commercially available NLTLs capable of delivering a 35 ps falling edge. This technique is simple and robust, and can potentially be extended to sub-ps switching by integrating the NLTL into the EOM waveguide. This fast switch can be used to implement an Optical Time Division Multiplexing (OTDM) network architecture.