Representation learning of genomic sequence motifs with convolutional neural networks.

Although convolutional neural networks (CNNs) have been applied to a variety of computational genomics problems, there remains a large gap in our understanding of how they build representations of regulatory genomic sequences. Here we perform systematic experiments on synthetic sequences to reveal how CNN architecture, specifically convolutional filter size and max-pooling, influences the extent that sequence motif representations are learned by first layer filters. We find that CNNs designed to foster hierarchical representation learning of sequence motifs-assembling partial features into whole features in deeper layers-tend to learn distributed representations, i.e. partial motifs. On the other hand, CNNs that are designed to limit the ability to hierarchically build sequence motif representations in deeper layers tend to learn more interpretable localist representations, i.e. whole motifs. We then validate that this representation learning principle established from synthetic sequences generalizes to in vivo sequences

Star Clusters in the Nearby Late-Type Galaxy NGC 1311

Ultraviolet, optical and near infrared images of the nearby (D ~ 5.5 Mpc) SBm galaxy NGC 1311, obtained with the Hubble Space Telescope, reveal a small population of 13 candidate star clusters. We identify candidate star clusters based on a combination of their luminosity, extent and spectral energy distribution. The masses of the cluster candidates range from ~1000 up to ~100000 Solar masses, and show a strong positive trend of larger mass with increasing with cluster age. Such a trend follows from the fading and dissolution of old, low-mass clusters, and the lack of any young super star clusters of the sort often formed in strong starbursts. The cluster age distribution is consistent with a bursting mode of cluster formation, with active episodes of age ~10 Myr, ~100 Myr and ~1 Gyr. The ranges of age and mass we probe are consistent with those of the star clusters found in quiescent Local Group dwarf galaxies.Comment: 21 pages, 11 figures, accepted by A

The tethering of chromatin to the nuclear envelope supports nuclear mechanics

The nuclear lamina is thought to be the primary mechanical defence of the nucleus. However, the lamina is integrated within a network of lipids, proteins and chromatin; the interdependence of this network poses a challenge to defining the individual mechanical contributions of these components. Here, we isolate the role of chromatin in nuclear mechanics by using a system lacking lamins. Using novel imaging analyses, we observe that untethering chromatin from the inner nuclear membrane results in highly deformable nuclei in vivo, particularly in response to cytoskeletal forces. Using optical tweezers, we find that isolated nuclei lacking inner nuclear membrane tethers are less stiff than wild-type nuclei and exhibit increased chromatin flow, particularly in frequency ranges that recapitulate the kinetics of cytoskeletal dynamics. We suggest that modulating chromatin flow can define both transient and long-lived changes in nuclear shape that are biologically important and may be altered in disease

Learning single-cell chromatin accessibility profiles using meta-analytic marker genes

MOTIVATION: Single-cell assay for transposase accessible chromatin using sequencing (scATAC-seq) is a valuable resource to learn cis-regulatory elements such as cell-type specific enhancers and transcription factor binding sites. However, cell-type identification of scATAC-seq data is known to be challenging due to the heterogeneity derived from different protocols and the high dropout rate. RESULTS: In this study, we perform a systematic comparison of seven scATAC-seq datasets of mouse brain to benchmark the efficacy of neuronal cell-type annotation from gene sets. We find that redundant marker genes give a dramatic improvement for a sparse scATAC-seq annotation across the data collected from different studies. Interestingly, simple aggregation of such marker genes achieves performance comparable or higher than that of machine-learning classifiers, suggesting its potential for downstream applications. Based on our results, we reannotated all scATAC-seq data for detailed cell types using robust marker genes. Their meta scATAC-seq profiles are publicly available at https://gillisweb.cshl.edu/Meta_scATAC. Furthermore, we trained a deep neural network to predict chromatin accessibility from only DNA sequence and identified key motifs enriched for each neuronal subtype. Those predicted profiles are visualized together in our database as a valuable resource to explore cell-type specific epigenetic regulation in a sequence-dependent and -independent manner

Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling

SummaryInsulin resistance is a primary defect in type 2 diabetes characterized by impaired peripheral glucose uptake and insufficient suppression of hepatic glucose output. Insulin signaling inhibits liver glucose production by inducing nuclear exclusion of the gluconeogenic transcription factor FOXO1 in an Akt-dependent manner. Through the concomitant application of genome-scale functional screening and quantitative image analysis, we have identified PTP-MEG2 as a modulator of insulin-dependent FOXO1 subcellular localization. Ectopic expression of PTP-MEG2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while RNAi-mediated reduction of PTP-MEG2 transcript levels enhanced insulin action. Additionally, adenoviral-mediated depletion of PTP-MEG2 in livers of diabetic (db/db) mice resulted in insulin sensitization and normalization of hyperglycemia. These data implicate PTP-MEG2 as a mediator of blood glucose homeostasis through antagonism of insulin signaling, and suggest that modulation of PTP-MEG2 activity may be an effective strategy in the treatment of type 2 diabetes

The lower mass function of the young open cluster Blanco 1: from 30 Mjup to 3 Mo

We performed a deep wide field optical survey of the young (~100-150 Myr) open cluster Blanco1 to study its low mass population well down into the brown dwarf regime and estimate its mass function over the whole cluster mass range.The survey covers 2.3 square degrees in the I and z-bands down to I ~ z ~ 24 with the CFH12K camera. Considering two different cluster ages (100 and 150 Myr), we selected cluster member candidates on the basis of their location in the (I,I-z) CMD relative to the isochrones, and estimated the contamination by foreground late-type field dwarfs using statistical arguments, infrared photometry and low-resolution optical spectroscopy. We find that our survey should contain about 57% of the cluster members in the 0.03-0.6 Mo mass range, including 30-40 brown dwarfs. The candidate's radial distribution presents evidence that mass segregation has already occured in the cluster. We took it into account to estimate the cluster mass function across the stellar/substellar boundary. We find that, between 0.03Mo and 0.6Mo, the cluster mass distribution does not depend much on its exact age, and is well represented by a single power-law, with an index alpha=0.69 +/- 0.15. Over the whole mass domain, from 0.03Mo to 3Mo, the mass function is better fitted by a log-normal function with m0=0.36 +/- 0.07Mo and sigma=0.58 +/- 0.06. Comparison between the Blanco1 mass function, other young open clusters' MF, and the galactic disc MF suggests that the IMF, from the substellar domain to the higher mass part, does not depend much on initial conditions. We discuss the implications of this result on theories developed to date to explain the origin of the mass distribution.Comment: 18 pages, 15 figures and 5 tables accepted in A&

Interpreting Potts and Transformer Protein Models Through the Lens of Simplified Attention

The established approach to unsupervised protein contact prediction estimates coevolving positions using undirected graphical models. This approach trains a Potts model on a Multiple Sequence Alignment. Increasingly large Transformers are being pretrained on unlabeled, unaligned protein sequence databases and showing competitive performance on protein contact prediction. We argue that attention is a principled model of protein interactions, grounded in real properties of protein family data. We introduce an energy-based attention layer, factored attention, which, in a certain limit, recovers a Potts model, and use it to contrast Potts and Transformers. We show that the Transformer leverages hierarchical signal in protein family databases not captured by single-layer models. This raises the exciting possibility for the development of powerful structured models of protein family databases

CANDELS Observations of the Structural Properties and Evolution of Galaxies in a Cluster at z=1.62

We discuss the structural and morphological properties of galaxies in a z=1.62 proto-cluster using near-IR imaging data from Hubble Space Telescope Wide Field Camera 3 data of the Cosmic Assembly Near-IR Deep Extragalactic Legacy Survey (CANDELS). The cluster galaxies exhibit a clear color-morphology relation: galaxies with colors of quiescent stellar populations generally have morphologies consistent with spheroids, and galaxies with colors consistent with ongoing star formation have disk-like and irregular morphologies. The size distribution of the quiescent cluster galaxies shows a deficit of compact (< 1kpc), massive galaxies compared to CANDELS field galaxies at z=1.6. As a result the cluster quiescent galaxies have larger average effective sizes compared to field galaxies at fixed mass at greater than 90% significance. Combined with data from the literature, the size evolution of quiescent cluster galaxies is relatively slow from z~1.6 to the present, growing as (1+z)^(-0.6+/-0.1). If this result is generalizable, then it implies that physical processes associated with the denser cluster region seems to have caused accelerated size growth in quiescent galaxies prior to z=1.6 and slower subsequent growth at z<1.6 compared to galaxies in the lower density field. The quiescent cluster galaxies at z=1.6 have higher ellipticities compared to lower redshift samples at fixed mass, and their surface-brightness profiles suggest that they contain extended stellar disks. We argue the cluster galaxies require dissipationless (i.e., gas-poor or "dry") mergers to reorganize the disk material and to match the relations for ellipticity, stellar mass, size, and color of early-type galaxies in z<1 clusters.Comment: Accepted for publication in ApJ. 14 pages in emulateapj format. Replacement includes improvements from referee report, and updates and additions to reference

Ca2+ Extrusion by NCX Is Compromised in Olfactory Sensory Neurons of OMP−/− Mice

The role of olfactory marker protein (OMP), a hallmark of mature olfactory sensory neurons (OSNs), has been poorly understood since its discovery. The electrophysiological and behavioral phenotypes of OMP knockout mice indicated that OMP influences olfactory signal transduction. However, the mechanism by which this occurs remained unknown.We used intact olfactory epithelium obtained from WT and OMP(-/-) mice to monitor the Ca(2+) dynamics induced by the activation of cyclic nucleotide-gated channels, voltage-operated Ca(2+) channels, or Ca(2+) stores in single dendritic knobs of OSNs. Our data suggested that OMP could act to modulate the Ca(2+)-homeostasis in these neurons by influencing the activity of the plasma membrane Na(+)/Ca(2+)-exchanger (NCX). Immunohistochemistry verifies colocalization of NCX1 and OMP in the cilia and knobs of OSNs. To test the role of NCX activity, we compared the kinetics of Ca(2+) elevation by stimulating the reverse mode of NCX in both WT and OMP(-/-) mice. The resulting Ca(2+) responses indicate that OMP facilitates NCX activity and allows rapid Ca(2+) extrusion from OSN knobs. To address the mechanism by which OMP influences NCX activity in OSNs we studied protein-peptide interactions in real-time using surface plasmon resonance technology. We demonstrate the direct interaction of the XIP regulatory-peptide of NCX with calmodulin (CaM).Since CaM also binds to the Bex protein, an interacting protein partner of OMP, these observations strongly suggest that OMP can influence CaM efficacy and thus alters NCX activity by a series of protein-protein interactions