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Baker, C. L.

Publications and source records attributed to Baker, C. L..

At least 19 recordsLinked to original sources

A panel of Diversity Outbred mouse embryonic stem cells: enabling the functional characterization of natural genetic variation in vitro

Phenotypic variation in pluripotent stem cells arises largely from genetic variants that impact stability of the pluripotent state, response to differentiation cues, and cell fate diversification. Panels derived from genetic reference populations leverage genetic diversity to map the loci influencing these molecular and cellular traits. Here we describe the first publicly available resource for in vitro systems genetics in Mus musculus: 299 genetically diverse, highly heterozygous embryonic stem cell lines derived from Diversity Outbred mice, with minimal kinship across the panel. We characterize genomic integrity and allelic variation across the panel and describe differences in pluripotency and differentiation networks in embryoid bodies. Mapping the genetic determinants of gene expression differences in response to cadmium exposure in embryoid bodies identified 13 regulatory hotspots, the largest acting on ribosome biogenesis genes. This panel enables mapping of loci and gene-by-environment interactions that influence molecular identity in pluripotent cells and their derived cell types.

systems biology↗

A shared genetic regulator of metabolism and addiction-related behavior in mice and humans

Substance use disorders and other mental health conditions often co-occur with metabolic disorders, suggesting shared biological underpinnings1. These heightened behavioral and physiological responses may have evolved to promote survival during resource scarcity but can become maladaptive in modern environments2. The genetic mechanisms linking these traits have remained elusive. Here, we show that a variable gene enhancer in mice jointly regulates genes encoding an epigenetic factor (Eed) and a mitochondrial enzyme (Me3) thereby influencing propensity to addiction-related behaviors and mitochondrial function. We further identify variation in a corresponding enhancer in humans regulating EED and ME3 associated with substance use, psychiatric and metabolic disorders. These findings reveal a convergent genetic regulatory network linking mitochondrial biology to behavioral and metabolic risk, offering insight into how genetic variation in beneficial regulatory pathways can predispose individuals to substance use disorders and related conditions.

genetics↗

Trans-regulation of heterochromatin underlies genetic variation in 3D genome contacts

Genetic variation drives phenotypic diversity and disease susceptibility. Trans-acting genetic variation coordinates genome-wide chromatin changes, yet the molecular mechanisms underlying this regulation remain unclear. Here, we use the power of mouse genetics to investigate how genetic variation at trans-acting loci regulates 3D chromatin interactions. Using HiChIP to map H3K27ac-associated regulatory elements in C57BL/6J and DBA/2J embryonic stem cells (ESCs), we identified 4,962 strain-differential interactions, 71% of which overlapped chromatin accessibility quantitative trait loci (QTL), establishing chromatin interaction variation is predominantly heritable. These differential interactions showed coordinated changes in chromatin state and gene expression, with stronger interactions associated with increased accessibility and transcription. Notably, loci regulated in trans exhibited a unique chromatin signature where weaker interactions were enriched for H3K9me3-marked heterochromatin. Analysis of F1 hybrids revealed dominant repressive effects, consistent with heterochromatin-mediated trans-regulation. To causally test this mechanism, we generated reciprocal congenic mouse strains carrying a Chr13 trans-QTL region. Integrated multiomic profiling of congenic ESC lines demonstrated that this single locus coordinates changes in H3K9me3, H3K27ac, chromatin accessibility, and 3D contact frequency at hundreds of distal targets. Consistent with our expectations, 73-83% of differential interactions at Chr13 trans-QTL targets changed in the predicted direction, demonstrating that heterochromatin-mediated trans-regulation coordinately regulates hundreds of regulatory loci. This work establishes heterochromatin formation as a mechanism by which genetic variation at trans-acting loci coordinates changes across chromatin accessibility, histone modifications, and 3D genome organization, providing a framework for understanding how early developmental chromatin states could generate phenotypic variation while preserving essential developmental programs.

genomics↗

Impaired perception of isoluminant contrast modulation stimuli: Evidence for a magnocellular pathway mechanism

Contrast modulation (CM) stimuli have been previously used to reveal nonlinear contributions of Y-like retinal ganglion cells (RGCs) such as parasol cells to cortical responses and perception. To test whether CMs are selectively processed within the magnocellular pathway, we assessed envelope motion discrimination and detection for achromatic (yellow-black) and chromatic (red-green) CMs in the presence of luminance masking noise to disrupt luminance-based mechanisms of motion processing. Compared to achromatic CMs, perception of chromatic CMs was more sensitive to luminance masking noise, suggesting that CM envelope motion perception relied predominantly on luminance signals. Specifically, envelope motion discrimination performance was better maintained for achromatic CMs than chromatic CMs, even at high masking noise levels. Notably, luminance masking noise greatly impaired envelope direction discrimination for chromatic CMs but had minimal impact on their detection, suggesting that chromatic aberrations may enhance envelope motion perception for chromatic CMs by introducing luminance signals. These findings collectively emphasize that CM stimuli selectively activate Y-like/parasol RGCs of the retino-geniculate magnocellular pathway, underscoring their potential to specifically target this pathway. This might have clinical advantages for early diagnosis in disorders such as glaucoma or dyslexia, where magnocellular pathway dysfunction is predominant.

neuroscience↗

Cross cell-type systems genetics reveals the influence of eQTL at multiple points in the developmental trajectory of mouse neural progenitor cells

Genetic variation leads to phenotypic variability in pluripotent stem cells that presents challenges for regenerative medicine. Although recent studies have investigated the impact of genetic variation on pluripotency maintenance and differentiation capacity, less is known about how genetic variants affecting the pluripotent state influence gene regulation in later stages of development. Here, we characterized expression of more than 12,000 genes in 127 donor-matched Diversity Outbred (DO) mouse embryonic stem cell (mESC) and neural progenitor cell (mNPC) lines. Quantitative trait locus (QTL) mapping identified 2,947 expression QTL (eQTL) unique to DO mNPCs and 1,113 eQTL observed in both mNPCs and mESCs with highly concordant allele effects. We mapped three eQTL hotspots on Chromosomes (Chrs) 1, 10, and 11 that were unique to mNPCs. Target genes of the Chr 1 hotspot were overrepresented for those involved in mRNA processing, DNA repair, chromatin organization, protein degradation, and cell cycle. Mediation analysis of the Chr 1 hotspot identified Rnf152 as the best candidate mediator expressed in mNPCs, while cross-cell type mediation using mESC gene expression along with partial correlation analysis strongly implicated genetic variant(s) affecting Pign expression in the mESC state as regulating the mNPC Chr 1 eQTL hotspot. Together these findings highlight that many local eQTL confer similar effects on gene expression in multiple cell states; distant eQTL in DO mNPCs are numerous and largely unique to that cell state, with many co-localizing to mNPC-specific hotspots; and mediation analysis across cell types suggests that expression of Pign early in development (mESCs) shapes the transcriptome of the more specialized mNPC state.

genetics↗

Boosting of CAR-T cells with rhabdovirus is limited by type I interferon and rapid contraction

Rhabdovirus vaccines that encode tumour-associated antigens are potent boosting agents for adoptively transferred tumour-specific T cells. Employing rhabdovirus vaccines to boost adoptively transferred T cells relies on a priori knowledge of tumour epitopes, isolation of matched epitope-specific T cells, and a personalized vaccine, which limit clinical feasibility. Here, we investigated a universal strategy for boosting transferred tumour-specific T cells where boosting is provided through a chimeric antigen receptor (CAR) that is paired with a vesicular stomatitis virus (VSV) vaccine encoding the CAR-target. Boosting CAR-engineered tumour-specific T cells with paired VSV vaccines was associated with robust T cell expansion and delayed tumour progression in syngeneic models. CAR-T cell expansion and anti-tumour function was enhanced by blocking IFNAR1. However, vaccine-boosted CAR-T cells rapidly contracted and antigen-positive tumours re-emerged. In contrast, when the same T cells were boosted with VSV encoding antigen that stimulates through the TCR, the adoptively transferred T cells displayed improved persistence, tumour-specific endogenous cells expanded in parallel, and tumour cells carrying the antigen target were completely eradicated. Our findings underscore the need for further research into CAR-mediated boosting, how this differs mechanistically from TCR-mediated boosting, and the importance of engaging endogenous tumour-reactive T cells to achieve long-term tumour control.

immunology↗

Enhlink infers distal and context-specific enhancer-promoter linkages

Enhancers play a crucial role in regulating gene expression and their functional status can be queried with cell type precision using using single-cell (sc)ATAC-seq. To facilitate analysis of such data, we developed Enhlink, a novel computational approach that leverages single -cell signals to infer linkages between regulatory DNA sequences, such as enhancers and promoters. Enhlink uses an ensemble strategy that integrates cell-level technical covariates to control for batch effects and biological covariates to infer robust condition-specific links and their associated p-values. It can integrate simultaneous gene expression and chromatin accessibility measurements of individual cells profiled by multi-omic experiments for increased specificity. We evaluated Enhlink using simulated and real scATAC-seq data, including those paired with physical enhancer-promoter links enumerated by promoter capture Hi-C and with multi-omic scATAC-/RNA-seq data we generated from the mouse striatum. These examples demonstrated that our method outperforms popular alternative strategies. In conjunction with eQTL analysis, Enhlink revealed a putative super-enhancer regulating key cell type-specific markers of striatal neurons. Taken together, our analyses demonstrate that Enhlink is accurate, powerful, and provides features that can lead to novel biological insights.

bioinformatics↗

Estimating receptive fields of simple and complex cells in early visual cortex: A convolutional neural network model with parameterized rectification

Neurons in the primary visual cortex respond selectively to simple features of visual stimuli, such as orientation and spatial frequency. Simple cells, which have phase-sensitive responses, can be modeled by a single receptive field filter in a linear-nonlinear model. However, it is challenging to analyze phase-invariant complex cells, which require more elaborate models having a combination of nonlinear subunits. Estimating parameters of these models is made additionally more difficult by cortical neurons trial-to-trial response variability. We develop a simple convolutional neural network method to estimate receptive field models for both simple and complex visual cortex cells from their responses to natural images. The model consists of a spatiotemporal filter, a parameterized rectifier unit (PReLU), and a two-dimensional Gaussian "map" of the receptive field envelope. A single model parameter determines the simple vs. complex nature of the receptive field, capturing complex cell responses as a summation of homogeneous subunits, and collapsing to a linear-nonlinear model for simple type cells. The convolutional method predicts simple and complex cell responses to natural image stimuli as well as grating tuning curves. The fitted models yield a continuum of values for the PReLU parameter across the sampled neurons, showing that the simple/complex nature of cells can vary in a continuous manner. We demonstrate that complex-like cells respond less reliably than simple-like cells - compensation for this unreliability reveals good predictive performance on novel sets of natural images, with predictive performance for complex cells proportionately closer to that for simple cells. Most spatial receptive field structures are well fit by Gabor functions, whose parameters confirm well-known properties of cat A17/18 receptive fields. Author summaryMethods for recording increasingly many visual cortex neurons are advancing rapidly, demanding new approaches to characterize diverse receptive fields. We present a compact convolutional neural network model of early cortical neurons, which is uniformly applicable to simple and complex cells, and whose parameters are straightforwardly interpretable and readily estimated from responses to natural image stimuli. This novel approach introduces a single estimated model parameter to capture the simple/complex nature of a neurons receptive field, revealing a continuum of simple vs complex-like behaviour. We show that almost all complex-like cells exhibit a lower response reliability to repeated presentations of the same stimuli, compared to more reliable responses from simple-like cells. Accounting for this "noise ceiling" brings predictive performance for complex cells proportionately closer to that for simple cells. Using this model estimation approach with natural images, we evaluate findings from previous approaches that were restricted to simple-type cells and the use of grating or white noise stimuli, revealing a diversity of Gabor-like spatial receptive field shapes, which lie along a continuum of spatial bandwidths.

neuroscience↗

Variation in histone configurations correlates with gene expression across nine inbred strains of mice

It is well established that epigenetic features, such as histone modifications and DNA methylation, are associated with variation in gene expression across cell types. Less well known is the extent to which epigenetic states vary across genetically diverse individuals, and whether such variation corresponds to inter-individual variation in gene expression. To investigate genetically driven variation in epigenetics, we conducted a survey of epigenetic modifications and gene expression in hepatocytes of nine inbred mouse strains. We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac), and DNA methylation. We used ChromHMM to identify 14 chromatin states, each of which represented a distinct combination of the four histone modifications. We found that chromatin states varied widely across the nine strains and that epigenetic state was strongly correlated with local gene expression. We replicated this correspondence between chromatin state and gene expression in an independent population of Diversity Outbred mice in which we imputed local chromatin state. In contrast, we found that DNA methylation did not vary across the inbred strains and was not correlated with variation in gene expression in DO mice. This work suggests that chromatin state is highly influenced by local genotype and may be a primary mode through which expression quantitative trait loci (eQTLs) are mediated. Through examples, we demonstrate that naturally occurring chromatin state variation, in conjunction with gene expression, can aid in functional annotation of the mouse genome. Finally, we provide a data resource that documents variation in chromatin state in hepatocytes across genetically distinct mice.

genomics↗

Genetic dissection of the pluripotent proteome through multi-omics data integration

Genetic background is a major driver of phenotypic variability in pluripotent stem cells (PSCs). Most studies of variation in PSCs have relied on transcript abundance as the primary molecular readout of cell state. However, little is known about how proteins, the primary functional units in the cell, vary across genetically diverse PSCs, how protein abundance relates to variation in other cell characteristics, and how genetic background confers these effects. Here we present a comprehensive genetic study characterizing the pluripotent proteome of 190 unique mouse embryonic stem cell lines (mESCs) derived from genetically heterogeneous Diversity Outbred (DO) mice. The quantitative proteome is highly variable across DO mESCs, and we identified differentially activated pluripotency-associated pathways in the proteomics data that were not evident in transcriptome data from the same cell lines. Comparisons of protein abundance to transcript levels and chromatin accessibility show broad co-variation across molecular layers and variable correlation across samples, with some lines showing high and others low correlation between these multi-omics datasets. Integration of these three molecular data types using multi-omics factor analysis revealed shared and unique drivers of quantitative variation in pluripotency-associated pathways. QTL mapping localized the genetic drivers of this quantitative variation to a number of genomic hotspots, and demonstrated that multi-omics data integration consolidates the influence of genetic signals shared across molecular traits to increase QTL detection power and overcome the limitations inherent in mapping individual molecular features. This study reveals transcriptional and post-transcriptional mechanisms and genetic interactions that underlie quantitative variability in the pluripotent proteome, and in so doing provides a regulatory map for mouse ESCs that can provide a rational basis for future mechanistic studies, including studies of human PSCs.

genetics↗

Behavioral signatures of Y-like neuronal responses in human vision

Retinal ganglion cells initiating the magnocellular/Y-cell visual pathways respond nonlinearly to high spatial frequencies (SFs) and temporal frequencies (TFs). This nonlinearity is implicated in the processing of contrast modulation (CM) stimuli in cats and monkeys, but its contribution to human visual perception is not well understood. Here, we evaluate human psychophysical performance for CM stimuli, consisting of a high SF grating carrier whose contrast is modulated by a low SF sinewave envelope. Subjects reported the direction of motion of CM envelopes or luminance modulation (LM) gratings at different eccentricities. The performance on SF (for LMs) or carrier SF (for CMs) was measured for different TFs (LMs) or carrier TFs (CMs). The best performance for LMs was at lower TFs and SFs, decreasing systematically with eccentricity. However, performance with CMs was bandpass with carrier SF, largely independent of carrier TF, and at the highest carrier TF (20 Hz) decreased minimally with eccentricity. Since the nonlinear subunits of Y-cells respond better at higher TFs compared to the linear response components and respond best at higher SFs that are relatively independent of eccentricity, these results suggest that behavioral tasks employing CM stimuli might reveal nonlinear contributions of retinal Y-like cells to human perception.

neuroscience↗

Imputation of 3D genome structure by genetic-epigenetic interaction modeling in mice

Gene expression is known to be affected by interactions between local genetic variation and DNA accessibility, with the latter organized into three-dimensional chromatin structures. Analyses of these interactions has previously been limited, obscuring their regulatory context, and the extent to which they occur throughout the genome. Here we undertake a genome-scale analysis of these interactions in a genetically diverse population to systematically identify global genetic-epigenetic interaction, and reveal constraints imposed by chromatin structure. We establish the extent and structure of genotype-by-epigenotype interaction using embryonic stem cells derived from Diversity Outbred mice. This mouse population segregates millions of variants from eight inbred founders, enabling precision genetic mapping with extensive genotypic and phenotypic diversity. With 176 samples profiled for genotype, gene expression, and open chromatin, we used regression modeling to infer genetic-epigenetic interactions on a genome-wide scale. Our results demonstrate that statistical interactions between genetic variants and chromatin accessibility are common throughout the genome. We found that these interactions occur within the local area of the affected gene, and that this locality corresponds to topologically associated domains (TADs). The likelihood of interaction was most strongly defined by the three-dimensional (3D) domain structure rather than linear DNA sequence. We show that stable 3D genome structure is an effective tool to guide searches for regulatory elements and, conversely, that regulatory elements in genetically diverse populations provide a means to infer 3D genome structure. We confirmed this finding with CTCF ChIP-seq that revealed strain-specific binding in the inbred founder mice. In stem cells, open chromatin participating in the most significant regression models demonstrated an enrichment for developmental genes and the TAD-forming CTCF binding complex, providing an opportunity for statistical inference of shifting TAD boundaries operating during early development. These findings provide evidence that genetic and epigenetic factors operate within the context of three- dimensional chromatin structure. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/479436v3_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@14d4221org.highwire.dtl.DTLVardef@130a812org.highwire.dtl.DTLVardef@16a6069org.highwire.dtl.DTLVardef@df9d9c_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

Transient inhibition to light explains stronger V1 responses to dark stimuli

Neurons in the primary visual cortex (V1) receive excitation and inhibition from distinct parallel pathways processing lightness (ON) and darkness (OFF). V1 neurons overall respond more strongly to dark than light stimuli, consistent with a preponderance of darker regions in natural images, as well as human psychophysics. However, it has been unclear whether this "dark-dominance" is due to more excitation from the OFF pathway or more inhibition from the ON pathway. To understand the mechanisms behind dark-dominance, we record electrophysiological responses of individual simple-type V1 neurons to natural image stimuli and then train biologically inspired convolutional neural networks to predict the neurons responses. Analyzing a sample of 74 neurons (in anesthetized, paralyzed cats) has revealed their responses to be more driven by dark than light stimuli, consistent with previous investigations. We show that this asymmetry is predominantly due to slower inhibition to dark stimuli rather than to stronger excitation from the thalamocortical OFF pathway. Consistent with dark-dominant neurons having faster responses than light-dominant neurons, we find dark-dominance to solely occur in the early latencies of neurons responses. Neurons that are strongly dark-dominated also tend to be less orientation selective. This novel approach gives us new insight into the dark-dominance phenomenon and provides an avenue to address new questions about excitatory and inhibitory integration in cortical neurons. SignificanceNeurons in the early visual cortex respond on average more strongly to dark than to light stimuli, but the mechanisms behind this bias have been unclear. Here we address this issue by combining single-unit electrophysiology with a novel machine learning model to analyze neurons responses to natural image stimuli in primary visual cortex. Using these techniques, we find slower inhibition to light than to dark stimuli to be the leading mechanism behind stronger dark responses. This slower inhibition to light might help explain other empirical findings, such as why orientation selectivity is weaker at earlier response latencies. These results demonstrate how imbalances in excitation vs. inhibition can give rise to response asymmetries in cortical neuron responses.

neuroscience↗

Visual perception of texture regularity: conjoint measurements and a wavelet response-distribution model

Texture regularity, such as the repeating pattern in a carpet, brickwork or tree bark, is a ubiquitous feature of the visual world. The perception of regularity has generally been studied using multi-element textures in which the degree of regularity has been manipulated by adding random jitter to the elements positions. Here we used three-factor Maximum Likelihood Conjoint Measurement (MLCM) to investigate the encoding of regularity information under more complex conditions in which element spacing and size, in addition to positional jitter, were manipulated. Human observers were presented with large numbers of pairs of multi-element stimuli with varying levels of the three factors, and indicated on each trial which stimulus appeared more regular. All three factors contributed to regularity perception. Jitter, as expected, strongly affected regularity perception. This effect of jitter on regularity perception is strongest at small element spacing and large texture element size, suggesting that the visual system utilizes the edge-to-edge distance between elements as the basis for regularity judgments. We then examined how the responses of a bank of Gabor wavelet spatial filters might account for our results. Our analysis indicates that SF-peakedness, a previously favored proposal, is insufficient for regularity encoding since it varied more with element spacing and size than with jitter. Instead, our results support the idea that the visual system may extract texture regularity information from the moments of the SF-distribution across orientation. In our best-performing model, the variance of SF-distribution skew across orientations can explain 70% of the variance of estimated texture regularity from our data, suggesting that it could provide a candidate readout for perceived regularity. Author SummaryWe investigated human perception of texture regularity, in which subjects made comparative judgements of regularity in pairs of texture stimuli with differing levels of three parameters of texture construction - spacing and size of texture elements, and their positional jitter. We analyzed the data using a novel approach involving three-factor Maximum Likelihood Conjoint Measurement (MLCM). We utilized a novel analysis-of-variance approach in MLCM to evaluate the effect size and significance of the three factors as well as their interactions. We found that all three factors contributed to perceived regularity, with significant main effects and interactions between factors, in a manner suggesting edge-to-edge distances between elements might contribute importantly to regularity judgments. Using a bank of Gabor wavelet spatial filters to model the response of the human visual system to our textures, we compared four types of ways that the distribution of wavelet responses could account for our measured data on perceived regularity. Our results suggest that the orientation as well as spatial frequency information from the wavelet filters also contributes importantly - in particular, the skew of the variance of the SF-distribution across orientation provides a candidate basis for perceived texture regularity.

neuroscience↗

Genetic Control of Pluripotency Epigenome Determines Differentiation Bias in Mouse Embryonic Stem Cells

Genetically diverse pluripotent stem cells (PSCs) display varied, heritable responses to differentiation cues in the culture environment. By harnessing these disparities through derivation of embryonic stem cells (ESCs) from the BXD mouse genetic reference panel, along with C57BL/6J (B6) and DBA/2J (D2) parental strains, we demonstrate genetically determined biases in lineage commitment and identify major regulators of the pluripotency epigenome. Upon transition to formative pluripotency using epiblast-like cells (EpiLCs), B6 quickly dissolves naive networks adopting gene expression modules indicative of neuroectoderm lineages; whereas D2 retains aspects of naive pluripotency with little bias in differentiation. Genetic mapping identifies 6 major trans-acting loci co-regulating chromatin accessibility and gene expression in ESCs and EpiLCs, indicating a common regulatory system impacting cell state transition. These loci distally modulate occupancy of pluripotency factors, including TRIM28, P300, and POU5F1, at hundreds of regulatory elements. One trans-acting locus on Chr 12 primarily impacts chromatin accessibility in ESCs; while in EpiLCs the same locus subsequently influences gene expression, suggesting early chromatin priming. Consequently, the distal gene targets of this locus are enriched for neurogenesis genes and were more highly expressed when cells carried B6 haplotypes at this Chr 12 locus, supporting genetic regulation of biases in cell fate. Spontaneous formation of embryoid bodies validated this with B6 showing a propensity towards neuroectoderm differentiation and D2 towards definitive endoderm, confirming the fundamental importance of genetic variation influencing cell fate decisions.

genomics↗

Nonsense mediated decay and a novel protein Period-2 regulate casein kinase I in an opposing manner to control circadian period in Neurospora crassa

Circadian clocks in fungi and animals are driven by a functionally conserved transcription-translation feedback loop. In Neurospora crassa, negative feedback is executed by a complex of Frequency (FRQ), FRQ-interacting RNA helicase (FRH), and Casein Kinase I (CKI), which inhibits the activity of the clocks positive arm, the White Collar Complex (WCC). Here, we show that the period-2 gene, whose mutation is characterized by recessive inheritance of a long 26-hour period phenotype, encodes an RNA-binding protein that stabilizes the ck-1a transcript, resulting in CKI protein levels sufficient for normal rhythmicity. Moreover, by examining the molecular basis for the short circadian period of period-6 mutants, we uncovered a strong influence of the Nonsense Mediated Decay pathway on CKI levels. The finding that circadian period defects in two classically-derived Neurospora clock mutants each arise from disruption of ck-1a regulation is consistent with circadian period being exquisitely sensitive to levels of casein kinase I.

genomics↗

Segmenting luminance-defined texture boundaries

Segmenting scenes into distinct surfaces is a basic visual perception task, and luminance differences between adjacent surfaces often provide an important segmentation cue. However, mean luminance differences between two surfaces may exist without any sharp change in albedo at their boundary, but rather from differences in the proportion of small light and dark areas within each surface, e.g. texture elements, which we refer to as a luminance texture boundary. Here we investigate the performance of human observers segmenting luminance texture boundaries. We demonstrate that a simple model involving a single stage of filtering cannot explain observer performance, unless it incorporates contrast normalization. Performing additional experiments in which observers segment luminance texture boundaries while ignoring super-imposed luminance step boundaries, we demonstrate that the one-stage model, even with contrast normalization, cannot explain performance. We then present a Filter-Rectify-Filter (FRF) model positing two cascaded stages of filtering, which fits our data well, and explains observers ability to segment luminance texture boundary stimuli in the presence of interfering luminance step boundaries. We propose that such computations may be useful for boundary segmentation in natural scenes, where shadows often give rise to luminance step edges which do not correspond to surface boundaries.

neuroscience↗

HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

Chromatin barriers prevent spurious interactions between regulatory elements and DNA-binding proteins. One such barrier, whose mechanism for overcoming is poorly understood, is access to recombination hotspots during meiosis. Here we show that the chromatin remodeler HELLS and DNA-binding protein PRDM9 function together to open chromatin at hotspots and provide access for the DNA double-strand break (DSB) machinery. Recombination hotspots are decorated by a unique combination of histone modifications, not found at other regulatory elements. HELLS is recruited to hotspots by PRDM9, and is necessary for both histone modifications and DNA accessibility at hotspots. In male mice lacking HELLS, DSBs are retargeted to other sites of open chromatin, leading to germ cell death and sterility. Together, these data provide a model for hotspot activation where HELLS and PRDM9 function as a pioneer complex to create a unique epigenomic environment of open chromatin, permitting correct placement and repair of DSBs.

genetics↗