Biology subjects

Sherman, S. M.

Publications and source records attributed to Sherman, S. M..

6 recordsLinked to original sources

bioRxiv2025

CUT&TIME captures the history of open chromatin indeveloping neurons

Chromatin structure plays a central role in defining cell identity by regulating gene expression. During development, shifts in chromatin structure facilitate changes in gene expression needed to specify distinct cell types. To understand how changes in chromatin structure influence the developmental trajectory of neural progenitor cells, we developed CUT&TIME, a technique that uses a hyperactive 6-methyl adenosine (6mA) methyltransferase pulsed in living cells to map historical chromatin accessibility genome-wide in single cells. We show that CUT&TIME produces a record of the chromatin landscape during neurogenesis in the developing retina, specifically as neural progenitors produce the major projection neuron type, retinal ganglion cells (RGCs). We further show that this method is compatible with single cell profiling technologies, which allows us to visualize and capture the diversity of chromatin states that produce RGCs. Additionally, we identify changes in promoter accessibility associated with the transition from progenitor to RGC. Together, these data demonstrate that CUT&TIME captures a historical record of chromatin structure, which can be used to identify early changes in accessibility associated with cell-fate commitment.

developmental biology↗

bioRxiv2025

Disruption of transthalamic circuitry from primary visual cortex impairs visual discrimination in mice

Layer 5 (L5) of the cortex provides strong driving input to higher-order thalamic nuclei, such as the pulvinar in the visual system, forming the basis of cortico-thalamo-cortical (transthalamic) circuits. These circuits provide a communication route between cortical areas in parallel to direct corticocortical connections, but their specific role in perception and behavior remains unclear. Using targeted optogenetic inhibition in mice performing a visual discrimination task, we selectively suppressed the corticothalamic input from L5 cells in primary visual cortex (V1) at their terminals in pulvinar. This suppresses transthalamic circuits from V1; furthermore, any effect on direct corticocortical projections and local V1 circuitry would thus result from transthalamic inputs (e.g., V1 to pulvinar back to V1 (Miller-Hansen and Sherman, 2022). Such suppression of transthalamic processing during visual stimulus presentation of drifting gratings significantly impaired discrimination performance across different orientations. The impact on behavior was specific to the portion of visual space that retinotopically coincided with the V1 L5 corticothalamic inhibition. These results highlight the importance of incorporating L5-initiated transthalamic circuits into cortical processing frameworks, particularly those addressing how the hierarchical propagation of sensory signals supports perceptual decision-making. SIGNIFICANCE STATEMENTAppreciation of pathways for transthalamic communication between cortical areas, organized in parallel with direct connections, has transformed our thinking about cortical functioning writ large. Studies of transthalamic pathways initially concentrated on their anatomy and physiology, but there has been a shift towards understanding their importance to cognitive behavior. Here, we have used an optogenetic approach in mice to selectively inhibit the transthalamic pathway from primary visual cortex to other cortical areas and back to itself. We find that such inhibition degrades the animals ability to discriminate, showing for the first time that specific inhibition of visual transthalamic circuitry reduces visual discrimination. This causal data adds to the growing evidence for the importance of transthalamic signaling in perceptual processing.

neuroscience↗

bioRxiv2024

Ciliary marginal zone of the developing human retina maintains retinal progenitor cells until late gestational stages

Non-mammalian vertebrates maintain a proliferative stem cell population at the far periphery of their retina called the ciliary marginal zone (CMZ), which gives rise to all retinal cell types and contributes to retinal regeneration upon injury. Humans do not maintain a proliferative CMZ into adulthood; however, it is not known how long in development this region continues to generate new neurons. Here, we identify a population of cells in the far peripheral retina of the fetal human that continues to proliferate long after the rest of the retina is quiescent. Single cell RNA-sequencing and EdU tracing at late time points in development reveal that this region has features of the non-mammalian CMZ, including the capacity to produce both early and late born cell types at late developmental stages, and a longer cell cycle than more centrally located retinal progenitor cells (RPCs). Moreover, while more central RPCs exit the cell cycle with the addition of a TGF{beta}-inhibitor, we show that early RPCs within the CMZ do not. These findings define the late stages of neurogenesis in human retinal development, and present a unique model system to study the fetal CMZ in humans.

developmental biology↗

bioRxiv2023

Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition

Resolving the molecular basis of a Mendelian condition (MC) remains challenging owing to the diverse mechanisms by which genetic variants cause disease. To address this, we developed a synchronized long-read genome, methylome, epigenome, and transcriptome sequencing approach, which enables accurate single-nucleotide, insertion-deletion, and structural variant calling and diploid de novo genome assembly, and permits the simultaneous elucidation of haplotype-resolved CpG methylation, chromatin accessibility, and full-length transcript information in a single long-read sequencing run. Application of this approach to an Undiagnosed Diseases Network (UDN) participant with a chromosome X;13 balanced translocation of uncertain significance revealed that this translocation disrupted the functioning of four separate genes (NBEA, PDK3, MAB21L1, and RB1) previously associated with single-gene MCs. Notably, the function of each gene was disrupted via a distinct mechanism that required integration of the four omes to resolve. These included nonsense-mediated decay, fusion transcript formation, enhancer adoption, transcriptional readthrough silencing, and inappropriate X chromosome inactivation of autosomal genes. Overall, this highlights the utility of synchronized long-read multi-omic profiling for mechanistically resolving complex phenotypes.

genetics↗

bioRxiv2023

A transthalamic pathway is crucial for stimulus feature selectivity in higher order cortex

Perception arises from activity between cortical areas, first primary cortex and then higher order cortices. This communication is served in part by transthalamic (cortico-thalamo-cortical) pathways, which ubiquitously parallel direct corticocortical pathways, but their role in sensory processing has largely remained unexplored. Here, we show that the transthalamic pathway linking somatosensory cortices propagates task-relevant information required for correct sensory decisions. Using optogenetics, we specifically inhibited the pathway at its synapse in higher order somatosensory thalamus of mice performing a texture-based discrimination task. We concurrently monitored the cellular effects of inhibition in primary or secondary cortex using two-photon calcium imaging. Inhibition severely impaired performance despite intact direct corticocortical projections, thus challenging the purely corticocentric map of perception. Interestingly, the inhibition did not reduce overall cell responsiveness to texture stimulation in somatosensory cortex, but rather disrupted the texture selectivity of cells, a discriminability that develops over task learning. This discriminability was more disrupted in the secondary than primary somatosensory cortex, emphasizing the feedforward influence of the transthalamic route. Transthalamic pathways thus appear critical in delivering performance-relevant information to higher order cortex and are critical hierarchical pathways in perceptual decision-making.

neuroscience↗

bioRxiv2018

Knowledge, attitudes and awareness of the human papillomavirus among health professionals in New Zealand

BackgroundHuman papillomavirus (HPV) is a common sexually transmitted infection that is implicated in 99.7% of cervical cancers and several other cancers that affect both men and women. Despite the role that HPV plays in an estimated 5% of all cancers and the evolving role of HPV vaccination and testing in protecting the public against these cancers, preliminary research in New Zealand health care professionals suggest knowledge about HPV may not be sufficient.\n\nMethodsA total of 230 practice nurses, smear takers and other clinical and laboratory staff who attended a range of training events completed a cross-sectional survey between April 2016 and July 2017. The survey explored four broad areas: demographics and level of experience, HPV knowledge (general HPV knowledge, HPV triage and test of cure (TOC) knowledge and HPV vaccine knowledge), attitudes towards the HPV vaccine and self-perceived adequacy of HPV knowledge.\n\nResultsThe mean score on the general HPV knowledge questions was 13.2 out of 15, with only 25.2% of respondents scoring 100%. In response to an additional question, 14.0% thought (or were unsure) that HPV causes HIV/AIDS. The mean score on the HPV Triage and TOC knowledge questions was 7.4 out of 10, with only 9.1% scoring 100%. The mean score on the HPV vaccine knowledge questions was 6.0 out of 7 and 44.3% scored 100%. Only 62.6% of respondents agreed or strongly agreed that they were adequately informed about HPV, although 71.8% agreed or strongly agreed that they could confidently answer HPV-related questions asked by patients. Multivariate analyses revealed that knowledge in each domain predicted confidence in responding to patient questions. Furthermore, the number of years since training predicted both HPV knowledge and Triage and TOC knowledge.\n\nDiscussionAlthough overall level of knowledge was adequate, there were significant gaps in knowledge, particularly about the role of HPV testing in the New Zealand National Cervical Screening Programme. More education is required to ensure that misinformation and stigma do not inadvertently result from interactions between health practitioners and the public.

pathology↗