Biology subjects

Schulmann, A.

Publications and source records attributed to Schulmann, A..

6 recordsLinked to original sources

bioRxiv2024

High-risk neuropsychiatric copy number variants are associated with convergent transcriptomic changes in human brain cells

Large, recurrent copy number variants (CNVs) are among the strongest risk factors for neuropsychiatric conditions, contributing to multiple phenotypes with overlapping psychiatric and cognitive symptoms. However, the molecular basis of this convergent risk remains unknown. We evaluated the human brain transcriptome in carriers of nine high-risk neuropsychiatric CNVs and matched non-carriers using single nucleus RNA-sequencing. Brain tissue from carriers displayed widespread disruptions of gene expression, with thousands of differentially expressed genes, mostly located outside of the respective CNV regions. There were greater changes in deletions compared to reciprocal duplications. Functional enrichment analysis revealed changes in mitochondrial energy metabolism and synaptic function that converged across CNVs and cell types. For mirror CNVs, the direction of effects was often reversed between deletions and duplications and showed correlation with CNV gene dosage. These findings suggest that a shared pathophysiology underlies risk for convergent brain phenotypes across CNVs and point toward promising therapeutic targets.

genetics↗

bioRxiv2024

A conserved cell-type gradient across the human mediodorsal and paraventricular thalamus

The mediodorsal thalamus (MD) and adjacent midline nuclei are important for cognition and mental illness, but their cellular composition is not well defined. Using single-nucleus and spatial transcriptomics, we identified a conserved excitatory neuron gradient, with distinct spatial mapping of individual clusters. One end of the gradient was expanded in human MD compared to mice, which may be related to the expansion of granular prefrontal cortex in hominids. Moreover, neurons preferentially mapping onto the parvocellular division MD were associated with genetic risk for schizophrenia and bipolar disorder. Midbrain-derived inhibitory interneurons were enriched in human MD and implicated in genetic risk for major depressive disorder.

neuroscience↗

bioRxiv2019

Cortical RORβ is required for layer 4 transcriptional identity and barrel integrity.

Retinoic Acid-Related Orphan Receptor Beta (ROR{beta}) is a transcription factor (TF) and marker of layer 4 (L4) neurons, which are distinctive both in transcriptional identity and the ability to form aggregates such as barrels in rodent somatosensory cortex. However, the relationship between transcriptional identity and L4 cytoarchitecture is largely unknown. We find ROR{beta} is required in the cortex for L4 aggregation into barrels and thalamocortical afferent (TCA) segregation. Interestingly, barrel organization also degrades with age. Loss of ROR{beta} delays excitatory input and disrupts gene expression and chromatin accessibility, with downregulation of L4 and upregulation of L5 genes, suggesting a shift in cellular identity. Expression and binding site accessibility change for many other TFs, including closure of neurodevelopmental TF binding sites and increased expression and binding capacity of activity-regulated TFs. Lastly, a putative target of ROR{beta}, Thsd7a, is downregulated without ROR{beta}, and Thsd7a knockout alone disrupts TCA organization in adult barrels.

neuroscience↗

bioRxiv2019

Super-resolution Imaging Reveals 3D Structure and Organizing Mechanism of Accessible Chromatin

Access to cis-regulatory elements packaged in chromatin is essential for directing gene expression and cell viability. Here, we report a super-resolution imaging strategy, 3D ATAC-PALM, that enables direct visualization of the entire accessible genome. We found that active chromosomal segments are organized into spatially-segregated accessible chromatin domains (ACDs). Rapid depletion of CTCF or Cohesin (RAD21 subunit) induced enhanced ACD clustering, reduced physical separation between intrachromosomal ACDs, and differentially regulated ACD compaction. Experimental perturbations and polymer modeling suggest that dynamic protein-protein and protein-DNA interactions within ACDs couple with loop extrusion to organize ACD topology. Dysorganization of ACDs upon CTCF or Cohesin loss alters transcription factor binding and target search dynamics in living cells. These results uncover fundamental mechanisms underpinning the formation of 3D genome architecture and its pivotal function in transcriptional regulation.

molecular biology↗

bioRxiv2017

A topographic axis of transcriptional identity in thalamus

Uncovering common principles by which diverse modalities of information are processed is a fundamental goal in neuroscience. In mammalian brain, thalamus is the central processing station for inputs from sensory systems, subcortical motor systems, and cortex; a function subserved by over 30 defined nuclei1,2. Multiple thalamic nuclei send convergent information to each region of the forebrain, but whether there is a conserved architecture across the set of thalamic pathways projecting to each forebrain area has remained unresolved3-5. To uncover organizational principles of thalamic pathways, we produced a near-comprehensive transcriptomic atlas of thalamus. This revealed a common logic for thalamic nuclei serving all major cortical modalities. We found that almost all nuclei belong to one of three major profiles, with a given cortical area getting input from each of these profiles. These profiles lie on a single axis of variance aligned with the mediolateral axis of thalamus, and this axis is strongly enriched in genes encoding receptors and ion channels. We further show that each projection profile exhibits different electrophysiological signatures. Single-cell profiling revealed that rather than forming discrete classes, thalamic neurons lie on a spectrum, with intermediate cells existing between profiles. Thus, in contrast to canonical models of thalamus that suggest it is a switchboard primarily concerned with routing distinct modalities of information to distinct cortical regions, we show that the thalamocortical system is more akin to a molecularly-defined filter bank repeatedly applied across modality. Together, we reveal striking covariation in the organization of thalamic pathways serving all input modalities and output targets, establishing a simple and comprehensive thalamic functional architecture.

neuroscience↗

bioRxiv2017

The Transcriptional Logic of Mammalian Neuronal Diversity

The mammalian nervous system is constructed of many cell types, but the principles underlying this diversity are poorly understood. To assess brain-wide transcriptional diversity, we sequenced the transcriptomes of the largest collection of genetically and anatomically identified neuronal classes. Using improved expression metrics that distinguish information content from signal-to-noise-ratio, we found that homeobox transcription factors contain the highest information about cell types and have the lowest noise. Genes that contribute the most to neuronal diversity tend to be long and enriched in factors specifically involved in neuronal function. Genome accessibility measurements reveal that long genes have more candidate regulatory elements arrayed in more distinct patterns. These elements frequently overlap interspersed repeats (mobile elements) and the pattern of repeats is predictive of gene expression. New regulatory sites resulting from elongation of neuronal genes by mobile elements may be an evolutionary force enhancing nervous system complexity.

neuroscience↗