Biology subjects

Dorrity, M.

Publications and source records attributed to Dorrity, M..

3 recordsLinked to original sources

bioRxiv2025

High-throughput single-cell CRISPRi screens stratify neurodevelopmental functions of schizophrenia-associated genes

Schizophrenia is a complex neuropsychiatric disorder with strong genetic underpinnings, yet the molecular mechanisms linking genetic risk to disrupted brain development remain poorly understood. Transcription factors (TFs) and chromatin regulators (CRs) are increasingly implicated in neuropsychiatric disorders, where their dysregulation may disrupt neurodevelopmental programs. Despite this, systematic functional interrogation in human models has been limited. Here, we combine pooled CRISPR interference (CRISPRi) screens with high- throughput single-cell multiomic profiling in hiPSC-derived neural progenitors and neurons to functionally assess 65 schizophrenia-associated genes. Based on public datasets and literature review, we selected 55 TFs and CRs, along with ten additional risk genes whose loss-of-function has been linked to schizophrenia. Our single-cell CRISPRi readouts revealed that perturbations in TFs and CRs converge on disrupting neurodevelopmental timing. CRISPRi of several factors delayed neural differentiation, whereas others, such as the knockdown of MCRS1, drove precocious neural commitment. Validation screens combined with cell cycle and metabolic indicators confirmed the differentiation-restricting or -promoting roles of these TFs and CRs. Multimodal trajectory analysis uncovered discrete transcriptional and epigenomic states representing delayed and accelerated neurodevelopment, enriched for schizophrenia GWAS loci and disease-relevant pathways. Gene regulatory network (GRN) inference identified TCF4 and ZEB1 as critical mediators opposing the neural differentiation trajectory. Functional overexpression of these TFs followed by chromatin profiling demonstrated that TCF4 restrains, while ZEB1 promotes, neural differentiation in a stage-specific and competitive manner. Furthermore, we show that MCRS1 represses ZEB1 expression, positioning MCRS1 as a key brake on premature neurodevelopment. Together, our study establishes a scalable framework that integrates genetic perturbation, single- cell multiomics, and GRN modeling to functionally annotate disease-linked genes. We reveal convergent regulatory axes that underlie altered neurodevelopmental timing in schizophrenia, offering mechanistic insights into how chromatin misregulation contributes to disease pathogenesis.

neuroscience↗

bioRxiv2025

A closed feedback between tissue phase transitions and morphogen gradients drives patterning dynamics

During development mechanochemical cues in the cell microenvironment are translated into signalling to drive cell fate decisions. As cells differentiate collectively, it raises the question of how tissue-level properties affect instructive cues of decision-making. Here, we show that a tissue rigidity phase transition guides patterning by tuning the length-scales and time-scales of morphogen signalling. By combining rigidity percolation theory, reaction-diffusion modelling, quantitative imaging, optogenetics and single-cell transcriptomics in zebrafish, we uncover dynamical global tissue rigidity patterns that actively shape the Nodal morphogen gradient by restricting ligand dispersal and accelerating its signalling activity. In this self-generated mechanism, Nodal, besides driving meso-endoderm fate specification, increases cell-cell adhesion strength via regulating planar cell polarity genes. Once adhesion strength reaches a critical point, it triggers a rigidity transition which collapses tissue porosity. The abrupt tissue reorganisation negatively feeds back on Nodal signalling impacting both its length-scales, by limiting Nodal diffusivity, and its time-scales, by speeding up the expression of its antagonist Lefty, thereby ensuring timely signal termination and robust patterning. Overall, we reveal how emergent properties set the spatiotemporal dynamics of morphogen gradients, uncovering macroscopic mechanisms of pattern formation.

developmental biology↗

bioRxiv2017

Profiling of accessible chromatin regions across multiple plant species and cell types reveals common gene regulatory principles and new control modules

The transcriptional regulatory structure of plant genomes remains poorly defined relative to animals. It is unclear how many cis-regulatory elements exist, where these elements lie relative to promoters, and how these features are conserved across plant species. We employed the Assay for Transposase-Accessible Chromatin (ATAC-seq) in four plant species (Arabidopsis thaliana, Medicago truncatula, Solanum lycopersicum, and Oryza sativa) to delineate open chromatin regions and transcription factor (TF) binding sites across each genome. Despite 10-fold variation in intergenic space among species, the majority of open chromatin regions lie within 3 kb upstream of a transcription start site in all species. We find a common set of four TFs that appear to regulate conserved gene sets in the root tips of all four species, suggesting that TF-gene networks are generally conserved. Comparative ATAC-seq profiling of Arabidopsis root hair and non-hair cell types revealed extensive similarity as well as many cell type-specific differences. Analyzing TF binding sites in differentially accessible regions identified a MYB-driven regulatory module unique to the hair cell, which appears to control both cell fate regulators and abiotic stress responses. Our analyses revealed common regulatory principles among species and shed light on the mechanisms producing cell type-specific transcriptomes during development.

plant biology↗