Biology subjects

Bodkin, N.

Publications and source records attributed to Bodkin, N..

3 recordsLinked to original sources

bioRxiv2025

Analysis of 14q12 microdeletions reveals novel regulatory loci for the neurodevelopmental disorder-related gene, FOXG1

Up to 17% of neurodevelopmental disorders (NDDs) can be explained by pathogenic structural variants (SVs) that disrupt coding regions and elicit gene dosage defects. However, noncoding SVs which can perturb cis-regulatory elements (CREs) and downstream gene expression are understudied. In this study, we describe multiple 14q12 deletions downstream of NDD-related gene FOXG1 in individuals with overlapping phenotypes of FOXG1 haploinsufficiency. We show that deletion of a minimum region of overlap (MRO) reduced FOXG1 expression, disrupted CREs and altered FOXG1s native genomic interactions. Deleting the MRO did not fully eliminate FOXG1 expression, indicating that multiple CREs likely cooperate to regulate FOXG1 and would need to be deleted to completely prevent expression. The transcriptomic profiles of MRO loss overlap in part with FOXG1 loss, including direct FOXG1 targets, indicating converging molecular pathways. These findings expand the scope of FOXG1s complex regulatory region, and more broadly, of regulatory SVs in NDD susceptibility.

genetics↗

bioRxiv2023

Prevalence of and gene regulatory constraints on transcriptional adaptation in single cells

Cells and tissues have a remarkable ability to adapt to genetic perturbations via a variety of molecular mechanisms. Nonsense-induced transcriptional compensation, a form of transcriptional adaptation, has recently emerged as one such mechanism, in which nonsense mutations in a gene can trigger upregulation of related genes, possibly conferring robustness at cellular and organismal levels. However, beyond a handful of developmental contexts and curated sets of genes, to date, no comprehensive genome-wide investigation of this behavior has been undertaken for mammalian cell types and contexts. Moreover, how the regulatory-level effects of inherently stochastic compensatory gene networks contribute to phenotypic penetrance in single cells remains unclear. Here we combine computational analysis of existing datasets with stochastic mathematical modeling and machine learning to uncover the widespread prevalence of transcriptional adaptation in mammalian systems and the diverse single-cell manifestations of minimal compensatory gene networks. Regulon gene expression analysis of a pooled single-cell genetic perturbation dataset recapitulates important model predictions. Our integrative approach uncovers several putative hits--genes demonstrating possible transcriptional adaptation--to follow up on experimentally, and provides a formal quantitative framework to test and refine models of transcriptional adaptation.

systems biology↗

bioRxiv2020

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

Appropriately modulating inflammation after traumatic brain injury (TBI) may prevent disabilities for the millions of those inflicted annually. In TBI, cellular mediators of inflammation, including macrophages and microglia, possess a range of phenotypes relevant for an immunomodulatory therapeutic approach. It is thought that early phenotypic modulation of these cells will have a cascading healing effect. In fact, an anti-inflammatory, "M2-like" macrophage phenotype after TBI has been associated with neurogenesis, axonal regeneration, and improved white matter integrity. There already exists clinical trials seeking an M2-like bias through mesenchymal stem/stromal cells (MSCs). However, MSCs do not endogenously synthesize key signals that induce robust M2-like phenotypes such as Interleukin-4 (IL-4). To enrich M2-like macrophages in a clinically relevant manner, we augmented MSCs to transiently express IL-4 via synthetic IL-4 mRNA. We observed that these IL-4 expressing MSCs indeed induce a robust M2-like macrophage phenotype and promote anti-inflammatory gene expression in a modified TBI model of closed head injury. However, here we demonstrate that acute enrichment of M2-like macrophages did not translate to improved functional or histological outcomes. This suggests that an acute enrichment of M2-like macrophages cannot solely orchestrate the neurogenesis, axonal regeneration, and improved WMI after diffuse TBI. To further understand whether dysfunctional pathways underlie the lack of therapeutic effect, we report transcriptomic analysis of injured and treated brains. Through this, we discovered that inflammation persists in spite of acute enrichment of M2-like macrophages in the brain. Last, we comment on our modified TBI model, behavioral studies, and propose that IL-4 expressing MSCs may also have relevance in other cavitary diseases or in improving biomaterial integration into tissues.

neuroscience↗