Biology subjects

Trostle, A. J.

Publications and source records attributed to Trostle, A. J..

5 recordsLinked to original sources

bioRxiv2026

Macrophage metabolism directs regenerative versus fibrotic healing through BMP signaling in the mouse digit tip

Macrophages play a central role in determining the outcomes of healing, coordinating regeneration in some injuries and scar formation in others. In both cases, this coordination involves the cross-talk between macrophages and surrounding cells. But what drives the different cross-communication pathways to determine healing outcomes is not well known. In this study, we make use of the mouse digit tip amputation model, in which an amputation through the third phalangeal element (P3) is able to completely regenerate whereas an amputation through the second phalangeal element (P2) forms a scar. We identify a population of macrophages that is specific to the P3 regenerating digit. By integrating single-cell RNAseq, spatial transcriptomics, and metabolomic analyses, we show that this population localizes specifically to the growing bone front, express BMP ligands that drive downstream BMP activation in neighboring osteoblasts and is governed by a two-part metabolic switch involving increased fatty acid oxidation coupled with reduced glycolytic activity. This spatially restricted, BMP-expressing macrophage population is entirely absent in the scar-forming P2 injury, and our data indicate that environmental conditions unique to the regenerating digit are responsible for its emergence. Together these findings identify a regeneration-specific macrophage signaling center for patterned bone formation and suggest that targeting the metabolic conditions that drive this population could improve the efficacy of regenerative therapies.

developmental biology↗

bioRxiv2022

MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function

Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, though identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we identified that MeCP2 finely regulates Growth differentiation factor 11 (Gdf11). Gdf11 is down-regulated in RTT mouse models and is inversely up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 alone was sufficient to cause multiple neurobehavioral deficits in mice, most notably hyperactivity and decreased learning and memory. This decrease in learning and memory was not due to changes in proliferation or numbers of progenitor cells in the hippocampus. Lastly, loss of one copy of Gdf11 decreased longevity and survival in mice, corroborating its putative role in aging. Our data demonstrate that Gdf11 dosage is important for brain function.

neuroscience↗

bioRxiv2022

Most High Throughput Expression Data Sets are Underpowered

Researchers handicap their high-throughput sequencing experiments when they do not perform enough biological replicates. Given that biological tissues can be highly variable, too few replicates will lead to false negatives, false positives, irreproducibility, and failure to detect real biological signatures. We propose that at least six biological replicates per condition becomes the standard for high-throughput expression datasets.

bioinformatics↗

bioRxiv2021

MECP2pedia: A Comprehensive Transcriptome Portal for MECP2 Disease Research

Mutations in MeCP2 result in a crippling neurological disease, but we lack a lucid picture of MeCP2s molecular role. Focusing on individual transcriptomic studies yields inconsistent differentially expressed genes. We have aggregated and homogeneously processed modern public MeCP2 transcriptome data, which we present in a web portal. With this big data, we discovered a commonly perturbed core set of genes that transcends the limitations of any individual study. We then found distinct consistently up and downregulated subsets within these genes. We observe enrichment for this mouse core in other species MeCP2 models and see overlap between this core and ASD models. Analysis of signal to noise finds that many studies lack enough biological replicates. By integrating and examining transcriptomic data at scale, we have generated a valuable resource and insight on MeCP2 function.

bioinformatics↗

bioRxiv2019

Loss of Dnmt3a dependent methylation in inhibitory neurons impairs neural function through a mechanism that impacts Rett syndrome

Methylated cytosine is an effector of epigenetic gene regulation. In the mammalian brain, the DNA methyltransferase, Dnmt3a, is the sole \"writer\" of atypical non-CpG methylation (mCH), and methyl CpG binding protein 2 (MeCP2) is the only known \"reader\" for mCH. We set out to determine if MeCP2 is the sole reader for Dnmt3a dependent methylation by comparing mice lacking either Dnmt3a or MeCP2 in GABAergic inhibitory neurons. Loss of either the writer or the reader causes overlapping and distinct features from the behavioral to the molecular level. Loss of Dnmt3a results in global loss of mCH and a small subset of mCG sites resulting in more widespread transcriptional alterations and severe neurological dysfunction than seen upon MeCP2 loss. These data indicate that MeCP2 is responsible for reading part of the Dnmt3a dependent methylation in the brain. Importantly, the impact of MeCP2 on genes differentially expressed in both cKO models shows a strong dependence on mCH, but not Dnmt3a dependent mCG, consistent with mCH playing a central role in the pathogenesis of Rett Syndrome.

neuroscience↗