Biology subjects

Donahue, M.

Publications and source records attributed to Donahue, M..

5 recordsLinked to original sources

bioRxiv2026

Multi-omic profiling reveals impaired luteal resolution and CHK2-regulated inflammation in ovarian aging

The ovary ages earlier than most other organs, but the molecular mechanisms that drive this decline remain unclear. To gain more insight into this process, we profiled ovaries from young and reproductively aged mice after synchronized ovulation and found that aging was marked by the accumulation of luteal cells with increased steroidogenic, antigen presentation and inflammatory gene expression. DNA methylation was globally preserved in aged ovaries but showed focal age-associated changes at gene regulatory regions. Protein profiling identified an increase in checkpoint kinase 2 (CHK2), a DNA damage response protein encoded by the CHEK2 gene associated with the timing of natural menopause in humans. CHK2 and DNA damage markers were increased in aged mice and human ovarian somatic cells. Transient CHK2 inhibition in aged mice increased the proportion of mature oocytes and blastocyst formation and reversed inflammatory signatures in granulosa cells. These findings identify defective luteal resolution and inflammation as features of ovarian aging and suggest that CHK2 induces a reversible age-associated inflammatory signature. Our results show that reproductive decline may remain pharmacologically modifiable during ovarian aging via regulation of the inflammatory response.

molecular biology↗

bioRxiv2026

Social Novelty Recruits a Dysfunctional Nucleus Accumbens Ensemble That Drives Social Avoidance in a Shank3-/- Autism Model

Social behavior deficits are a common symptom of neuropsychiatric disorders, including autism spectrum disorder (ASD), but there are limited pharmacological treatments for these symptoms. Understanding how neurons encode social information will give insight into identifying novel pharmacological targets to address this unmet need. SHANK3 encodes a postsynaptic scaffold protein and is a common risk gene for several neuropsychiatric disorders characterized by social deficits, including ASD. Our lab previously developed the Shank3{Delta}e4-22 mouse model, which shows a loss of social preference and altered connectivity in the nucleus accumbens (NAc), a critical region for social behaviors. However, it remains unknown how Shank3 deletion alters the encoding of social cues in the NAc. To address this gap in knowledge, we characterized the function of neurons activated by social interaction, or social ensembles, in WT and Shank3{Delta}e4-22 mice using a combination of genetic capture techniques, chemogenetics, optogenetics, and one-photon calcium imaging. We show that NAc social ensembles of WTs and Shank3{Delta}e4-22 mice drive opposing social behaviors: while NAc social ensembles encode appetitive social cues in WT mice, they encode avoidance in Shank3{Delta}e4-22 mice. We further find that, in Shank3{Delta}e4-22 mice, NAc neurons are hyperactive and have hypermodulatory responses to social novelty. Suppressing the activity of social ensembles during social novelty prevents future social avoidance and restores social investigation in Shank3{Delta}e4-22 mice. Taken together, our data show that Shank3{Delta}e4-22 mice have an enhanced NAc response to social novelty that actively drives social aversion, rather than a loss of social motivation.

neuroscience↗

bioRxiv2025

Deficiency of Shank3 in the Nucleus Accumbens Reveals a Loss of Social-Specific Motivation

Deficits in social interaction are a hallmark symptom of autism and other neuropsychiatric disorders. SHANK3 encodes a postsynaptic density scaffold protein and is one of the most common causal genes for autism. SHANK3 protein is highly expressed in the nucleus accumbens (NAc), a critical brain region underlying motivated behavior, including social motivation. We previously reported that global Shank3{Delta}e4-22 deletion mice have decreased motivation for palatable food, increased unilateral social investigation, and show a hypoactive NAc and NAc-connected circuits. We thus developed a new Shank3flox/floxmouse tool to conditionally knockdown SHANK3 in a region-specific manner. We found that knockdown of Shank3 in the NAc decreased social preference in the 3-chamber assay and decreased social motivation in the social conditioned place preference (sCPP) assay. Shank3-NAc deletion did not alter food reward seeking, reciprocal social investigation, or anxiety-like behaviors, that we report in global Shank3{Delta}e4-22 deletion mice. These data establish a novel and specific role of Shank3 in the NAc on social motivation.

neuroscience↗

bioRxiv2022

Splicing modulators impair DNA damage response and induce killing of cohesin-mutant MDS/AML

Splicing modulation is a promising treatment strategy pursued to date only in splicing-factor mutant cancers; however, its therapeutic potential is poorly understood outside of this context. Like splicing factors, genes encoding components of the cohesin complex are frequently mutated in cancer, including myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (AML), where they are associated with poor outcomes. Here, we show that cohesin mutations are biomarkers of sensitivity to drugs targeting the splicing-factor SF3B1 (H3B-8800 and E-7107). We identify drug-induced alterations in splicing and corresponding reduced gene expression of a large number of DNA repair genes, including BRCA1 and BRCA2, as the mechanism underlying this sensitivity in cell line models, primary patient samples and patient-derived xenograft (PDX) models of AML. We find that DNA damage repair genes are particularly sensitive to exon skipping induced by SF3B1 modulators given their long length and large number of exons per transcript. Furthermore, we demonstrate that treatment of cohesin-mutant cells with SF3B1 modulators not only results in impaired DNA damage response and accumulation of DNA damage, but it significantly sensitizes cells to subsequent killing by PARP inhibitors and chemotherapy, and leads to improved overall survival of PDX models of cohesin-mutant AML in vivo. Our findings expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS and AML, and we propose this as a broader strategy for therapeutic targeting of other DNA damage-repair deficient cancers. One Sentence SummaryWe identify an unexpected effect of SF3B1 splicing inhibitors on regulation of DNA damage repair genes and show efficacy of combination treatment in cohesin-mutant MDS and AML.

cancer biology↗

bioRxiv2017

A Next Generation Connectivity Map: L1000 Platform And The First 1,000,000 Profiles

We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io.\n\nHIGHLIGHTSO_LIA new gene expression profiling method, L1000, dramatically lowers cost\nC_LIO_LIThe Connectivity Map database now includes 1.3 million publicly accessible L1000 perturbational profiles\nC_LIO_LIThis expanded Connectivity Map facilitates discovery of small molecule mechanism of action and functional annotation of genetic variants\nC_LIO_LIThe work establishes feasibility and utility of a truly comprehensive Connectivity Map\nC_LI

genomics↗