Biology subjects

Kane, E.

Publications and source records attributed to Kane, E..

7 recordsLinked to original sources

bioRxiv2025

ATF4 activates a transcriptional program that chronically suppresses mTOR activity promoting neurodegeneration in Parkinson's disease models

The Integrated Stress Response (ISR) is a cell signaling pathway that enables cells to adapt to diverse cellular stresses. Conversely, during chronic/unmitigated cellular stress the ISR becomes maladaptive and has been implicated in a range of neurodegenerative conditions including Parkinsons Disease (PD). However, the mechanisms by which maladaptive ISR/ATF4 signaling contributes to neurodegeneration have not been elucidated. In this study we establish a critical mechanism by which chronic ISR activation becomes maladaptive and promotes neurodegeneration in neurotoxin and - synucleinopathy models of PD in vitro and in vivo. Specifically, we demonstrate that chronic activation of ATF4, the central transcription factor of the ISR, promotes neurodegeneration by regulating the transcriptional induction of SESN2, DDIT4 and Trib3 that co-operate to suppress both mTORC1 and mTORC2 activity. Furthermore, we demonstrate that ATF4-mediated suppression of mTORC1/2 activity promotes dopaminergic neuronal death in PD models by facilitating the activation of the pro- apoptotic BCL-2 family protein PUMA. Taken together, we have discovered a novel maladaptive ISR/ATF4 signaling pathway leading to chronic suppression of mTORC1/2 activity resulting in PUMA-mediated neuronal death that may have therapeutic implications in a range of neurodegenerative conditions that exhibit chronic ISR activation. O_FIG O_LINKSMALLFIG WIDTH=125 HEIGHT=200 SRC="FIGDIR/small/658667v1_ufig1.gif" ALT="Figure 1000"> View larger version (36K): org.highwire.dtl.DTLVardef@4fa02forg.highwire.dtl.DTLVardef@19d9f0forg.highwire.dtl.DTLVardef@13597beorg.highwire.dtl.DTLVardef@17d47e0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Epithelial miR-149-5p up-regulation is associated with immune evasion in progressive bronchial premalignant lesions

The molecular drivers bronchial premalignant lesion progression to invasive lung squamous cell carcinoma are not well defined. Prior work profiling longitudinally collected bronchial premalignant lesion biopsies by RNA sequencing defined a proliferative subtype, enriched with bronchial dysplasia. We found that a gene co-expression module associated with interferon gamma signaling and antigen processing/presentation was down-regulated in progressive/persistent versus regressive lesions within the proliferative subtype, suggesting a functional impact of these genes on immune evasion. RNA from these same premalignant lesions was profiled by microRNA (miRNA) sequencing and a miRNA-gene network analysis identified hsa-miR-149-5p as a potential regulator of this antigen presentation gene co-expression module associated with lesion progression. hsa-miR-149-5p was found to be predominantly expressed in the epithelium and up-regulated in progressive/persistent versus regressive proliferative lesions while targets of this miRNA, the transcriptional coactivator of MHC-I gene expression, NLRC5, and the genes it regulates were down-regulated. MicroRNA in situ hybridization of hsa-miR-149-5p in tissue from adjacent fixed biopsies showed that hsa-miR-149-5p was increased in areas of bronchial dysplasia in progressive/persistent versus regressive lesions. Imaging mass cytometry showed that NLRC5 protein expression was decreased in progressive/persistent versus regressive lesions within areas of hyperplasia, metaplasia, and dysplasia. Additionally, basal cells with high versus low levels of NLRC5 were found to be in close spatial proximity to CD8 T cells, suggesting that these cells exhibit increased functional MHC-I gene expression in lesions with low hsa-miR-149-5p expression. Collectively, our data suggests a functional role for hsa-miR-149-5p in bronchial premalignant lesions and may serve as a therapeutic target for PML immunomodulation. STATEMENT OF SIGNIFICANCEIntegrative analysis across bronchial premalignant lesions has identified and localized a potential regulator of immune evasion in progressive/persistent lesions that could be a novel therapeutic target.

cancer biology↗

bioRxiv2023

PARALLEL LOSS OF SEX IN FIELD POPULATIONS OF A BROWN ALGA SHEDS LIGHT ON THE MECHANISMS UNDERLYING THE EMERGENCE OF ASEXUALITY

AO_SCPLOWBSTRACTC_SCPLOWSexual reproduction is widespread among eukaryotes, but asexual lineages have repeatedly arisen from sexual ancestors across a wide range of taxa. Despite extensive research on the evolution of asexuality from sexual ancestors, the molecular changes underpinning the switch to asexual reproduction remain elusive, particularly in organisms with haploid sexual systems such as bryophytes, and red and brown algae in which males and females are haploid and multicellular. Here, we investigate independent events in which asexuality has emerged from sexual ancestor lineages in species of the brown algal Scytosiphon, we examine the proximate and evolutionary mechanisms involved, and test the importance of sexual conflict on gene expression changes following loss of sex. We find that individuals from asexual, female-only ( Amazon) populations lose their ability to produce and sex pheromone and, consequently, are unable to attract and fuse with male gametes, whereas they gain the ability to trigger parthenogenic (asexual) development from large, unfertilized eggs. This independent and convergent decline in pheromone production and optimization of asexual traits is accompanied by convergent changes in gene expression, including de-feminization and masculinization of the Amazon gamete transcriptomes. These data are consistent with the idea that decay of female functions, rather than relaxation of sexual antagonism, is the dominant force at play during the emergence of asexuality in haploid sexual systems. Moreover, we identify a locus on an autosomal protein-coding gene that is associated with the switch to asexuality. We propose that the sex chromosome, together with this autosomal locus, may underlie the switch to obligate asexuality in the Amazon populations.

evolutionary biology↗

bioRxiv2022

The impact of Mmu17 non-Hsa21 orthologous genes in the Ts65Dn mouse model of Down syndrome: the "gold standard" revisited

Despite many successful preclinical treatment studies to improve neurocognition in the Ts65Dn mouse model of Down syndrome (DS), translation to humans has failed. This raises critical questions about the appropriateness of the Ts65Dn mouse as the "gold standard" for DS research given that it carries, in addition to Mmu16 orthologous genes, triplication of 50 Mmu17 non-orthologous genes that might contribute to the observed brain and behavioral phenotypes. We used the novel Ts66Yah mouse that carries both an extra mini chromosome and the identical segmental Mmu16 trisomy as Ts65Dn, but in which the Mmu17 non-orthologous region was removed using CRISPR/Cas9 technology. We demonstrate that the Ts65Dn exhibits a more severe phenotype throughout the lifespan compared to the Ts66Yah mouse. Several Mmu17 non-orthologous genes were uniquely overexpressed in Ts65Dn embryonic forebrain; this produced major differences in dysregulated genes and pathways. Despite these genome-wide differences, the primary Mmu16 trisomic effects were highly conserved in both models, resulting in several commonly dysregulated disomic genes and pathways. During the neonatal period, delays in motor development, communication and olfactory spatial memory were observed in both Ts66Yah and Ts65Dn pups but were more pronounced in Ts65Dn. Adult Ts66Yah mice showed working memory deficits and sex-specific effects in exploratory behavior and spatial hippocampal memory, while long-term memory was preserved. Like the neonates, adult Ts66Yah mice exhibited fewer and milder behavioral deficits when compared to Ts65Dn mice. Our findings suggest that trisomy of the non-orthologous Mmu17 genes significantly contributes to the phenotype of the Ts65Dn mouse and may be one major reason why preclinical trials that used this model have unsuccessfully translated to human therapies.

neuroscience↗

bioRxiv2021

A nuclear cAMP microdomain suppresses tumor growth by Hippo pathway inactivation

cAMP signaling pathways are critical for both oncogenesis and tumor suppression. cAMP signaling is localized to multiple spatially distinct microdomains, but the role of cAMP microdomains in cancer cell biology is poorly understood. We developed a tunable genetic system that allows us to activate cAMP signaling in specific microdomains. We uncovered a previously unappreciated nuclear cAMP microdomain that functionally activates a tumor suppressive pathway in a broad range of cancers by inhibiting YAP, a key effector protein of the Hippo pathway, inside the nucleus. We show that nuclear cAMP induces a LATS-dependent pathway leading to phosphorylation of nuclear YAP solely at serine 397, export of YAP from the nucleus, without YAP protein degradation. Thus, nuclear cAMP inhibition of nuclear YAP is distinct from other known mechanisms of Hippo regulation. Pharmacologic targeting of specific cAMP microdomains remains an untapped therapeutic approach for cancer, and since Hippo pathway deregulation can lead to oncogenesis and chemotherapeutic resistance, drugs directed at the nuclear cAMP microdomain may provide new avenues for the treatment of cancer.

cancer biology↗

bioRxiv2021

The power of peer networking for improving STEM faculty job applications: a successful pilot program

In order to successfully obtain a faculty position, postdoctoral fellows or postdocs, must submit an application which requires considerable time and effort to produce. These job applications are often reviewed by mentors and colleagues, but rarely are postdocs offered the opportunity to solicit feedback multiple times from reviewers with the same breadth of expertise often found on an academic search committee. To address this gap, this manuscript describes an international peer reviewing program for small groups of postdocs with a broad range of expertise to reciprocally and iteratively provide feedback to each other on their application materials. Over 145 postdocs have participated, often multiple times, over three years. A survey of participants in this program revealed that nearly all participants would recommend participation in such a program to other faculty applicants. Furthermore, this program was more likely to attract participants who struggled to find mentoring and support elsewhere, either because they changed fields or because of their identity as a woman or member of an underrepresented population in STEM. Participation in programs like this one could provide early career academics like postdocs with a diverse and supportive community of peer mentors during the difficult search for a faculty position. Such psychosocial support and encouragement has been shown to prevent attrition of individuals from these populations and programs like this one target the largest leak in the pipeline, that of postdoc to faculty. Implementation of similar peer reviewing programs by universities or professional scientific societies could provide a valuable mechanism of support and increased chances of success for early-career academics in their search for independence.

scientific communication and education↗

bioRxiv2019

β-cell dedifferentiation is associated with epithelial-mesenchymal transition triggered by miR-7-mediated repression of mSwi/Snf complex

{beta}-cell dedifferentiation has been revealed as a pathological mechanism underlying pancreatic dysfunction in diabetes. However, little is known on the genetic and epigenetic changes linked with the dedifferentiation of {beta}-cells. We now report that {beta}-cell dedifferentiation is associated with epithelial to mesenchymal transition (EMT) triggered by miR-7-mediated repression of Smarca4/Brg1 expression, a catalytic subunit of the mSwi/Snf chromatin remodeling complexes essential for {beta}-cell transcription factors ({beta}-TFs) activity. miR-7-mediated repression of Brg1 expression in diabetes causes an overall compaction of chromatin structure preventing {beta}-TFs from accessing and transactivating genes maintaining the functional and epithelial identity of {beta}-cells. Concomitantly, loss of {beta}-cell identity impairs the ability of {beta}-TFs Pdx1, Nkx6-1, Neurod1 to repress non-{beta}-cell genes enriched selectively in mesenchymal cells leading to EMT, change in islet microenvironment, and fibrosis. Remarkably, anti-EMT agents normalized glucose tolerance of diabetic mice, thus revealing mesenchymal reprogramming of {beta}-cells as a novel therapeutic target in diabetes. This study sheds light on the genetic signature of dedifferentiated {beta}-cells and highlights how loss of mSwi/Snf activity in diabetes initiating a step-wise remodeling of epigenetic landscapes of {beta}-cells leading to the induction of an EMT process reminiscent of a response to tissue injury.

genomics↗