Biology subjects

Creighton, C.

Publications and source records attributed to Creighton, C..

5 recordsLinked to original sources

bioRxiv2021

Does Communal Breeding Promote an Increase in Social Immunity in Burying Beetles? A Test Case with Nicrophorus Defodiens

Communal breeding is a reproductive system in which more than a single pair of individuals share parental care duties. Burying beetles (genus Nicrophorus) breed on small vertebrate carcasses, which is used as a food source for their young. On larger carcasses, burying beetles will breed communally, forming multiple male-female associations. A significant and costly component of parental investment by burying beetles is the preservation of the carcass with secretions containing immune molecules. Because this immune investment is for the benefit of the offspring, the behavior is a form of social immunity. We test the hypothesis that communal breeding in burying beetles evolved as a mechanism to increase the social immune investment on larger carcasses, which are more difficult to preserve. We used N. defodiens, a communal breeding burying beetle species to test the hypothesis. There were two experimental treatments wherein, the females either bred communally or non-communally. Our results show that the combined immune activity in the secretions were higher in communally breeding pairs than in the immune contribution of single male-female pairs. However, subordinate females were rarely observed on the carcass, and the level of social immune activity of dominant females was lower than females breeding singly. These data suggest that communal breeding in N. defodiens decreases the level of investment in social immunity. Our results demonstrate that the presence of multiple females, which is common under natural conditions, can greatly complicate patterns of social immunity investment in burying beetles.

ecology↗

bioRxiv2020

Tead1 reciprocally regulates adult β-cell proliferation and function

Proliferative quiescence in {beta}-cells is required to maintain functional competence. While this presents a significant hurdle in regenerative therapy for diabetes, the molecular underpinnings of this reciprocal relationship remain unclear. Here, we demonstrate that TEAD1, the transcription effector of the mammalian-Hippo pathway, drives developmental stage-specific {beta}-cell proliferative capacity in conjunction with its functional maturation. TEAD1 promotes adult {beta}-cell mature identity by direct transcriptional control of a network of critical {beta}-cell transcription factors, including, Pdx1, Nkx6.1, and MafA, while its regulation of Cdkn2a maintains proliferative quiescence. Consequently, mice with either constitutive or inducible genetic deletion of TEAD1 in {beta}-cells developed overt diabetes due to a severe loss of secretory function despite induction of proliferation. Furthermore, we show that TEAD1 has a similar regulatory role in human {beta}-cells. Consistent with this function in {beta}-cells, variants in TEAD1 have been associated with c-HOMA-B in American Indians. We propose that TEAD1 is an essential intrinsic molecular switch coordinating adult {beta}-cell proliferative quiescence with mature identity and its differential modulation may be necessary to overcome the challenge of inducing proliferation with functional competence in human beta cells.

molecular biology↗

bioRxiv2017

Comprehensive Molecular Characterization of Mitochondrial Genomes in Human Cancers

Mitochondria are essential cellular organelles that play critical roles in cancer development. Through International Cancer Genome Consortium, we performed a multidimensional characterization of mitochondrial genomes using the whole-genome sequencing data of ~2,700 patients across 37 cancer types and related RNA-sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes including a novel hypermutated case. We observe similar mutational signatures across cancer types, suggesting powerful endogenous mutational processes in mitochondria. Truncating mutations are remarkably enriched in kidney, colorectal and thyroid cancers and associated with the activation of critical signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA (especially in skin and lung cancers), some of which disrupt therapeutic target genes (e.g., ERBB2). The mitochondrial DNA copy number shows great variations within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair, and cell cycle; and reveals their connections with clinically actionable genes. Our study, including an open-access data portal, lays a foundation for understanding the interplays between the cancer mitochondrial and nuclear genomes and translating mitochondrial biology into clinical applications.

genomics↗

bioRxiv2017

Daam2 Driven Degradation Of VHL Promotes Gliomagenesis

Von Hippel-Landau (VHL) protein is a potent tumor suppressor regulating numerous pathways that drive cancer, but mutations in VHL are restricted to limited subsets of malignancies. Here we identified a novel mechanism for VHL suppression in tumors that do not have inactivating mutations. Using developmental processes to uncover new pathways contributing to tumorigenesis, we found that Daam2 promotes glioma formation. Protein expression screening identified an inverse correlation between Daam2 and VHL expression across a host of cancers, including glioma. These in silico insights guided corroborating functional studies, which revealed that Daam2 promotes tumorigenesis by suppressing VHL expression. Furthermore, biochemical analyses demonstrate that Daam2 associates with VHL and facilitates its ubiquitination and degradation. Together, these studies are the first to define an upstream mechanism regulating VHL suppression in cancer and describe the role of Daam2 in tumorigenesis.\n\nStatement of SignificanceWe found that the glial developmental factor Daam2 promotes glioma tumorigenesis by suppressing VHL expression. Our studies show, for the first time, a regulatory mechanism that operates upstream of VHL in cancer and provides an explanation for how VHL expression is extinguished in tumors that do not have inactivating mutations.

cancer biology↗

bioRxiv2017

Genomic rearrangements near genes leading to upregulation across a diverse subset of human cancers

Using a dataset of somatic Structural Variants (SVs) in cancers from 2658 patients--1220 with corresponding gene expression data--we identified hundreds of genes for which the nearby presence (within 100kb) of an SV breakpoint was associated with altered expression. For the vast majority of these genes, expression was increased rather than decreased with corresponding SV event. Well-known up-regulated cancer-associated genes impacted by this phenomenon included TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. SVs upstream of TERT involved ~3% of cancer cases and were most frequent in liver-biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involved ~1% of non-amplified cases. For many genes, SVs were significantly associated with either increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the gene promoter was often increased with nearby SV breakpoint, which may involve inactivation of repressor elements.\n\nAbbreviations

genomics↗