Biology subjects

Kennedy, J. A.

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

3 recordsLinked to original sources

bioRxiv2021

Fanconi Anemia Pathway Deficiency Drives Copy Number Variation in Squamous Cell Carcinomas

Fanconi anemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink (ICL) repair resulting in chromosome breakage1-3. The FA repair pathway comprises at least 22 FANC proteins including BRCA1 and BRCA24-6, and protects against carcinogenic endogenous and exogenous aldehydes7-10. Individuals with FA are hundreds to thousands-fold more likely to develop head and neck (HNSCC), esophageal and anogenital squamous cell carcinomas (SCCs) with a median onset age of 31 years11. The aggressive nature of these tumors and poor patient tolerance of platinum and radiation-based therapy have been associated with short survival in FA11-16. Molecular studies of SCCs from individuals with FA (FA SCCs) have been limited, and it is unclear how they relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or human papillomavirus (HPV) infection17. Here, by sequencing FA SCCs, we demonstrate that the primary genomic signature of FA-deficiency is the presence of a high number of structural variants (SVs). SVs are enriched for small deletions, unbalanced translocations, and fold-back inversions that arise in the context of TP53 loss. The SV breakpoints preferentially localize to early replicating regions, common fragile sites, tandem repeats, and SINE elements. SVs are often connected forming complex rearrangements. Resultant genomic instability underlies elevated copy number alteration (CNA) rates of key HNSCC-associated genes, including PIK3CA, MYC, CSMD1, PTPRD, YAP1, MXD4, and EGFR. In contrast to sporadic HNSCC, we find no evidence of HPV infection in FA HNSCC, although positive cases were identified in gynecologic tumors. A murine allograft model of FA pathway-deficient SCC was enriched in SVs, exhibited dramatic tumor growth advantage, more rapid epithelial-to-mesenchymal transition (EMT), and enhanced autonomous inflammatory signaling when compared to an FA pathway-proficient model. In light of the protective role of the FA pathway against SV formation uncovered here, and recent findings of FA pathway insufficiency in the setting of increased formaldehyde load resulting in hematopoietic stem cell failure and carcinogenesis18-20, we propose that high copy-number instability in sporadic HNSCC may result from functional overload of the FA pathway by endogenous and exogenous DNA crosslinking agents. Our work lays the foundation for improved FA patient treatment and demonstrates that FA SCC is a powerful model to study tumorigenesis resulting from DNA crosslinking damage.

cancer biology↗

bioRxiv2021

Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML

Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSC) point to shared core stemness properties. However, discordance between mRNA and protein signatures underscores an important role for post-transcriptional regulation by miRNAs in governing this critical nexus. Here, we identified miR-130a as a regulator of HSC self-renewal and differentiation. Enforced expression of miR-130a impaired B lymphoid differentiation and expanded long-term HSC. Integration of protein mass spectrometry and chimeric AGO2 eCLIP-seq identified TBL1XR1 as a primary miR-130a target, whose loss of function phenocopied miR-130a overexpression. Moreover, we found that miR-130a is highly expressed in t(8;21) AML where it is critical for maintaining the oncogenic molecular program mediated by AML1-ETO. Our study establishes that identification of the comprehensive miRNA targetome within primary cells enables discovery of novel genes and molecular networks underpinning stemness properties of normal and leukemic cells. HIGHLIGHTSO_LImiR-130a is a regulator of HSC self-renewal and lineage commitment C_LIO_LITBL1XR1 is a principal target of miR-130a C_LIO_LITBL1XR1 loss of function in HSPC phenocopies enforced expression of miR-130a C_LIO_LIElevated miR-130a levels maintain the AML1-ETO repressive program in t(8;21) AML C_LI

cell biology↗

bioRxiv2020

Back to the future: a refined single user photostation for massively scaling herbarium digitization

The digitization and online mobilization of herbarium specimens has greatly facilitated their access and helped ignite a revolution in the biodiversity sciences (Drew et al., 2017; Hedrick et al., 2020; Nelson et al., 2015; Soltis, 2017; Sweeney et al., 2018; Thiers et al., 2016). These efforts have mobilized millions of specimens with significant economies of scale and accelerated advances in scientific investigations, including phenological studies of climate change, species range assessments, and biotic interactions (Hedrick et al., 2020; Meineke et al., 2019; Meineke et al., 2018; Pearson et al., 2020; Willis et al., 2017). In addition, the use of natural history collections to answer scientific questions using only their digitized representation, rather than the physical specimen itself-i.e., Digitization 2.0 sensu Hedrick et al. (2020)-has sparked the integration and development of new scholarly disciplines and lines of inquiry not previously possible. Despite these exciting new directions, however, Digitization 1.0 sensu Hedrick et al. (2020)-i.e., the generation of digitized products from the physical specimen-remains an active area of innovation and development. This relates to both hardware and workflow innovations as well as their integration with advancements in software. Along these lines, innovations in these areas have greatly increased the cost-effectiveness of digitizing herbarium specimens and enabled the successful mobilization of entire collections and whole floristic regions (Heerlien et al., 2015; Pignal and Michiels, 2012; Schorn et al., 2016; Slijkhuis, 2014; Sweeney et al., 2018; van Oever and Gofferje, 2012). Here, we present a novel photostation and workstation design for imaging herbarium specimen that represents a dramatic improvement upon existing approaches and is scalable for large and small institutions alike.

plant biology↗