Bella Archibald

All Publications

• The H3.3K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation. Molecular cell Sinha, J., Nickels, J. F., Thurm, A. R., Ludwig, C. H., Archibald, B. N., Hinks, M. M., Wan, J., Fang, D., Bintu, L. 2024

  Abstract

  Histone H3.3 is frequently mutated in tumors, with the lysine 36 to methionine mutation (K36M) being a hallmark of chondroblastomas. While it is known that H3.3K36M changes the epigenetic landscape, its effects on gene expression dynamics remain unclear. Here, we use a synthetic reporter to measure the effects of H3.3K36M on silencing and epigenetic memory after recruitment of the ZNF10 Kruppel-associated box (KRAB) domain, part of the largest class of human repressors and associated with H3K9me3 deposition. We find that H3.3K36M, which decreases H3K36 methylation and increases histone acetylation, leads to a decrease in epigenetic memory and promoter methylation weeks after KRAB release. We propose a modelfor establishment and maintenance of epigenetic memory, where the H3K36 methylation pathway is necessary to maintain histone deacetylation and convert H3K9me3 domains into DNA methylation for stable epigenetic memory. Our quantitative model can inform oncogenic mechanisms and guide development of epigenetic editing tools.

  View details for DOI 10.1016/j.molcel.2024.09.015

  View details for PubMedID 39368466

• Policy makers, genetic engineers, and an engaged public can work together to create climate-resilient plants. PLoS biology Archibald, B. N., Zhong, V., Brophy, J. A. 2023; 21 (7): e3002208

  Abstract

  As climate change affects weather patterns and soil health, agricultural productivity could decrease substantially. Synthetic biology can be used to enhance climate resilience in plants and create the next generation of crops, if the public will accept it.

  View details for DOI 10.1371/journal.pbio.3002208

  View details for PubMedID 37440471

• Transcriptional and post-transcriptional controls for tuning gene expression in plants. Current opinion in plant biology Zhong, V., Archibald, B. N., Brophy, J. A. 2022; 71: 102315

  Abstract

  Plant biotechnologists seek to modify plants through genetic reprogramming, but our ability to precisely control gene expression in plants is still limited. Here, we review transcription and translation in the model plants Arabidopsis thaliana and Nicotiana benthamiana with an eye toward control points that may be used to predictably modify gene expression. We highlight differences in gene expression requirements between these plants and other species, and discuss the ways in which our understanding of gene expression has been used to engineer plants. This review is intended to serve as a resource for plant scientists looking to achieve precise control over gene expression.

  View details for DOI 10.1016/j.pbi.2022.102315

  View details for PubMedID 36462457

• Comparison of Gene Editing versus a Neutrophil Elastase Inhibitor as Potential Therapies for ELANE Neutropenia. Journal of cellular immunology Makaryan, V., Kelley, M., Fletcher, B., Archibald, I., Poulsen, T., Dale, D. 2022; 4 (1): 19-28

  Abstract

  Heterozygous mutations in ELANE, the gene for neutrophil elastase, cause cyclic and congenital neutropenia through the programed cell death of neutrophil progenitors in the bone marrow. Granulocyte colony-stimulating factor is an effective therapy for these diseases, but alternative therapies are needed, especially for patients who do not respond well or are at high risk of developing myeloid malignancies. We developed an HL60 cell model for ELANE neutropenia and previously demonstrated that transient and regulated expression of mutant ELANE causes cell death by accelerated apoptosis. Knocking down the mutant gene or exposure to a potent inhibitor of neutrophil elastase rescued neutrophil development. Because of the great diversity in causative ELANE mutations, we generated stable HL60 clones expressing mutant P139L, C151Y and G214R and compared the effects of elastase inhibitor exposure to an ELANE knock-out line on cell development and function. ATRA induced differentiation demonstrated comparably impaired myeloid cell development for all three lines with upregulated expression of GRP78/BIP, an abnormality corrected by exposure of these cells to the elastase inhibitor MK-0339. The inhibitor and KO of mutant ELANE led to formation of neutrophils with comparable chemotactic and bactericidal capacities. We concluded that both strategies have great potential for the treatment of cyclic and congenital neutropenia. However, an orally absorbed, cell permeable inhibitor of neutrophil elastase, if proven safe and effective in a clinical trial, might be the better alternative to G-CSF or gene editing to treat ELANE neutropenia.

  View details for DOI 10.33696/immunology.4.129

  View details for PubMedID 36052149

  View details for PubMedCentralID PMC9431957

• CRISPR/Cas9 Mediated ELANE Knock-out Restores Survival and Granulocytic Differentiation of HL60 Cells Expressing Mutant Neutrophil Elastase: Is Neutrophil Elastase a Dispensible Granulocyte Protease? Makaryan, V., Archibald, I. N., Kelley, M. L., Fletcher, B., Dale, D. C. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-124988

  View details for Web of Science ID 000518218500121