Research – Frontiers – Adipocyte-mediated Epigenomic Instability in Human T-ALL cells is Cytotoxic and Phenocopied by Epigenetic Modifying Drugs

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MLee_2022_blog thumbnailAdipocyte-mediated Epigenomic Instability in Human T-ALL cells is Cytotoxic and Phenocopied by Epigenetic Modifying Drugs
Lee M, Geitgey D, Hamilton JAG, Boss J, Scharer CD, Haynes KA, Henry CJ. (2022) Front Cell Dev Biol.
PMID: 36060800 | PMCID: PMC9438935

An alarming trend in public health is the increase in obesity, with a projection of 1.5 billion people with obesity by 2030. This trend is expected to impact personalized medicine because the progression and treatment of cell development-related diseases, such as cancer, differ in patients with obesity versus without. On one hand, acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL) are positively associated with obesity. On the other hand, epidemiological studies show the the opposite for patients with T-cell acute lymphoblastic leukemia (T-ALL). To investigate the negative relationship between obesity and T-ALL development, we analyzed T-ALL cells from the diet-induced obese (DIO) mice and human T-ALL cells cultured in adipocyte-conditioned media (ACM). Lean mice transplanted with T-ALL cells showed worse survival (~20%) than obese mice (~50-80%). ACM-treated human T-ALL cells showed accelerated cell cycle progression, DNA damage, and cell death. We determined epigenetic changes that accompanied these changes in cell behavior. Transcription of genes involved in cellular responses to stimuli, cell cycle, DNA replication and repair, metabolism of RNA, and transcription were elevated. Acetylation and methylation marks on histone 3 were elevated when human T-ALL cells were cultured in ACM, indicating a loss of histone demethylase and deacetylase activity or gain of histone acetyltransferase activity. Treatment of T-ALL cells with inhibitors of histone demethylase and histone deacetylase reproduced the changes in chromatin and cell viability observed for ACM treatment. Our data support epidemiological studies demonstrating that adiposity suppresses T-ALL pathogenesis, and suggest a pharmacological option (epigenetic drug treatment) may benefit lean patients with T-ALL.

Research – Scientific Reports – B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12

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Hunter_2022_SciRepB-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12
Hunter R, Imbach K, Dougan J, Do P, Townsel A, Zhou C, Gibson G, Dreaden E, Haynes K, Henry CJ, Porter CC. (2022) Sci Reports.
PMID: 35831470 | PMCID: PMC9279427

Immunotherapy is an exciting and important new approach for cancer treatment. As with any emerging cancer therapy, a critical challenge is to optimize the therapy to be effective for an array of diverse cancer cell types, i.e. blood cancer versus solid tumors and cancer cells from diverse organs, and the chemically diverse spaces where they reside within the body (microenvironments). The duration of responses of B-cell acute lymphoblastic leukemia (B-ALL) to immunotherapy remains sub-optimal. To find out what it is that blocks immunotherapy in patients with B-ALL, we analyzed plasma collected from children with B-ALL and found decreased cytokine levels (particularly IL-7), increased expression from immune exhaustion genes, and factors that suppressed T-cell function. To determine how to restore the immune response, we used a B-ALL mouse model to show that treatment with IL-12 proteins restored the levels of several pro-inflammatory cytokines and chemokines, increased the number of splenic and bone marrow resident T-cells and dendritic cells, and blocked the activation of immune exhaustion genes. These results demonstrate that treatment with IL-12 proteins can be used to alter the leukemia microenvironment so that immunotherapy can be more effective.

Symposium – BME Symposium on Health Disparities

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Coulter-BME-5Ltext-4515-540Triple negative breast cancer is highly lethal, is resistant to therapy, and continues to disproportionately affect African-American women (X Du 2022). Some studies suggest that mortality is highest in Black women with obesity (LA Carey et al 2006). To investigate the molecular mechanism of obesity-induced aggressiveness in triple negative breast cancer, we have teamed up with the Henry lab (Dr. Curtis Henry, Emory Pediatrics), the first group to discover an obesity-associated drug target in patients with leukemia.  Results from our new collaboration, “Murine model to identify epigenetic mediators of obesity-associated drug resistance in triple negative breast cancer” will be presented by Dr. Haynes at the BME Symposium on Health Disparities on Monday, April 18, 2022 at the Historic Academy of Medicine in Atlanta, GA.

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Review – Trends in Biochem Sci – Beyond the marks: reader-effectors as drivers of epigenetics and chromatin engineering

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TIBS_2022_reviewBeyond the marks: reader-effectors as drivers of epigenetics and chromatin engineering
Franklin KA, Shields C, Haynes KA. (2022) Trends Biochem Sci. 47: 417–432. Free access (until June 3, 2022)
PMID: 35267540 | PMCID: PMC9074927

Epigenetics is a process where changes in gene expression are inherited through cell divisions and in some cases across familial generations. As more links between epigenetics and human development and disease have emerged, scientists have become more interested in controlling epigenetic states using molecular technologies including protein engineering. In this review, we discuss a relatively new substrate for epigenetic engineering, a class of gene regulators called “reader-effectors.” These are different from DNA-binding transcription factors in that a single reader-effector type can engage at multiple sites through interactions with biochemical marks (“signals”) on chromatin, the protein/DNA structure that organizes the genome. So far, scientists have used “epigenome editing” to generate or erase signals to alter epigenetic states. Relatively little has been done to control how these signals are transduced into outputs, such as gene regulation, to ultimately control cell behavior. We discuss what natural systems have taught us about the mechanism of two basic composable parts, the “reader” and “effector” domains,  and discuss potential of reader-effector engineering, a technique we call “epigenome actuation.”

Perspective – Nature – The living interface between synthetic biology and biomaterial design

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Nature_biomat_rev_2022The living interface between synthetic biology and biomaterial design
Liu AP, Appel EA, Ashby PD, Baker BM, Franco E, Gu L, Haynes K, Joshi NS, Kloxin AM, Kouwer PHJ, Mittal J, Morsut L, Noireaux V, Parekh S, Schulman R, Tang SKY, Valentine MT, Vega SL, Weber W, Stephanopoulos N, Chaudhuri O. (2022) Nature Materials. 21: 390–397.

This Perspective reviews recent key advances in the fields of synthetic biology and biomaterials engineering, and lays out a general strategy for collaboration between the two fields. Potential applications are described, such as bio-inspired building blocks, and ‘living’ materials that sense and respond based on the interactions between materials and embedded cells. Such applications have the potential to address grand challenges in health, biotechnology and sustainability.

New Member – Seong Hu Kim

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SKim1Seong Hu “Rick” Kim has joined the Haynes lab this fall as a PhD student from the GA Tech/ Emory Biomedical Engineering graduate program. He earned his B.S. in Biomedical Engineering with a Mathematics Minor from Georgia Tech. at Stanford University in Stanford, CA in 2017. As an undergraduate student, he gained lab research experience at the Nano System Application Laboratory, University of Seoul (2018) and in the lab of Dr. Susan Margulies (2019 – 2020) at Georgia Tech. Welcome to the Haynes lab! We look forward to working with you.

Research – RETM – Differential epigenetic effects of BMI1 inhibitor PTC-028 on fusion-positive rhabdomyosarcoma cell lines from distinct metastatic sites

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CShields_RETM2021_Abstract_Fig_KAHDifferential epigenetic effects of BMI1 inhibitor PTC-028 on fusion-positive rhabdomyosarcoma cell lines from distinct metastatic sites
Shields C, Schnepp RW, Haynes KA. (2022) Regen Eng Transl Med. https://doi.org/10.1007/s40883-021-00244-9

Previously, we reported in “Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target” that genetic and pharmacologic inhibition of BMI1 reduces the viability of alveolar rhabdomyosarcoma (ARMS) cells, suggesting a new treatment option for patients with the rare pediatric cancer fusion-positive rhabdomyosarcoma (FP-RMS). In a follow-on study, we identified gene expression changes that underlie the loss of cell viability and proliferation, and addressed some open questions about the affect of BMI1 inhibition on ARMS. For instance, in our previous study, BMI1 inhibition affected phosphorylation of LATS1/2, but BMI1 is a transcriptional regulator, not a kinase or phosphatase. In the new study, through RNA-sequencing we found that the mRNA levels of two kinases EPHA2 and PDGFRA were affected during BMI1 inhibition, revealing a possible gene regulation link between BMI1 and kinases that target LATS1/2. RNA-seq also revealed transcription profile differences between ARMS cells derived from two different sites (metastases to an axillary lymph node and bone marrow). Despite this heterogeneity, epigenetic intervention (BMI1 inhibition) induces an anti-cancer response.

Research – bioRxiv – Targeted regulation of episomal plasmid DNA expression in eukaryotic cells with a methylated-DNA-binding activator

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Fig_abstract_v1Targeted regulation of episomal plasmid DNA expression in eukaryotic cells with a methylated-DNA-binding activator
Enwerem-Lackland I, Warga E, Dugoni M, Elmer J, Haynes KA. (2021) bioRxiv. https://www.biorxiv.org/content/10.1101/2021.11.01.466616v1

This work was inspired by our team’s interest in making DNA delivery into human cells easier and more more reliable. Currently, synthetic viruses are the most efficient method, but only up to ~1000 bp of DNA can be reliably packaged in these vectors, and current DNA-delivering viruses can cause dangerous and lethal immunogenic reactions. Non-viral plasmid DNA may be a safer alternative, but delivery and expression tends to be poor and unreliable. Our work and research from other labs has implicated epigenetic blockades as one culprit. Therefore, we developed a small protein, inspired by work from the van Steensel lab and Khalil lab, that carries a gene expression activator to newly-delivered methylated plasmid DNA to boost its expression. The “landing pad” for the activator is the smallest of its kind (4 base pair unit, GAmeTC), and therefore should be easy to use in any plasmid DNA. We named this system The Dpn Adaptor Linked Effector (DAL-E) to honor the pioneering biochemist Marie M. Daly, the first scientist to determine that a central epigenetic protein (histone) is lysine-rich, and the first black woman to earn a PhD in Chemistry in the U.S.

Kierra Franklin – QE Passed!

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KFranklin1Congratulations to Kierra Franklin, first-year PhD student in the Wallace H. Coulter Biomedical Engineering graduate program! She passed her qualifying exam on September 9, 2021 and is now ready to start her thesis work on chromatin engineering for cancer research and treatment.

Karmella Haynes Joins NIH Biosecurity Advisory Board

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NIH_logoDr. Karmella Haynes is joining the National Institutes of Health (NIH) National Science Advisory Board for Biosecurity (NSABB), a federal advisory committee chartered to provide advice, guidance, and leadership for dual-use research.  She will serve a three-year term to help the U.S. evaluate research with legitimate and important scientific purpose that could also produce technologies or information that could be harmful if they are misused.

 

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