BINA Scientific Speaker Series

Eunice Fabian-Morales – April 11

Advanced Microscopy Applications Unit (ADMiRA) at the National Cancer Institute of Mexico

Presentation Title:
Super-resolution imaging, a powerful tool for the analysis of chromosome topology applied to the study of treatment resistance in cancer.

Abstract:
Chromosomes in interphase occupy a distinct, limited space within the nucleus, called chromosome territory (CT). It has been postulated that the non-random CT’s spatial organization within the cell nucleus contributes to the emergence of chromosome translocations. The consistent appearance of t(9;22) in pluripotent hematopoietic stem cells, apart from being the etiological factor for chronic myeloid leukemia (CML), is a clear example of what is considered a non-random chromosome aberration. This rearrangement leads to the fusion of BCR and ABL1 genes giving rise to a chimeric protein with constitutive kinase activity. Tyrosine kinase inhibitors (TKI), such as Imatinib, are used as first-line treatment for CML, though approximately 40% of CML patients do not respond to Imatinib.
In order to highlight the importance of spatial proximity, and evaluate the topological CT changes caused by t(9;22), before and after TKI treatment, we performed 3D-FISH of CT9 and CT22 in stem cells from CML patients followed by super-resolution microscopy, and image 3D reconstruction.
We found that resistance to TKI treatment in CML is characterized by high levels of CT9 and CT22 structural disruption, increased CT volumes (especially for CT22), increased intermingling between CT9 and CT22, and increased occupancy of H3K9ac, an open-chromatin epigenetic mark, in CT22.
Taken together, our findings suggest that CT9 and CT22 disruption is a potential predictive marker of response or non-response to therapy in CML, our results also provide novel insights into how the genome structure associates with the response to cancer treatments, highlighting the importance of microscopy in analyzing the topological features of the genome.

Alissa Armstrong – May 9

Armstrong Research Lab, University of South Carolina

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Presentation Title:
Inter-organ communication: uncovering molecular mechanisms that mediate adipose tissue control of oogenesis

Abstract:
Adult stem cells support tissue homeostasis and damage repair in a wide range of organisms. Physiological factors, like diet, influence the activity of adult stem cell populations, yet not enough is known about how inter-organ communication modulates stem cell responses to dynamic nutritional input. We leverage the power of Drosophila melanogaster genetics to uncover the cellular and molecular mechanisms that underlie fat-to-ovary communication about diet. The stem cell-supported ovary of Drosophila melanogaster females, which sustains robust reproductive capacity, is sensitive to dietary changes. Female flies fed suboptimal diets, e.g. protein-poor, high-sugar, or high-fat, display significantly reduced egg production rates; a response mediated by highly conserved nutrient-sensing pathways that function tissue autonomously and non-autonomously. We have shown that amino acid sensing pathways and insulin/insulin-like growth factor signaling (IIS) within adipocytes impact the ovarian germline stem cell lineage, including germline stem cell maintenance, germline survival, and ovulation. Interestingly, distinct signaling pathways downstream of nutrient sensing in adipocytes modulate different stages of oogenesis. Thus far, our work using adipocyte-specific manipulation of gene expression indicates that amino acid response pathway activity and mTOR signaling in adipocytes modulate translation of different factors that have specific effects on the germline stem cell lineage. Currently, we are using genetic and cell biological tools to answer two main questions – 1) what mechanisms do nutrient-sensing pathways use within adipocytes to relay dietary macronutrient information to ovarian stem cells and their progeny, and 2) how do adipose-derived factors communicate dietary status from the fat to the ovary? This work will illuminate how inter-organ communication coordinates organismal nutritional status with oocyte production and adult stem cell activity.

Chantell Evans – June 13

Evans Research Lab, Duke University

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Presentation Title: Investigating mitochondria quality control dynamics in neuronal homeostasis and disease

Abstract:
Neurodegenerative diseases are characterized by the progressive structural and functional loss of neurons. A hallmark of these incurable diseases is the accumulation of aberrant mitochondria accompanied by increased mitochondrial stress and dysfunction, suggesting that mitochondrial dysregulation plays a role in disease progression. Emerging evidence from our work and others suggests that several mechanisms are required to maintain mitochondrial health. Mitophagy is one of these quality control pathways, where damaged mitochondria are selectively removed from the cell via autophagosome engulfment and downstream lysosomal acidification. Mitophagy appears important for neuronal homeostasis, and mutations in pathway components are causative of Parkinson’s disease and ALS. Here, we used live imaging to gain mechanistic insight into the temporal dynamics of mitophagy in primary neurons. We find that mild oxidative stress induces low levels of mitochondrial damage and mitophagy without compromising the entire neuronal network. To probe the time-course of neuronal mitophagy, we developed a pulse-chase labeling paradigm to monitor turnover based on spectrally distinct “aged” mitochondrial populations. Mitophagy-associated proteins, including Parkin, TBK1, and OPTN, rapidly translocated to depolarized mitochondria, and damaged organelles were efficiently sequestered in autophagosomes within an hour of damage. Surprisingly, we determined that damaged organelles persist in the soma of neurons for hours to days after initial mitochondrial insult. The time course of mitochondrial turnover was slower in neurons compared to non-neuronal cells, where we visualized rapid acidification of depolarized mitochondria an hour after the insult. We identified lysosome fusion and acidification to remove damaged mitochondria as a rate-limiting step in neuronal mitophagy. The slow rates of turnover that we describe likely contribute to the mitochondrial accumulation detected on early neurodegenerative disease onset.

Scientific Speaker Series 2023

Andres Nevarez – February 14

Delissa McMillen – March 14

Eunice Fabian-Morales – April 11

Alissa Armstrong – May 9

Chantell Evans – June 13

Paul Hernandez-Herrera – July 11