Biology subjects

Rhee, C.

Publications and source records attributed to Rhee, C..

5 recordsLinked to original sources

bioRxiv2025

Interrupting Elmsan1 repression of nuclear Acetyl-CoA production therapeutically reprograms cancer cells

Metabolites are essential substrates for epigenetic modifications. Although nuclear acetyl-CoA constitutes a small fraction of the whole cell pool, it regulates cell fate by locally providing histone acetylation substrate. Here, we combined phenotypic chemical screen and genome-wide CRISPR screen to demonstrate a nucleus-specific acetyl-CoA regulatory mechanism that can be modulated to achieve therapeutic cancer cell reprogramming. While previously thought that nucleus-localized pyruvate dehydrogenase complex (nPDC) is constitutively active, we found that nPDC is constitutively inhibited by the nuclear protein ELMSAN1 through direct interaction. Pharmacologic inhibition of the ELMSAN1-nPDC interaction derepressed nPDC activity, enhancing nuclear acetyl-CoA generation and reprogramming cancer cells to a postmitotic state with diminished cell-of-origin signatures. Reprogramming was synergistically enhanced by histone deacetylase 1/2 inhibition, resulting in inhibited tumor growth, durably suppressed tumor-initiating ability, and improved survival in multiple cancer types in vivo, including therapy-resistant sarcoma patient-derived xenografts and carcinoma cell line xenografts. Our findings highlight the potential of targeting ELMSAN1-nPDC as epigenetic cancer therapy.

cancer biology↗

bioRxiv2023

CD45-antibody-drug conjugate clears tissue resident myeloid cells from their niches enabling therapeutic adoptive cell transfer

Tissue resident myeloid cells (TRM) in adults have highly variable lifespans and may be derived from early embryonic yolk sac, fetal liver or bone marrow. Some of these TRM are known pathogenic participants in congenital and acquired diseases. Myeloablative conditioning and hematopoietic stem cell transplant can replace long-lived brain TRM resulting in clinical improvements in metabolic storage diseases. With the advent of antibody-drug-conjugate (ADC) targeted cell killing as a cell selective means of transplant conditioning, we assessed the impact of anti-CD45-ADC on TRM in multiple tissues. Replacement of TRM ranged from 40 to 95 percent efficiencies in liver, lung, and skin tissues, after a single anti-CD45-ADC dose and bone marrow hematopoietic cell transfer. Of note, the population size of TRM in tissues returned to pre-treatment levels suggesting a regulated control of TRM abundance. As expected, brain, microglia were not affected, but brain monocytes and macrophages were 50% replaced. Anti-CD45-ADC and adoptive cell transfer were then tested in the chronic acquired condition, atherosclerosis exacerbated by Tet2 mutant clonal hematopoiesis. Plaque resident myeloid cells were efficiently replaced with anti-CD45-ADC and wild-type bone marrow cells. Notably, this reduced existent atherosclerotic plaque burden. Overall, these results indicate that anti-CD45-ADC clears both HSC and TRM niches enabling cell replacement to achieve disease modification in a resident myeloid cell driven disease.

immunology↗

bioRxiv2023

Cell of origin epigenetic priming determines susceptibility to Tet2 mutation

Hematopoietic stem cell mutations can result in clonal hematopoiesis (CH) but the clinical outcomes are heterogeneous. The nature of the founder mutation and secondary mutations likely drive emergent neoplastic disease. We investigated how the state of the cell of origin where the Tet2 mutation occurs affects susceptibility to that commonly occurring CH mutation. Here, we provide evidence that risk is written in the epigenome of the cell of origin. By characterizing cell states that underlie myeloid differentiation and linking this information to an inducible system to assess myeloid progenitor clones, we provide evidence that epigenetic markers of the cell where Tet2 mutation occurs stratifies clonal behaviors. Specifically, Sox4 fosters a global cell state of high sensitization towards Tet2 KO. Using GMP and primary HSC models, we show that Sox4 promotes cell dedifferentiation, alters cell metabolism and increases the in vivo clonal output of mutant cells. Our results validate the hypothesis that epigenetic features can predispose specific clones for dominance and explain why an identical mutation can result in different outcomes.

cancer biology↗

bioRxiv2022

Predestined neutrophil heterogeneity in homeostasis varies in transcriptional and phenotypic response to Candida

Once perceived to be homogenous effector cells, neutrophils have since been shown to exhibit population heterogeneity. Here, we established an experimental model of clonal neutrophil heterogeneity using conditionally immortalized clonal granulocyte monocyte progenitors (GMPs) and their mature neutrophil progeny. Transcriptional and epigenetic profiling showed conserved genome-wide signatures of transcription and chromatin accessibility that were specific to individual GMP clones and their paired neutrophil progeny, suggesting that clone specificity is established as early as the GMP stage. Clone-specific genes in vital regulatory pathways were pre-programmed and exhibited delayed expression in the mature neutrophil stage. The clone-specific gene expression in the mature neutrophils paired to enhancer activation in their parental GMPs. To determine whether transcriptional heterogeneity predicted the response to fungal pathogens, neutrophil clones were functionally profiled. Clones demonstrated heterogeneous responses to fungal pathogens in vitro and revealed neutrophil subsets with evidence for tailored functional responses to Candida spp. as well as specific transcriptional and epigenetic patterns that may explain these differences. Together, this work establishes that heterogenous GMP and neutrophil compartments exist under homeostatic conditions and that these represent predefined clusters that are uniquely adapted to control invasive fungal pathogens. Short SummaryClonal neutrophil progenitors demonstrate heterogeneity in transcription and chromatin accessibility which may inform response to later fungal challenges.

immunology↗

bioRxiv2018

Lymphoid origin of a lineage of intrinsically activated plasmacytoid dendritic cell in mice and humans

We identified a novel mouse plasmacytoid dendritic cell (pDC) lineage derived from the common lymphoid progenitors (CLPs) that is dependent on expression of Bcl11a. These CLP-derived pDCs, which we refer to as "B-pDCs", have a unique gene expression profile that includes hallmark B cell genes, normally not expressed in conventional pDCs. Despite expressing most classical pDC markers such as SIGLEC-H and PDCA1, B-pDCs lack IFN- secretion, exhibiting a distinct inflammatory profile. Functionally, B-pDCs induce T cell proliferation more robustly than canonical pDCs following Toll-like receptor 9 (TLR9) engagement. B-pDCs, along with another homogeneous subpopulation of myeloid derived pDCs, display elevated levels of the cell-surface receptor tyrosine kinase AXL, mirroring human AXL+ transitional DCs in function and transcriptional profile. Murine B-pDCs therefore represent a phenotypically and functionally distinct CLP-derived DC lineage specialized in T cell activation and previously not described in mice.

immunology↗