Biology subjects

Chou, S. T.

Publications and source records attributed to Chou, S. T..

5 recordsLinked to original sources

bioRxiv2024

Human erythroid progenitors express antigen presentation machinery

Early-life immune exposures can profoundly impact lifelong health. However, functional mechanisms underlying fetal immune development remain incomplete. Erythrocytes are not typically considered active immune mediators, primarily because erythroid precursors discard their organelles as they mature, thus losing the ability to alter gene expression in response to stimuli. Erythroid progenitors and precursors circulate in human fetuses and neonates. Although there is limited evidence that erythroid precursors are immunomodulatory, our understanding of the underlying mechanisms remains inadequate. To define the immunobiological role of fetal and perinatal erythroid progenitors and precursors, we analyzed single cell RNA-sequencing data and found that transcriptomics support erythroid progenitors as putative immune mediators. Unexpectedly, we discovered that human erythroid progenitors constitutively express Major Histocompatibility Complex (MHC) class II antigen processing and presentation machinery, which are hallmarks of specialized antigen presenting immune cells. Furthermore, we demonstrate that erythroid progenitors internalize and cleave foreign proteins into peptide antigens. Unlike conventional antigen presenting cells, erythroid progenitors express atypical costimulatory molecules and immunoregulatory cytokines that direct the development of regulatory T cells, which are critical for establishing maternal-fetal tolerance. Expression of MHC II in definitive erythroid progenitors begins during the second trimester, coinciding with the appearance of mature T cells in the fetus, and is absent in primitive progenitors. Lastly, we demonstrate physical and molecular interaction potential of erythroid progenitors and T cells in the fetal liver. Our findings shed light on a unique orchestrator of fetal immunity and provide insight into the mechanisms by which erythroid cells contribute to host defense.

immunology↗

bioRxiv2024

Single-cell transcriptomics reveal synergistic and antagonistic effects of T21 and GATA1s on hematopoiesis

Trisomy 21 (T21), or Down syndrome (DS), is associated with baseline macrocytic erythrocytosis, thrombocytopenia, and neutrophilia, as well as transient abnormal myelopoiesis (TAM) and myeloid leukemia of DS (ML-DS). TAM and ML-DS blasts both arise from an aberrant megakaryocyte-erythroid progenitor and exclusively express GATA1s, the truncated isoform of GATA1, while germline GATA1s mutations in a non-T21 context lead to congenital cytopenia(s) without a leukemic predisposition. This suggests that T21 and GATA1s both perturb hematopoiesis in multipotent progenitors, but studying their individual effects is challenging due to limited access to relevant human progenitor populations. To dissect individual developmental impacts, we used single-cell RNA-sequencing to interrogate hematopoietic progenitor cells (HPCs) from isogenic human induced pluripotent stem cells differing only by chromosome 21 and/or GATA1 status. The transcriptomes of these HPCs revealed significant heterogeneity and lineage skew dictated by T21 and/or GATA1s. T21 and GATA1s each disrupted temporal regulation of lineage-specific transcriptional programs and specifically perturbed cell cycle genes. Trajectory inference revealed that GATA1s nearly eliminated erythropoiesis, slowed MK maturation, and promoted myelopoiesis in the euploid context, while in T21 cells, GATA1s competed with the enhanced erythropoiesis and impaired megakaryopoiesis driven by T21 to promote production of immature erythrocytes, MKs, and myeloid cells. The use of isogenic cells revealed distinct transcriptional programs that can be attributed specifically to T21 and GATA1s, and how they independently and synergistically result in HPC proliferation at the expense of maturation, consistent with a pro-leukemic phenotype.

molecular biology↗

bioRxiv2024

BMI1 regulates human erythroid self-renewal through both gene repression and gene activation

The limited proliferative capacity of erythroid precursors is a major obstacle to generate sufficient numbers of in vitro-derived red blood cells (RBC) for clinical purposes. We and others have determined that BMI1, a member of the polycomb repressive complex 1 (PRC1), is both necessary and sufficient to drive extensive proliferation of self-renewing erythroblasts (SREs). However, the mechanisms of BMI1 action remain poorly understood. BMI1 overexpression led to 10 billion-fold increase BMI1-induced (i)SRE self-renewal. Despite prolonged culture and BMI1 overexpression, human iSREs can terminally mature and agglutinate with typing reagent monoclonal antibodies against conventional RBC antigens. BMI1 and RING1B occupancy, along with repressive histone marks, were identified at known BMI1 target genes, including the INK-ARF locus, consistent with an altered cell cycle following BMI1 inhibition. We also identified upregulated BMI1 target genes with low repressive histone modifications, including key regulator of cholesterol homeostasis. Functional studies suggest that both cholesterol import and synthesis are essential for BMI1-associated self-renewal. These findings support the hypothesis that BMI1 regulates erythroid self-renewal not only through gene repression but also through gene activation and offer a strategy to expand the pool of immature erythroid precursors for eventual clinical uses.

cell biology↗

bioRxiv2023

Generation of a human Tropomyosin 1 knockout iPSC line

The CHOPWT17_TPM1KOc28 iPSC line was generated to interrogate the functions of Tropomyosin 1 (TPM1) in primary human cell development. This line was reprogrammed from a previously published wild type control iPSC line.

cell biology↗

bioRxiv2021

Obesity and adiposity have opposing genetic impacts on human blood traits

Obesity, hyperlipidemia, and truncal adiposity concordantly elevate cardiovascular disease risks, but have unknown genetic effects on blood trait variation. Using Mendelian randomization, we define unexpectedly opposing roles for generalized obesity and truncal adiposity on blood traits. Elevated genetically determined body mass index (BMI) and lipid levels decreased hemoglobin and hematocrit levels, explaining consistent with clinical observations associating obesity and anemia. However, lipid-related effects were confined to erythroid traits, whereas BMI affected multiple blood lineages, indicating broad effects on hematopoiesis. BMI-related effects were unexpectedly opposed by truncal adipose distribution, which increased hemoglobin and blood cell counts across lineages. Conditional analyses indicated genes, pathways, and cell types responsible for these effects, including Leptin Receptor and other blood cell-extrinsic factors in adipocytes and endothelium, which regulate hematopoietic stem and progenitor cell biology. Our findings identify novel roles for obesity and adipose distribution on hematopoiesis and show that genetically determined adiposity plays a previously underappreciated role in determining blood cell formation and function.

genetics↗