Biology subjects

Pasricha, S.-R.

Publications and source records attributed to Pasricha, S.-R..

6 recordsLinked to original sources

bioRxiv2026

Megakaryocytic proteomic signatures define myeloproliferative neoplasms

The classical Philadelphia-negative myeloproliferative neoplasms (MPNs) are clonal stem cell disorders of the bone marrow with significant niche dysregulation driven in part by abnormal megakaryocytes. The three classical MPNs: polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), display established megakaryocytic morphological differences which aid in their diagnostic classification. The paucity of megakaryocytes in the bone marrow aspirate has previously limited a proteomic analysis of megakaryocytes in clinical samples. We aimed to undertake an unbiased proteomic analysis of in situ megakaryocytes from the bone marrow of patients with PV, ET, and PMF. Using a novel, deep visual proteomics strategy, we dissected and analyzed megakaryocytes from 60 MPN patients and 20 controls (patients with limited stage non-Hodgkin lymphoma who had uninvolved bone marrow). We reveal that megakaryocyte proteomics from MPN patients are distinct to those from control patients, and further, that the megakaryocytes from the three MPNs have unique, disease-specific signatures. The disease-specific megakaryocyte proteome highlights novel pathways of disease.

cancer biology↗

bioRxiv2026

Regulation of Human Erythroferrone Expression

Erythroferrone (ERFE) is an erythroblast-secreted hormone that suppresses hepatic hepcidin expression to increase iron availability for erythropoiesis, ensuring recovery from anaemia. ERFE excess drives iron overload in disorders of ineffective erythropoiesis. Despite its pivotal role in systemic iron homeostasis and diseases of erythropoiesis, ERFEs molecular regulation has remained undefined. Here, we applied a genomic approach to characterise the molecular mechanisms governing ERFE expression. Using the HUDEP-2 human erythroid progenitor model, integrative ATAC-seq, CUT&RUN and micro capture-C analysis we identified a stage-specific accessible chromatin region within the ERFE 3 UTR that interacts with the promotor. We also identified enhancer-associated chromatin marks including H3K4me1 and H3K27ac in this region, and demonstrate that this cis-regulatory element is bound by key erythroid transcription factors KLF1, GATA1, TAL1 and STAT5. Functional dissection using CRISPR-Cas9-mediated deletion of the central 3 UTR enhancer element led to marked reduction in ERFE mRNA expression, and we show a corresponding reduction in nascent mRNA, confirming a key role for this region in transcriptional regulation. We define the transcriptional regulatory mechanism by which maturing human erythroblasts activate ERFE, the endocrine signal that coordinates erythropoietic demand with systemic iron mobilisation.

molecular biology↗

bioRxiv2025

Host iron deficiency protects against Plasmodium infection and drives parasite molecular reprofiling.

Iron deficiency, anemia and Plasmodium infection represent significant global health challenges with overlapping geographical distributions, particularly affecting pregnant women in Africa, yet the mechanisms underlying their interactions remain poorly understood. We employed a multilayered approach combining clinical data from Malawian pregnant women (n=711) in the REVAMP trial, a genetic mouse model (Tmprss6-knockout), and in vitro P. falciparum cultures to clarify associations between iron status and malaria susceptibility. Iron deficiency was associated with 50% reduced P. falciparum parasitemia in pregnant women (95% CI [30%-64%], p<0.0001), while iron-deficient mice exhibited significantly improved survival against P. berghei (median 15.5 days vs. 7.0 days for WT mice) and protection from cerebral malaria (83% vs 17% survival). Iron chelation induced substantial transcriptomic and proteomic changes in cultured parasites, affecting host cell invasion and nutrient acquisition processes. Importantly, intravenous iron supplementation did not increase subsequent parasitemia when coupled with malaria prevention. These findings demonstrate that iron deficiency protects against Plasmodium infection and support WHO recommendations for iron supplementation in malaria-endemic regions when combined with adequate malaria prevention strategies.

cell biology↗

bioRxiv2023

Spatial analysis of Hofbauer cell transcriptome, distribution and morphology in placentas exposed to Plasmodium falciparum

Placental infection remains a significant health burden for mothers and their babies in low-income countries, especially in sub-Saharan Africa, where malaria transmission is intense. An increase in inflammatory biomarkers and poor vascularisation are characteristics of placentas infected with malaria. Hofbauer cells (HBCs) - placental villous macrophages of fetal origin - are one of the most abundant immune cells in the placenta. HBCs are thought to have roles in angiogenic processes and have been linked with the pathophysiology of several infections and inflammatory conditions during pregnancy, including malaria (caused by Plasmodium falciparum). However, there is limited in situ data on the transcriptional, proteomic or morphologic profile of these cells either during or following clearance of P. falciparum infection. We leveraged placental samples prospectively collected at delivery from 610 Malawian women enduring a high burden of malaria and other infections and nutritional deficiencies. We profiled placentas through spatial transcriptomic and proteomic platforms to discern in situ HBC features that could distinguish placentas with or without evidence of past malaria. In this cohort, past placental infection was common and was associated with lower birth weight babies (adjusted effect [95% confidence interval], -80.9 [-165.9, -3.7] g, P= 0.040). However, at term, HBC numbers, abundance, and transcriptional profiles from placentas with evidence of past infection were similar to those of placentas without malaria. HBCs may recover post-infection back to a basal state or may be replaced in the tissue over the course of pregnancy. Placentas with evidence of past malaria did show evidence of reduced fetal vessel development (mean area difference: -22.8% [-37.6, -7.9], P=0.003). Reduced vascular development following infection early in pregnancy may reflect disturbances to the normal vasculogenic and angiogenic processes, of which HBCs are an integral part.

immunology↗

bioRxiv2023

Serum iron and hepatic transferrin receptor expression are circadian-regulated

Serum iron has long been thought to exhibit diurnal variation and is subsequently considered an unreliable biomarker of systemic iron status. Circadian regulation (endogenous [~]24-hour periodic oscillation of a biologic function) governs many critical physiologic processes. It is unknown whether serum iron levels are regulated by circadian machinery; likewise, the circadian nature of key players of iron homeostasis is unstudied. Here we show that serum iron, hepatic transferrin receptor (TFR1) gene (Tfrc) expression and erythropoietic activity exhibit circadian rhythms. Daily oscillations of serum iron, hepatic Tfrc expression and erythropoietic activity are maintained in mice housed in constant darkness, where oscillation reflects an endogenous circadian period. Oscillations of serum iron, hepatic Tfrc and erythropoietic activity were ablated when circadian machinery was disrupted in Bmal1 knockout mice. Interestingly, we find that circadian oscillations of erythropoietic activity and hepatic Tfrc expression are maintained in opposing phase, likely allowing for optimised usage and storage of serum iron whilst maintaining adequate serum levels. This study provides the first confirmatory evidence that serum iron is circadian regulated and uncovers liver-specific circadian regulation of TFR1, a major player in cellular iron uptake.

molecular biology↗

bioRxiv2022

Iron homeostasis governs erythroid phenotype in Polycythemia Vera

Polycythemia Vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients hematocrit and hemoglobin concentration, placing them at risk of life-threatening thrombotic events. Our GWAS of 440 PV cases and 403,351 controls utilising UK Biobank data found that SNPs in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed over-representation of homozygous HFE mutations in PV patients. HFE influences expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of PV mouse models, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Further, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signalling via GP130 coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.

cancer biology↗