Roman Reggiardo

All Publications

• Autoantibody hotspots reveal origin and impact of immunogenic XIST ribonucleoprotein complex. bioRxiv : the preprint server for biology Yan, B., Lee, J., Srinivasan, S., Shi, Q., Dou, D. R., Davuluri, S., Nandyala, S., Woods, A., Leatherman, G., Zhao, Y., Reggiardo, R. E., Sawant, M., Thiam, H. R., Shah, A. A., Fiorentino, D. F., Chung, L. S., Chang, H. Y. 2025

  Abstract

  Four out of five patients with autoimmune diseases are women. The XIST ribonucleoprotein (RNP) complex, comprising the female-specific long noncoding RNA XIST and over 100 associated proteins, may drive several autoimmune diseases that disproportionately affect women, who have elevated levels of autoantibodies against the XIST RNP. However, the structural distribution, potential origin, and clinical significance of XIST RNP autoantibodies remained unexplored. Here, we find that XIST RNP is associated with autoantigens associated with six female-biased autoimmune conditions. Mapping autoantibody targets to their occupancy sites on XIST shows that these autoantigens are concentrated at discrete "hotspots" along the XIST lncRNA, notably the A-repeat. Cell type-specific protein expression data nominated neutrophils as a predominant source of hotspot antigens, and we confirmed the presence of both XIST and hotspot antigens in neutrophil extracellular traps during NETosis, an immunogenic programmed cell death pathway triggered by neutrophil activation upon which neutrophils extrude their nuclear content. Furthermore, we found that levels of autoantibodies against a top hotspot antigen, SPEN, that binds the A-repeat, correlate with severe digital ischemia in systemic sclerosis in two independent cohorts. Together, these data show a plausible mechanism for the origin of AXA, guided by RNA structure and RNA-protein interactions, and show that antibodies to XIST RNP holds promise for disease endotyping and prognostication in female-biased autoimmune conditions.Novel autoantibodies target hotspots on XIST ribonucleoprotein complex in female-biased autoimmune diseases.

  View details for DOI 10.1101/2025.01.16.633465

  View details for PubMedID 39896599

  View details for PubMedCentralID PMC11785099

• An age-progressive platelet differentiation path from hematopoietic stem cells causes exacerbated thrombosis CELL Poscablo, D. M., Worthington, A. K., Smith-Berdan, S., Rommel, M. E., Manso, B. A., Adili, R., Mok, L., Reggiardo, R. E., Cool, T., Mogharrab, R., Myers, J., Dahmen, S., Medina, P., Beaudin, A. E., Boyer, S. W., Holinstat, M., Jonsson, V. D., Forsberg, E. 2024; 187 (12): 3090-3107.e21

  Abstract

  Platelet dysregulation is drastically increased with advanced age and contributes to making cardiovascular disorders the leading cause of death of elderly humans. Here, we reveal a direct differentiation pathway from hematopoietic stem cells into platelets that is progressively propagated upon aging. Remarkably, the aging-enriched platelet path is decoupled from all other hematopoietic lineages, including erythropoiesis, and operates as an additional layer in parallel with canonical platelet production. This results in two molecularly and functionally distinct populations of megakaryocyte progenitors. The age-induced megakaryocyte progenitors have a profoundly enhanced capacity to engraft, expand, restore, and reconstitute platelets in situ and upon transplantation and produce an additional platelet population in old mice. The two pools of co-existing platelets cause age-related thrombocytosis and dramatically increased thrombosis in vivo. Strikingly, aging-enriched platelets are functionally hyper-reactive compared with the canonical platelet populations. These findings reveal stem cell-based aging as a mechanism for platelet dysregulation and age-induced thrombosis.

  View details for DOI 10.1016/j.cell.2024.04.018

  View details for Web of Science ID 001251232400001

  View details for PubMedID 38749423

• Profiling of repetitive RNA sequences in the blood plasma of patients with cancer. Nature biomedical engineering Reggiardo, R. E., Maroli, S. V., Peddu, V., Davidson, A. E., Hill, A., LaMontagne, E., Aaraj, Y. A., Jain, M., Chan, S. Y., Kim, D. H. 2023

  Abstract

  Liquid biopsies provide a means for the profiling of cell-free RNAs secreted by cells throughout the body. Although well-annotated coding and non-coding transcripts in blood are readily detectable and can serve as biomarkers of disease, the overall diagnostic utility of the cell-free transcriptome remains unclear. Here we show that RNAs derived from transposable elements and other repeat elements are enriched in the cell-free transcriptome of patients with cancer, and that they serve as signatures for the accurate classification of the disease. We used repeat-element-aware liquid-biopsy technology and single-molecule nanopore sequencing to profile the cell-free transcriptome in plasma from patients with cancer and to examine millions of genomic features comprising all annotated genes and repeat elements throughout the genome. By aggregating individual repeat elements to the subfamily level, we found that samples with pancreatic cancer are enriched with specific Alu subfamilies, whereas other cancers have their own characteristic cell-free RNA profile. Our findings show that repetitive RNA sequences are abundant in blood and can be used as disease-specific diagnostic biomarkers.

  View details for DOI 10.1038/s41551-023-01081-7

  View details for PubMedID 37652985

  View details for PubMedCentralID 3684276

• Mutant KRAS regulates transposable element RNA and innate immunity via KRAB zinc-finger genes. Cell reports Reggiardo, R. E., Maroli, S. V., Halasz, H., Ozen, M., Hrabeta-Robinson, E., Behera, A., Peddu, V., Carrillo, D., LaMontagne, E., Whitehead, L., Kim, E., Malik, S., Fernandes, J., Marinov, G., Collisson, E., Brooks, A., Demirci, U., Kim, D. H. 2022; 40 (3): 111104

  Abstract

  RAS genes are the most frequently mutated oncogenes in cancer, yet the effects of oncogenic RAS signaling on the noncoding transcriptome remain unclear. We analyzed the transcriptomes of human airway and bronchial epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We find that oncogenic KRAS signaling upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements (TEs). These TE RNAs exhibit differential expression, are preferentially released in extracellular vesicles, and are regulated by KRAB zinc-finger (KZNF) genes, which are broadly downregulated in mutant KRAS cells and lung adenocarcinomas invivo. Moreover, mutant KRAS induces an intrinsic IFN-stimulated gene (ISG) signature that is often seen across many different cancers. Our results indicate that mutant KRAS remodels the repetitive noncoding transcriptome, demonstrating the broad scope of intracellular and extracellular RNAs regulated by this oncogenic signaling pathway.

  View details for DOI 10.1016/j.celrep.2022.111104

  View details for PubMedID 35858545

• LncRNA Biomarkers of Inflammation and Cancer. Advances in experimental medicine and biology Reggiardo, R. E., Maroli, S. V., Kim, D. H. 2022; 1363: 121-145

  Abstract

  Long noncoding RNAs (lncRNAs) are promising candidates as biomarkers of inflammation and cancer. LncRNAs have several properties that make them well-suited as molecular markers of disease: (1) many lncRNAs are expressed in a tissue-specific manner, (2) distinct lncRNAs are upregulated based on different inflammatory or oncogenic stimuli, (3) lncRNAs released from cells are packaged and protected in extracellular vesicles, and (4) circulating lncRNAs in the blood are detectable using various RNA sequencing approaches. Here we focus on the potential for lncRNA biomarkers to detect inflammation and cancer, highlighting key biological, technological, and analytical considerations that will help advance the development of lncRNA-based liquid biopsies.

  View details for DOI 10.1007/978-3-030-92034-0_7

  View details for PubMedID 35220568

• Chromatin accessibility maps provide evidence of multilineage gene priming in hematopoietic stem cells EPIGENETICS & CHROMATIN Martin, E. W., Krietsch, J., Reggiardo, R. E., Sousae, R., Kim, D. H., Forsberg, E. 2021; 14 (1): 2

  Abstract

  Hematopoietic stem cells (HSCs) have the capacity to differentiate into vastly different types of mature blood cells. The epigenetic mechanisms regulating the multilineage ability, or multipotency, of HSCs are not well understood. To test the hypothesis that cis-regulatory elements that control fate decisions for all lineages are primed in HSCs, we used ATAC-seq to compare chromatin accessibility of HSCs with five unipotent cell types. We observed the highest similarity in accessibility profiles between megakaryocyte progenitors and HSCs, whereas B cells had the greatest number of regions with de novo gain in accessibility during differentiation. Despite these differences, we identified cis-regulatory elements from all lineages that displayed epigenetic priming in HSCs. These findings provide new insights into the regulation of stem cell multipotency, as well as a resource to identify functional drivers of lineage fate.

  View details for DOI 10.1186/s13072-020-00377-1

  View details for Web of Science ID 000608237800002

  View details for PubMedID 33407811

  View details for PubMedCentralID PMC7789351