Siavash Moghadami

All Publications

• Single-Cell Atlas of Transcription and Chromatin States Reveals Regulatory Programs in the Human Brain. bioRxiv : the preprint server for biology Xie, Y., Chang, L., Zhong, G., Rink, J. A., Báez-Becerra, T., Armand, E., Ding, W., Li, K., Bonne, E., Lie, A., Indralingam, H. S., Dong, K., Loe, T., Huang, B., Wang, Z., Barcoma, A. S., Willier, J. K., Knutson, K. W., Liu, J., Cho, S., Cao, S., Russo, K. G., Young, C. K., Arzavala, J., Sanchez, Y., Bikkina, A., Schenker-Ahmed, N., Kern, C., Zhao, Z., Klein, A., Flores, J., Tai, C. Y., Olness, J., Monell, A., Moghadami, S., Barragan, C., Chen, C., Owens, W., O'Connor, C., Liem, M., Marrin, M. V., Rose, C., Alt, S. N., Emerson, N., Osteen, J., Lucero, J., Li, D., Hodge, R. D., Wang, T., Keene, C. D., Xu, X., Zhu, Q., Ecker, J. R., Behrens, M. M., Ren, B. 2026

  Abstract

  Directly measuring chromatin states alongside transcription is essential for understanding how cell-type-specific regulatory programs are established and maintained in the adult human brain. We present a large-scale single-cell multimodal atlas generated by jointly profiling transcriptome with active (H3K27ac) and repressive (H3K27me3) histone modifications across 18 brain regions. We profile >750,000 nuclei spanning 160 cell types and integrate these data with chromatin accessibility, DNA methylation, 3D genome architecture, and spatial transcriptome. This framework annotates >500,000 regulatory elements and resolves cell-type-specific chromatin states. We link enhancers to target genes, infer gene regulatory networks, and classify chromatin interactions, revealing neuron-enriched long-range Polycomb repression of developmental genes. Integrating these maps with GWAS data and sequence-based model prioritizes noncoding variants, effector genes, and vulnerable cell types for neuropsychiatric disorders. Finally, cross-species comparisons show conserved activation but more divergent repression. Together, this study provides a functional reference for interpreting noncoding variants, epigenetic memory, and brain organization.Joint single-cell profiling of transcriptomes with active or repressive histone modification in >750,000 nuclei across adult human brain. Chromatin state annotation of >500,000 candidate cis -regulatory elements distinguishes active enhancers from accessible and Polycomb-repressed regions. Cell-type-resolved regulatory networks and sequence-based deep learning model prioritize functional neuropsychiatric risk variants.Spatial epigenomic imputation reveals laminar layer-specific Polycomb repression programs.Integration with 3D genome architecture reveals neuron-specific super long-range chromatin loops silencing early developmental genes.Evolutionary analysis uncovers conserved active regulatory grammar but divergent repressive landscape.

  View details for DOI 10.64898/2026.02.02.703166

  View details for PubMedID 41676679

  View details for PubMedCentralID PMC12889664

• MERFISH+, a large-scale, multi-omics spatial technology resolves the molecular holograms of the 3D human developing heart. bioRxiv : the preprint server for biology Kern, C., Zhang, Q., Lu, Y., Eschbach, J., Zeng, Z., Farah, E. N., Tai, C. Y., Yang, K., Jenie, I., Yao, F., Zhao, Z., Ma, Q., Padilla, C. G., Monell, A., Moghadami, S., Zhu, F., Li, B., Hou, A., Tucker, G., Ellison, D., Chi, N. C., Qiu, X., Zhu, Q., Bintu, B. 2025

  Abstract

  Hybridization-based spatial transcriptomics technologies have advanced our ability to map cellular and subcellular organization in complex tissues. However, existing methods remain constrained in gene coverage, multimodal compatibility, and scalability. Here, we present MERFISH+, an enhanced version of Multiplexed Error-Robust Fluorescence in Situ Hybridization (MERFISH), which integrates chemical probe anchoring in protective hydrogels with high-throughput microfluidics and microscopy. This optimized design supports robust and repeated hybridization cycles across an entire centimeter-scale tissue sample. MERFISH+ allowed to simultaneously quantify over 1,800 genes and resolve the 3D organization of chromatin loci and their associated epigenomic marks in developing human hearts. Using a generative integration framework for spatial multimodal data (Spateo-VI), we harmonized these MERFISH+ transcriptomic and chromatin data to reconstruct a 3D spatially-resolved multi-omic atlas of the developing human heart at subcellular resolution capturing 3.1 million cells across 34 distinct populations. This 3D atlas provides a holistic view of an entire organ enabling the characterization of 3D cellular neighborhoods and transcriptional gradients of substructures such as the descending arteries. Thus, MERFISH+ offers a robust, large-format platform for spatial multi-omics that enables high resolution mapping of gene expression at subcellular resolution and the characterization of cellular organization within 3D organs.MERFISH+ is an spatial multi-omics platform that integrates hydrogel-based probe anchoring, automated high-throughput microfluidics, and large-format multimodal data production to enable comprehensive, subcellular resolution mapping of gene expression and chromatin organization across millions of cells within complex developing human organs.MERFISH+ expands MERFISH capabilities to measure >1,800 genes and at whole-organ 3D imaging scaleCombines chemical probe anchoring with high-throughput volumetric microscopy and microfluidicsGenerates a 3D molecular atlas of a developing human heart with > 3.1 million cells at subcellular resolutionIntroduces Spateo-VI, a novel generative framework integrating 3D multimodal datasets.

  View details for DOI 10.1101/2025.11.02.686137

  View details for PubMedID 41279640

  View details for PubMedCentralID PMC12637541

• Mst1-mediated phosphorylation of FoxO1 and C/EBP-β stimulates cell-protective mechanisms in cardiomyocytes. Nature communications Maejima, Y., Nah, J., Aryan, Z., Zhai, P., Sung, E. A., Liu, T., Takayama, K., Moghadami, S., Sasano, T., Li, H., Sadoshima, J. 2024; 15 (1): 6279

  Abstract

  The molecular mechanisms by which FoxO transcription factors mediate diametrically opposite cellular responses, namely death and survival, remain unknown. Here we show that Mst1 phosphorylates FoxO1 Ser209/Ser215/Ser218/Thr228/Ser232/Ser243, thereby inhibiting FoxO1-mediated transcription of proapoptotic genes. On the other hand, Mst1 increases FoxO1-C/EBP-β interaction and activates C/EBP-β by phosphorylating it at Thr299, thereby promoting transcription of prosurvival genes. Myocardial ischemia/reperfusion injury is larger in cardiac-specific FoxO1 knockout mice than in control mice. However, the concurrent presence of a C/EBP-β T299E phospho-mimetic mutation reduces infarct size in cardiac-specific FoxO1 knockout mice. The C/EBP-β phospho-mimetic mutant exhibits greater binding to the promoter of prosurvival genes than wild type C/EBP-β. In conclusion, phosphorylation of FoxO1 by Mst1 inhibits binding of FoxO1 to pro-apoptotic gene promoters but enhances its binding to C/EBP-β, phosphorylation of C/EBP-β, and transcription of prosurvival genes, which stimulate protective mechanisms in the heart.

  View details for DOI 10.1038/s41467-024-50393-y

  View details for PubMedID 39060225

  View details for PubMedCentralID PMC11282193

• Lifelong restructuring of 3D genome architecture in cerebellar granule cells. Science (New York, N.Y.) Tan, L., Shi, J., Moghadami, S., Parasar, B., Wright, C. P., Seo, Y., Vallejo, K., Cobos, I., Duncan, L., Chen, R., Deisseroth, K. 2023; 381 (6662): 1112-1119

  Abstract

  The cerebellum contains most of the neurons in the human brain and exhibits distinctive modes of development and aging. In this work, by developing our single-cell three-dimensional (3D) genome assay-diploid chromosome conformation capture, or Dip-C-into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we resolved the first 3D genome structures of single cerebellar cells, created life-spanning 3D genome atlases for both humans and mice, and jointly measured transcriptome and chromatin accessibility during development. We found that although the transcriptome and chromatin accessibility of cerebellar granule neurons mature in early postnatal life, 3D genome architecture gradually remodels throughout life, establishing ultra-long-range intrachromosomal contacts and specific interchromosomal contacts that are rarely seen in neurons. These results reveal unexpected evolutionarily conserved molecular processes that underlie distinctive features of neural development and aging across the mammalian life span.

  View details for DOI 10.1126/science.adh3253

  View details for PubMedID 37676945

• SINGLE NUCLEI PROFILING OF CILIA-RELATED GENES IN MYOCARDIAL SENESCENCE, DILATED AND HYPERTROPHIC CARDIOMYOPATHIES Aryan, Z., Moghadami, S., Sadoshima, J. ELSEVIER SCIENCE INC. 2023: 377

  View details for Web of Science ID 000990866100378

• Cerebellar Granule Cells Develop Non-neuronal 3D Genome Architecture over the Lifespan. bioRxiv : the preprint server for biology Tan, L., Shi, J., Moghadami, S., Wright, C. P., Parasar, B., Seo, Y., Vallejo, K., Cobos, I., Duncan, L., Chen, R., Deisseroth, K. 2023

  Abstract

  The cerebellum contains most of the neurons in the human brain, and exhibits unique modes of development, malformation, and aging. For example, granule cells-the most abundant neuron type-develop unusually late and exhibit unique nuclear morphology. Here, by developing our high-resolution single-cell 3D genome assay Dip-C into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we were able to resolve the first 3D genome structures of single cerebellar cells, create life-spanning 3D genome atlases for both human and mouse, and jointly measure transcriptome and chromatin accessibility during development. We found that while the transcriptome and chromatin accessibility of human granule cells exhibit a characteristic maturation pattern within the first year of postnatal life, 3D genome architecture gradually remodels throughout life into a non-neuronal state with ultra-long-range intra-chromosomal contacts and specific inter-chromosomal contacts. This 3D genome remodeling is conserved in mice, and robust to heterozygous deletion of chromatin remodeling disease-associated genes ( Chd8 or Arid1b ). Together these results reveal unexpected and evolutionarily-conserved molecular processes underlying the unique development and aging of the mammalian cerebellum.

  View details for DOI 10.1101/2023.02.25.530020

  View details for PubMedID 36865235

• Mannose-Binding Lectin is Dysregulated in Cardiac Endothelial Cells of Women With Peripartum Cardiomyopathy Aryan, Z., Moghadami, S., Wang, W., Sadoshima, J. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000890856903015