Biology subjects

Majeti, R.

Publications and source records attributed to Majeti, R..

18 recordsLinked to original sources

bioRxiv2026

Single cell multi-omics enables high-resolution identification and functionalpurification of human acute myeloid leukemia stem cells

In human acute myeloid leukemia (AML), a sub-population of leukemia stem cells (LSCs) drive disease initiation, therapeutic resistance, and relapse. However, the lack of reliable markers to distinguish LSCs from bulk leukemia cells has impeded progress in studying LSC pathogenesis and developing meaningful LSC-specific diagnostics and therapeutics. Existing LSC gene signatures, derived from bulk populations, cannot definitively identify LSCs at single-cell resolution. To address this, we analyzed large patient cohorts with bulk gene expression data and single-cell multi-omic assays to identify a prognostic gene signature that is specifically enriched in a clinically adverse AML sub-population. Using this signature, we defined and prospectively isolated CD34+CD90-CLL1-CD69+CD53- immunophenotypic LSCs that are significantly enriched for LSC content based on limiting dilution xenotransplantation assays. Our findings demonstrate the power of single-cell multi-omics to precisely identify a clinically relevant LSC population and establish a clear framework for future translational research in AML. Key PointsO_LISingle cell multi-omics identifies human AML LSCs at high resolution. C_LIO_LIHOPX and SOCS2 co-expression (hrLSC2) defines a prognostic gene signature in de novo acute myeloid leukemia. C_LIO_LIhrLSC2 marks an AML subpopulation (iLSCs) with a distinct immunophenotype. C_LIO_LIiLSCs can be purified using flow cytometry and are significantly enriched for LSCs. C_LI

cancer biology↗

bioRxiv2026

Organoid modeling of tumor-associated macrophages reveals phagocytosis checkpoint blockade-induced conversion to an immunosuppressive SPP1+ phenotype

Tumor-associated macrophages (TAM) exert essential functions during the immune response to cancer. However, investigations of TAM within a native human tumor microenvironment (TME) have been impeded by a lack of appropriate model systems. Here, patient-derived organoids (PDO) from air-liquid interface (ALI)-grown tumor fragments, containing a human TME that encompassed stroma and immune subsets, robustly preserved TAM that were maintained by endogenous CSF-1 and appropriately responded to polarization signals. Antibody blockade of the CD47 regulatory checkpoint in organoids stimulated phagocytosis and remodeled TAM cytokine secretion profiles that were confirmed in anti-CD47 phase I trial patients. Amongst PDO histologies screened, anti-CD47 tumor killing was notable in clear cell renal cell carcinoma (ccRCC) which was associated with increased TAM infiltration. PDO contained diverse previously described TAM subsets; however, anti-CD47 reprogrammed organoid TAM toward an immunosuppressive SPP1+ phenotype, highlighting a negative feedback mechanism. Our findings uncover a resistance circuit engaged by macrophage checkpoint blockade and position ALI PDO as a robust translational platform for dissecting human macrophage biology and informing precision immunotherapy.

cancer biology↗

bioRxiv2026

Lipid Nanoparticles for Spleen-Targeted RNA delivery

Lipid nanoparticles (LNPs) formulated with neutral helper lipids efficiently deliver RNA to the liver in pre-clinical models and humans but achieving clinically relevant delivery to other tissues remains a major challenge. To reduce liver uptake, targeting strategies often range from active targeting relying on antibodies to quasi-active targeting by employing permanently charged helper lipids which influence biodistribution after administration. In this study, we present an alternative approach based on varying ionizable lipids and stabilizers, along with optimizing formulation parameters for targeted delivery of circular RNA via a passive targeting approach. We generated a library of 216 LNP formulations and evaluated their performance in vitro in Jurkat cells and human primary T cells. The lead LNPs showcasing activity in both Jurkat and T cells were explored for their efficacy in vivo via multiple routes of administrations. Our results show that both the identity of stabilizer and ionizable lipid had effects on decreasing hepatic vs. splenic delivery while enhancing splenic accumulation. In line with this improved tissue tropism, spleen-tropic LNPs induced distinct transcriptomic remodeling in vivo compared with conventional, FDA-approved SM-102 LNPs. These findings demonstrate that extrahepatic targeting of LNPs can be achieved without altering charge of the LNPs and further reveal that hepatic de-targeting efficiency could be influenced by the immune status of the recipient.

bioengineering↗

bioRxiv2025

Donor-Targeted Anti-HLA-A2 Antibody Shows Nanogram-Level Efficacy in a Novel GVHD Mouse Model

Acute graft-versus-host disease (GVHD) remains a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), with limited treatment options for steroid-refractory cases. Current therapies broadly suppress immune responses, increasing infection risk and impairing graft function. We hypothesized that selective depletion of donor immune cells through HLA allele-specific targeting could offer a safer and more precise alternative. To test this, we developed a monoclonal antibody (AN7) against HLA-A2 by immunizing HLA-A24 transgenic mice with recombinant HLA-A2 tetramers, followed by hybridoma screening. AN7 specifically recognized HLA-A2 and HLA-A68, and was reformatted into murine IgG2a and human chimeric IgG1 recombinant antibodies. These retained binding specificity and mediated robust complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) against HLA-A2+ target cells. To evaluate therapeutic potential, we established a fully MHC-mismatched allo-HSCT model using HLA-A2 transgenic donor bone marrow in lethally irradiated BALB/c recipients. A single ultra-low dose of AN7 (1-100 ng) administered post-transplant significantly improved survival and reduced GVHD while preserving donor hematopoiesis. These findings highlight the potential of allele-specific antibody-mediated clearance as a mechanistically distinct approach to donor immune modulation in GVHD.

immunology↗

bioRxiv2024

DNMT3AR882H Is Not Required for Disease Maintenance in Primary Human AML, but Is Associated With Increased Leukemia Stem Cell Frequency

Genetic mutations are being thoroughly mapped in human cancers, yet a fundamental question in cancer biology is whether such mutations are functionally required for cancer initiation, maintenance of established cancer, or both. Here, we study this question in the context of human acute myeloid leukemia (AML), where DNMT3AR882 missense mutations often arise early, in pre-leukemic clonal hematopoiesis, and corrupt the DNA methylation landscape to initiate leukemia. We developed CRISPR-based methods to directly correct DNMT3AR882 mutations in leukemic cells obtained from patients. Surprisingly, DNMT3AR882 mutations were largely dispensable for disease maintenance. Replacing DNMT3AR882 mutants with wild-type DNMT3A did not impair the ability of AML cells to engraft in vivo, and minimally altered DNA methylation. Taken together, DNMT3AR882 mutations are initially necessary for AML initiation, but are largely dispensable for disease maintenance. The notion that initiating oncogenes differ from those that maintain cancer has important implications for cancer evolution and therapy. STATEMENT OF SIGNIFICANCEUnderstanding which driver mutations are required for cancer initiation, maintenance, or both phases remains poorly understood. Here, we uncover that highly prevalent pre-leukemic DNMT3A mutations are only required during disease initiation, but become dispensable after leukemic transformation, uncovering the context-specific role of this driver mutation with important therapeutic implications.

cancer biology↗

bioRxiv2024

DNA methylation stochasticity is linked to transcriptional variability and identifies convergent epigenetic disruption across genetically-defined subtypes of AML

Disruption of the epigenetic landscape is of particular interest in acute myeloid leukemia (AML) due to its relatively low mutational burden and frequent occurrence of mutations in epigenetic regulators. Here, we applied an information-theoretic analysis of methylation potential energy landscapes, capturing changes in mean methylation level and methylation entropy, to comprehensively analyze DNA methylation stochasticity in subtypes of AML defined by mutually exclusive genetic mutations. We identified AML subtypes with CEBPA double mutation and those with IDH mutations as distinctly high-entropy subtypes, marked by methylation disruption over a convergent set of genes. We found a core program of epigenetic landscape disruption across all AML subtypes, with discordant methylation stochasticity and transcriptional dysregulation converging on functionally important leukemic signatures, suggesting a genotype-independent role of stochastic disruption of the epigenetic landscape in mediating leukemogenesis. We further established a relationship between methylation entropy and gene expression variability, connecting the disruption of the epigenetic landscape to transcription in AML. This approach identified a convergent program of epigenetic dysregulation in leukemia, clarifying the contribution of specific genetic mutations to stochastic disruption of the epigenetic and transcriptional landscapes of AML.

cancer biology↗

bioRxiv2024

Integrative multiomic approaches reveal ZMAT3 and p21 as conserved hubs in the p53 tumor suppression network

TP53, the most frequently mutated gene in human cancer, encodes a transcriptional activator that induces myriad downstream target genes. Despite the importance of p53 in tumor suppression, the specific p53 target genes important for tumor suppression remain unclear. Recent studies have identified the p53-inducible gene Zmat3 as a critical effector of tumor suppression, but many questions remain regarding its p53-dependence, activity across contexts, and mechanism of tumor suppression alone and in cooperation with other p53-inducible genes. To address these questions, we used Tuba-seqUltra somatic genome editing and tumor barcoding in a mouse lung adenocarcinoma model, combinatorial in vivo CRISPR/Cas9 screens, meta-analyses of gene expression and Cancer Dependency Map data, and integrative RNA-sequencing and shotgun proteomic analyses. We established Zmat3 as a core component of p53-mediated tumor suppression and identified Cdkn1a as the most potent cooperating p53-induced gene in tumor suppression. We discovered that ZMAT3/CDKN1A serve as near-universal effectors of p53-mediated tumor suppression that regulate cell division, migration, and extracellular matrix organization. Accordingly, combined Zmat3-Cdkn1a inactivation dramatically enhanced cell proliferation and migration compared to controls, akin to p53 inactivation. Together, our findings place ZMAT3 and CDKN1A as hubs of a p53-induced gene program that opposes tumorigenesis across various cellular and genetic contexts.

cancer biology↗

bioRxiv2024

A single cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis

Hematopoietic multipotent progenitors (MPPs) regulate blood cell production to appropriately meet the biological demands of the human body. Human MPPs remain ill-defined whereas mouse MPPs have been well characterized with distinct immunophenotypes and lineage potencies. Using multiomic single cell analyses and complementary functional assays, we identified new human MPPs and oligopotent progenitor populations within Lin-CD34+CD38dim/lo adult bone marrow with distinct biomolecular and functional properties. These populations were prospectively isolated based on expression of CD69, CLL1, and CD2 in addition to classical markers like CD90 and CD45RA. We show that within the canonical Lin-CD34+CD38dim/loCD90CD45RA-MPP population, there is a CD69+ MPP with long-term engraftment and multilineage differentiation potential, a CLL1+ myeloid-biased MPP, and a CLL1-CD69-erythroid-biased MPP. We also show that the canonical Lin-CD34+CD38dim/loCD90-CD45RA+ LMPP population can be separated into a CD2+ LMPP with lymphoid and myeloid potential, a CD2-LMPP with high lymphoid potential, and a CLL1+ GMP with minimal lymphoid potential. We used these new HSPC profiles to study human and mouse bone marrow cells and observe limited cell type specific homology between humans and mice and cell type specific changes associated with aging. By identifying and functionally characterizing new adult MPP sub-populations, we provide an updated reference and framework for future studies in human hematopoiesis.

cancer biology↗

bioRxiv2023

Convergent Epigenetic Evolution Drives Relapse in Acute Myeloid Leukemia

Relapse of acute myeloid leukemia (AML) is highly aggressive and often treatment refractory. We analyzed previously published AML relapse cohorts and found that 40% of relapses occur without changes in driver mutations, suggesting that non-genetic mechanisms drive relapse in a large proportion of cases. We therefore characterized epigenetic patterns of AML relapse using 26 matched diagnosis-relapse samples with ATAC-seq. This analysis identified a relapse-specific chromatin accessibility signature for mutationally stable AML, suggesting that AML undergoes epigenetic evolution at relapse independent of mutational changes. Analysis of leukemia stem cell (LSC) chromatin changes at relapse indicated that this leukemic compartment underwent significantly less epigenetic evolution than non-LSCs, while epigenetic changes in non-LSCs reflected overall evolution of the bulk leukemia. Finally, we used single-cell ATAC-seq paired with mitochondrial sequencing (mtscATAC) to map clones from diagnosis into relapse along with their epigenetic features. We found that distinct mitochondrially-defined clones exhibit more similar chromatin accessibility at relapse relative to diagnosis, demonstrating convergent epigenetic evolution in relapsed AML. These results demonstrate that epigenetic evolution is a feature of relapsed AML and that convergent epigenetic evolution can occur following treatment with induction chemotherapy.

cancer biology↗

bioRxiv2023

AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML

T cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human engineered cytotoxic CD4+ T cells. Single-cell RNA-seq of primary AML samples and CD4+ T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4+ T cell killing. Resistance-associated AML programs were enriched in AML patients with poor survival, and killing-resistant AML cells did not engage T cells in vitro. Killing-sensitive AML potently activated T cells before being killed, and upregulated ICAM1, a key component of the immune synapse with T cells. Without ICAM1, killing-sensitive AML became resistant to killing to primary ex vivo-isolated CD8+ T cells in vitro, and engineered CD4+ T cells in vitro and in vivo. Thus, ICAM1 on AML acts as an immune trigger, allowing T cell killing, and could affect AML patient survival in vivo. SIGNIFICANCEAML is a common leukemia with sub-optimal outcomes. We show that AML transcriptional programs correlate with susceptibility to T cell killing. Killing resistance-associated AML programs are enriched in patients with poor survival. Killing-sensitive, but not resistant AML activate T cells and upregulate ICAM1 that binds to LFA-1 on T cells, allowing immune synapse formation which is critical for AML elimination. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/558911v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@84e2e1org.highwire.dtl.DTLVardef@4b2a40org.highwire.dtl.DTLVardef@c2d1f3org.highwire.dtl.DTLVardef@65db2c_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Genetically Corrected RAG2-SCID Human Hematopoietic Stem CellsRestore V(D)J-Recombinase and Rescue Lymphoid Deficiency

Recombination-activating genes (RAG1 and RAG2) are critical in lymphoid cell development and function for initiating the V(D)J-recombination process to generate polyclonal lymphocytes with broad antigen-specificity. Clinical manifestations of defective RAG1/2 genes range from immune dysregulation to severe combined immunodeficiencies (SCID), causing life-threatening infections and death early in life in the absence of hematopoietic cell transplantation (HCT). Haploidentical HCT without myeloablative conditioning carries a high risk of graft failure and incomplete immune reconstitution. The RAG complex is only expressed during the G0-G1 phases of the cell cycle at the early stages of T and B cell development, underscoring that a direct gene correction would capture the precise temporal expression of the endogenous gene, is a promising therapeutic approach for RAG1/2-deficiencies. Here, we report a feasibility study using the CRISPR/Cas9-based "universal gene-correction" approach for the RAG2 locus in human hematopoietic stem/progenitor cells (HSPCs) in healthy donors and one RAG2-SCID patient. V(D)J recombinase activity was restored following gene correction of RAG2-SCID-derived HSPCs, resulting in the development of TCR {beta} and {gamma}{delta} CD3+ cells and single-positive CD4+ and CD8+ lymphocytes. TCR repertoire analysis indicated a normal distribution of the CDR3 length and preserved usage of distal TRAV genes. We confirmed in vivo rescue of B-cell development, with normal IgM surface expression and a significant decrease in CD56bright NK cells. Together, we provide specificity, toxicity, and efficacy data supporting the development of a gene-correction therapy to benefit all RAG2-deficient patients. KEY POINTSO_LIHuman hematopoietic stem cells can be corrected to restore endogenous RAG2 gene expression while preserving durable engraftment potential. C_LIO_LIGene-corrected RAG2 locus restores V(D)J recombination in RAG2-SCID patient stem cells, promoting T and B-cells receptor formation. C_LI

immunology↗

bioRxiv2021

Anti-GD2 antibody disrupts GD2:Siglec-7 interactions and synergizes with CD47 blockade to mediate tumor eradication

The disialoganglioside GD2 is consistently overexpressed in neuroblastoma and osteosarcoma, and is variably expressed in other sarcomas, gliomas, neuroendocrine tumors, and epithelial cancers. Anti-GD2 antibodies have improved the survival rates of patients with neuroblastoma only when administered as part of intense chemotherapy-based cytotoxic regimens, which are associated with debilitating late effects including hearing loss, growth retardation, and secondary leukemias. Despite broad expression of GD2 on osteosarcoma, anti-GD2 antibody has not mediated significant antitumor activity in that disease or any other GD2+ cancers. CD47 is a checkpoint molecule overexpressed on tumor cells that inhibits macrophage activity, and CD47 blockade has demonstrated promising clinical activity in early human trials. We investigated whether anti-CD47 antibody could enhance the efficacy of anti-GD2 antibody in neuroblastoma and other GD2+ malignancies. We demonstrate substantial synergy of these two agents, resulting in the recruitment of tumor associated macrophages (TAMs) to mediate robust and durable anti-tumor responses. The responses are driven by GD2-specific factors that reorient the balance of macrophage activity towards phagocytosis of tumor cells, including disruption of a newly described GD2:Siglec-7 axis. These results demonstrate the unique synergy of combining anti-GD2 with anti-CD47, which has the potential to significantly enhance outcomes for children with neuroblastoma and osteosarcoma and will soon be investigated in a first-in-human clinical trial.

immunology↗

bioRxiv2020

Gene replacement of α-globin with β-globin restores hemoglobin balance in β-thalassemia-derived hematopoietic stem and progenitor cells

{beta}-thalassemia pathology is not only due to loss of {beta}-globin (HBB), but also erythrotoxic accumulation and aggregation of the {beta}-globin binding partner, -globin (HBA1/2). Here we describe a Cas9/AAV6-mediated genome editing strategy that can replace the entire HBA1 gene with a full-length HBB transgene in {beta}-thalassemia-derived hematopoietic stem and progenitor cells (HSPCs), which is sufficient to normalize {beta}-globin:-globin mRNA and protein ratios and restore functional adult hemoglobin tetramers in patient-derived red blood cells. Edited HSPCs were capable of long-term and bi-lineage hematopoietic reconstitution in mice, establishing proof-of-concept for replacement of HBA1 with HBB as a novel therapeutic strategy for curing {beta}-thalassemia.

molecular biology↗

bioRxiv2020

TRACE-Seq Reveals Clonal Reconstitution Dynamics of Gene Targeted Human Hematopoietic Stem Cells

Targeted DNA correction of disease-causing mutations in hematopoietic stem and progenitor cells (HSPCs) may usher in a new class of medicines to treat genetic diseases of the blood and immune system. With state-of-the-art methodologies, it is now possible to correct disease-causing mutations at high frequencies in HSPCs by combining ribonucleoprotein (RNP) delivery of Cas9 and chemically modified sgRNAs with homologous DNA donors via recombinant adeno-associated viral vector serotype six (AAV6). However, because of the precise nucleotide-resolution nature of gene correction, these current approaches do not allow for clonal tracking of gene targeted HSPCs. Here, we describe Tracking Recombination Alleles in Clonal Engraftment using sequencing (TRACE-Seq), a novel methodology that utilizes barcoded AAV6 donor template libraries, carrying either in-frame silent mutations or semi-randomized nucleotide sequences outside the coding region, to track the in vivo lineage contribution of gene targeted HSPC clones. By targeting the HBB gene with an AAV6 donor template library consisting of [~]20,000 possible unique exon 1 in-frame silent mutations, we track the hematopoietic reconstitution of HBB targeted myeloid-skewed, lymphoid-skewed, and balanced multi-lineage repopulating human HSPC clones in immunodeficient mice. We anticipate that this methodology has the potential to be used for HSPC clonal tracking of Cas9 RNP and AAV6-mediated gene targeting outcomes in translational and basic research settings.

molecular biology↗

bioRxiv2019

A single cell framework for multi-omic analysis of disease identifies malignant regulatory signatures in mixed phenotype acute leukemia

In order to identify the molecular determinants of human diseases, such as cancer, that arise from a diverse range of tissue, it is necessary to accurately distinguish normal and pathogenic cellular programs.1-3 Here we present a novel approach for single-cell multi-omic deconvolution of healthy and pathological molecular signatures within phenotypically heterogeneous malignant cells. By first creating immunophenotypic, transcriptomic and epigenetic single-cell maps of hematopoietic development from healthy peripheral blood and bone marrow mononuclear cells, we identify cancer-specific transcriptional and chromatin signatures from single cells in a cohort of mixed phenotype acute leukemia (MPAL) clinical samples. MPALs are a high-risk subtype of acute leukemia characterized by a heterogeneous malignant cell population expressing both myeloid and lymphoid lineage-specific markers.4, 5 Our results reveal widespread heterogeneity in the pathogenetic gene regulatory and expression programs across patients, yet relatively consistent changes within patients even across malignant cells occupying diverse portions of the hematopoietic lineage. An integrative analysis of transcriptomic and epigenetic maps identifies 91,601 putative gene-regulatory interactions and classifies a number of transcription factors that regulate leukemia specific genes, including RUNX1-linked regulatory elements proximal to CD69. This work provides a template for integrative, multi-omic analysis for the interpretation of pathogenic molecular signatures in the context of developmental origin.

genomics↗

bioRxiv2019

Mebendazole for Differentiation Therapy of Acute Myeloid Leukemia Identified by a Lineage Maturation Index

Accurate assessment of changes in cellular differentiation status in response to drug treatments or genetic perturbations is crucial for understanding tumorigenesis and developing novel therapeutics for human cancer. We have developed a novel computational approach, the Lineage Maturation Index (LMI), to define the changes in differentiation state of hematopoietic malignancies based on their gene expression profiles. We have confirmed that the LMI approach can detect known changes of differentiation state in both normal and malignant hematopoietic cells. To discover novel differentiation therapies, we applied this approach to analyze the gene expression profiles of HL-60 leukemia cells treated with a small molecule drug library. Among multiple drugs that significantly increased the LMIs, we identified mebendazole, an anti-helminthic clinically used for decades with no known significant toxicity. We tested the differentiation activity of mebendazole using primary leukemia blast cells isolated from human acute myeloid leukemia (AML) patients. We determined that treatment with mebendazole induces dramatic differentiation of leukemia blast cells as shown by cellular morphology and cell surface markers. Furthermore, mebendazole treatment significantly extended the survival of leukemia-bearing mice in a xenograft model. These findings suggest that mebendazole may be utilized as a low toxicity therapeutic for human acute myeloid leukemia and confirm the LMI approach as a robust tool for the discovery of novel differentiation therapies for cancer.

cancer biology↗

bioRxiv2018

Single-cell lineage tracing by endogenous mutations enriched in transposase accessible mitochondrial DNA

Simultaneous measurement of cell lineage and cell fates is a longstanding goal in biomedicine. Here we describe EMBLEM, a strategy to track cell lineage using endogenous mitochondrial DNA variants in ATAC-seq data. We show that somatic mutations in mitochondrial DNA can reconstruct cell lineage relationships at single cell resolution with high sensitivity and specificity. Using EMBLEM, we define the genetic and epigenomic clonal evolution of hematopoietic stem cells and their progenies in patients with acute myeloid leukemia. EMBLEM extends lineage tracing to any eukaryotic organism without genetic engineering.

genomics↗

bioRxiv2017

Single-cell epigenomics maps the continuous regulatory landscape of human hematopoietic differentiation

AbstractNormal human hematopoiesis involves cellular differentiation of multipotent cells into progressively more lineage-restricted states. While epigenomic landscapes of this process have been explored in immunophenotypically-defined populations, the single-cell regulatory variation that defines hematopoietic differentiation has been hidden by ensemble averaging. We generated single-cell chromatin accessibility landscapes across 8 populations of immunophenotypically-defined human hematopoietic cell types. Using bulk chromatin accessibility profiles to scaffold our single-cell data analysis, we constructed an epigenomic landscape of human hematopoiesis and characterized epigenomic heterogeneity within phenotypically sorted populations to find epigenomic lineage-bias toward different developmental branches in multipotent stem cell states. We identify and isolate sub-populations within classically-defined granulocyte-macrophage progenitors (GMPs) and use ATAC-seq and RNA-seq to confirm that GMPs are epigenomically and transcriptomically heterogeneous. Furthermore, we identified transcription factors and cis-regulatory elements linked to changes in chromatin accessibility within cellular populations and across a continuous myeloid developmental trajectory, and observe relatively simple TF motif dynamics give rise to a broad diversity of accessibility dynamics at cis-regulatory elements. Overall, this work provides a template for exploration of complex regulatory dynamics in primary human tissues at the ultimate level of granular specificity - the single cell.\n\nOne Sentence SummarySingle cell chromatin accessibility reveals a high-resolution, continuous landscape of regulatory variation in human hematopoiesis.

genomics↗