A5085352215- Single-cell and spatial transcriptomics
- T-cell and B-cell Immunology
- Genomics and Chromatin Dynamics
- Immune Cell Function and Interaction
- CAR-T cell therapy research
- Bioinformatics and Genomic Networks
- NF-κB Signaling Pathways
- CRISPR and Genetic Engineering
- RNA modifications and cancer
- RNA Research and Splicing
- Acute Lymphoblastic Leukemia research
- IL-33, ST2, and ILC Pathways
- Cell Image Analysis Techniques
- Mesenchymal stem cell research
- vaccines and immunoinformatics approaches
- Immunotherapy and Immune Responses
- Advanced Biosensing Techniques and Applications
- interferon and immune responses
- RNA and protein synthesis mechanisms
- Gene Regulatory Network Analysis
- Cancer Cells and Metastasis
- Immune cells in cancer
- Cancer-related molecular mechanisms research
- Neurogenesis and neuroplasticity mechanisms
- Nuclear Receptors and Signaling
Harvard University
2019-2023
Brigham and Women's Hospital
2021-2023
Boston VA Research Institute
2021-2023
University of California, Irvine
2017-2022
Universidad Católica de la Santísima Concepción
2012
Although regeneration through the reprogramming of one cell lineage to another occurs in fish and amphibians, it has not been observed mammals. We discovered mouse that during wound healing, adipocytes regenerate from myofibroblasts, a type thought be differentiated nonadipogenic. Myofibroblast required neogenic hair follicles, which triggered bone morphogenetic protein (BMP) signaling then activation adipocyte transcription factors expressed development. Overexpression BMP antagonist Noggin...
Abstract Neutrophils are implicated in multiple homeostatic and pathological processes, but whether functional diversity requires discrete neutrophil subsets is not known. Here, we apply single-cell RNA sequencing to neutrophils from normal inflamed mouse tissues. Whereas conventional clustering yields alternative organizational structures, diffusion mapping plus velocity discloses a single developmental spectrum, ordered chronologically. Termed here neutrotime, this spectrum extends...
Highlights•PGE2 induces specific upregulation of DNMT3A in MDSCs•MDSC-suppressive properties depend on and hypermethylation myeloid genes•Specific DNMT3A-mediated changes MDSCs suggest potential therapeutic targets•PGE2- DNMT3A-dependent effects occur vitro models primary samplesSummaryMyeloid-derived suppressor cells (MDSCs) dendritic (DCs) arise from common progenitors. Tumor-derived factors redirect differentiation immune-promoting DCs to tolerogenic MDSCs, an immunological hallmark...
Significance Applying artificial intelligence tools to a highly complex question of immunology, we show that deep neural network can learn predict the patterns chromatin opening across 81 stem and differentiated cells immune system, solely from DNA sequence regulatory regions. It does so by discovering ab initio binding motifs for known master regulators, along with some unknown ones, their combinatorial operation. These predictions validated biochemically, mouse-trained predicts human...
Slug (SNAI2), a member of the well-conserved Snail family transcription factors, has multiple developmental roles, including in epithelial-to-mesenchymal transition (EMT). Here, we show that is critical for pathological angiogenesis needed to sustain tumor growth, and transiently necessary normal angiogenesis. We find upregulation angiogenic endothelial cells (EC) regulates an EMT-like suite target genes, suppresses Dll4-Notch signaling thereby promoting VEGFR2 expression. Both EC-specific...
Epigenetic editing holds the promise of durable therapeutic effects by silencing disease-causing genes without changing underlying DNA sequence. In this study, we designed an epigenetic editor to target human PCSK9 and thereby induce methylation at locus. A single administration lipid nanoparticles encapsulating mRNA encoding was sufficient drive near-complete in transgenic mice. Silencing for least 1 year fully maintained after partial hepatectomy-induced liver regeneration. addition,...
Rapid advances in single-cell assays have outpaced methods for analysis of those data types. Different show extensive variation sensitivity and signal to noise levels. In particular, scATAC-seq generates extremely sparse noisy datasets. Existing developed analyze this require cells amenable pseudo-time or datasets with drastically different cell-types. We describe a novel approach using self-organizing maps (SOM) link regions scRNA-seq genes that overcomes these challenges can generate draft...
Gene expression programs are specified by higher-order chromatin structure and enhancer-promoter loops (EPLs). T regulatory cell (Treg) identity is dominantly the transcription factor (TF) FoxP3, whose mechanism of action unclear. We applied conformation capture with immunoprecipitation (HiChIP) in Treg closely related conventional CD4+ cells (Tconv). EPLs identified H3K27Ac HiChIP showed a range connection intensity, some superconnected genes. TF-specific that FoxP3 interacts at large...
FoxP3 is an essential transcription factor (TF) for immunologic homeostasis, but how it utilizes the common forkhead DNA-binding domain (DBD) to perform its unique function remains poorly understood. We here demonstrated that unlike other known TFs, formed a head-to-head dimer using linker (Runx1-binding region [RBR]) preceding domain. Head-to-head dimerization conferred distinct specificity and created docking site cofactor Runx1. RBR was also important proper folding of domain, as...
Mutations of the transcription factor FoxP3 in patients with "IPEX" (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) disrupt regulatory T cells (Treg), causing an array multiorgan autoimmunity. To understand functional impact mutations across domains, without genetic and environmental confounders, six human FOXP3 missense are engineered into mice. Two classes emerge from combined immunologic genomic analyses. A mutation DNA-binding domain shows same...
FOXP3 is a transcription factor that essential for the development of regulatory T cells, branch cells suppress excessive inflammation and autoimmunity
Abstract Multi-omics approaches use a diversity of high-throughput technologies to profile the different molecular layers living cells. Ideally, integration this information should result in comprehensive systems models cellular physiology and regulation. However, most multi-omics projects still include limited number assays there have been very few multi-omic studies that evaluate dynamic processes such as growth, development adaptation. Hence, we lack formal analysis methods datasets can...
SUMMARY Gene expression programs are specified by higher-order chromatin structure and enhancer-promoter loops (EPL). T regulatory cells (Treg) identity is dominantly the transcription factor FoxP3, whose mechanism of action unclear. We applied proximity-ligation with immunoprecipitation (HiChIP) in Treg closely related conventional CD4+ (Tconv). EPL identified H3K27Ac HiChIP showed a range connection intensity, some super-connected genes. TF-specific that FoxP3 interacts EPLs at large...
Aire controls immunological tolerance by driving promiscuous expression of a large swath the genome in medullary thymic epithelial cells (mTECs). Its molecular mechanism remains enigmatic. High-resolution chromosome-conformation capture (Hi-C) experiments on ex vivo mTECs revealed to have widespread impact higher-order chromatin structure, disfavoring architectural loops while favoring transcriptional loops. In presence Aire, cohesin complexes concentrated superenhancers together with...
Human embryonic stem cells (hESCs) are exquisitely sensitive to WNT ligands, which rapidly cause differentiation. Therefore, hESC self-renewal requires robust mechanisms keep the in a inactive but responsive state. How they achieve this is largely unknown. We explored role of transcriptional regulators signaling, TCF/LEFs. As mouse ESCs, TCF7L1 predominant family member expressed hESCs. Genome-wide, it binds gene cohort involved primitive streak formation at gastrulation, including NODAL,...
Abstract Background Reducing the risk of atherosclerotic cardiovascular disease is dependent on both magnitude and cumulative duration LDL-C lowering. However, in clinical practice achieving treatment goals often hampered by low adherence to standard care. Although PCSK9 inhibitors represent an effective option for lowering, they require chronic life-long treatment. Epigenetic editing a new therapeutic approach designed durably silence genes leveraging nature’s endogenous cellular mechanism...
The differentiation of self-renewing progenitor cells requires not only the regulation lineage- and developmental stage–specific genes but also coordinated adaptation housekeeping functions from a metabolically active, proliferative state toward quiescence. How metabolic cell-cycle states are with cell type–specific is an important question, because dissociation between differentiation, cycle, hallmark cancer. Here, we use model system to systematically identify key transcriptional...