Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis

DNA methylation is tightly regulated throughout mammalian development, and altered DNA methylation patterns are a general hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in hematological disorders, including acute myeloid leukemia (AML), and has been suggested to protect CG dinucleotide (CpG) islands and promoters from aberrant DNA methylation. In this study, we present a novel Tet2-dependent leukemia mouse model that closely recapitulates gene expression profiles and hallmarks of human AML1-ETO-induced AML. Using this model, we show that the primary effect of Tet2 loss in preleukemic hematopoietic cells is progressive and widespread DNA hypermethylation affecting up to 25% of active enhancer elements. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner but increases relative to population doublings. We confirmed this specific enhancer hypermethylation phenotype in human AML patients with TET2 mutations. Analysis of immediate gene expression changes reveals rapid deregulation of a large number of genes implicated in tumorigenesis, including many down-regulated tumor suppressor genes. Hence, we propose that TET2 prevents leukemic transformation by protecting enhancers from aberrant DNA methylation and that it is the combined silencing of several tumor suppressor genes in TET2 mutated hematopoietic cells that contributes to increased stem cell proliferation and leukemogenesis

Single cell RNA-seq and ATAC-seq analysis of cardiac progenitor cell transition states and lineage settlement.

Formation and segregation of cell lineages forming the heart have been studied extensively but the underlying gene regulatory networks and epigenetic changes driving cell fate transitions during early cardiogenesis are still only partially understood. Here, we comprehensively characterize mouse cardiac progenitor cells (CPCs) marked by Nkx2-5 and Isl1 expression from E7.5 to E9.5 using single-cell RNA sequencing and transposase-accessible chromatin profiling (ATAC-seq). By leveraging on cell-to-cell transcriptome and chromatin accessibility heterogeneity, we identify different previously unknown cardiac subpopulations. Reconstruction of developmental trajectories reveal that multipotent Isl1+ CPC pass through an attractor state before separating into different developmental branches, whereas extended expression of Nkx2-5 commits CPC to an unidirectional cardiomyocyte fate. Furthermore, we show that CPC fate transitions are associated with distinct open chromatin states critically depending on Isl1 and Nkx2-5. Our data provide a model of transcriptional and epigenetic regulations during cardiac progenitor cell fate decisions at single-cell resolution

Single-cell and spatial transcriptomic profiling of human glioblastomas

This deposition includes scRNA-seq and Spatial Transcriptomics data for 24 GBM patients, which are categorized as follows: a) 7 patients with newly diagnosed GBM (ND group) b) 5 patients with recurrent GBM (Rec group) c) 12 patients who have undergone neoadjuvant therapy (Neo group). Additionally, this deposition contains scRNA-seq data for both wild-type (WT) and SiglecE knockout (KO) mice bearing intracranial CT2A glioma. The provided data includes both the raw matrix and the processed Seurat objects.</p

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CPC ATAC-seq bigwi

Data Compression and Vectorization of Matrix Multiplication on HXDSP

In order to solve the problem of low efficiency of hardware resources and low data processing ability of vector processors, this paper uses data compression and vectorization method to realize matrix multiplication based on the HXDSP platform with the DCT algorithm in HEVC. It can make full use of the hardware resources of DSP to achieve the optimal optimization. The experimental results show that this method can achieve 32GMACS which is the peak-point multiply-accumulate capability of HXDSP. It can achieve to 2Gpixel/s for the data processing capability, which meets the performance requirements of HEVC coding standard and provides a reference for hardware implementation of HEVC

Identification of FABP5 as an immunometabolic marker in human hepatocellular carcinoma

Background Regulating T-cell metabolism is crucial for their anticancer activity. Therefore, understanding the function and metabolism of human tumor-infiltrating T cells is of broad interest and clinical importance.Methods CD3+CD45+ T cells were sorted from adjacent area or tumor core of human hepatocellular carcinoma (HCC), then the clusters and heterogeneity of T cells were further interrogated by single-cell transcriptomic profiling. 118 surgical samples from patients with HCC were histologically examined for infiltration of CD8+ T cells in tumor and adjacent tissue.Results Single-cell transcriptomic profiling indicated that several exhausted T-cell (Tex) populations differentially coexisted in the tumor and adjacent tissue. CD137 identifies and enriches Tex with superior effector functions and proliferation capacity. Furthermore, enhanced fatty acid-binding protein 5 (FABP5) expression along with increased mitochondrial oxidative metabolism were evident in these CD137-enriched Tex. Inhibiting FABP5 expression and mitochondrial fatty acid oxidation impaired the anti-apoptosis and proliferation of CD137-enriched Tex. These observations have been verified by generating CD137 CART. Immunohistochemistry staining on the tissue microarray of 118 patients with HCC showed intra-tumoral FABP5 high CD8+ T-cell infiltration was linked to overall and recurrence-free survival.Conclusions The tumor microenvironment can impose metabolic restrictions on T-cell function. CD137, a costimulatory molecule highly expressed on some Tex, uses exogenous fatty acids and oxidative metabolism to mediate antitumor immunity. The immunometabolic marker FABP5 should be investigated in larger, longitudinal studies to determine their potential as prognostic biomarkers for HCC

Heterogeneity of exhausted T cells in the tumor microenvironment is linked to patient survival following resection in hepatocellular carcinoma

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. T-cell infiltration and/or the presence of PD-L1 in tumors may be used as indicators of clinical response; However, recent studies reported that preexisting tumor-specific T cells may have limited reinvigoration capacity. Therefore, evaluating status of T cells of tumor-adjacent area and its impact on the prognosis are very important. Here, we examined 117 surgical samples from HCC patients for infiltration of exhausted T cell (Tex) including CD4+-Tex, CD8+-Tex and regulatory T cell (FOXP3+-Treg) in tumor and adjacent tissue. CD3+CD45RO+T cells were sorted from adjacent area or tumor core, then the clusters and heterogeneity of T cells were further interrogated by single-cell RNA sequencing. As a result, we suggested that abundance or location of T cell subsets is differentially correlate with long-term clinical outcome of HCC. In contrast with CD4+T or CD4+-Tex, the infiltration of CD8+T or CD8+-Tex cells was closely linked to overall or recurrence-free survival. FOXP3+-Treg is more predictive of early recurrence. Single-cell transcriptional analysis demonstrates the composition of CD4+-Tex, CD8+-Tex, and FOXP3+-Treg is shifted in tumor and adjacent tissue. Molecular profiles including genes coding checkpoint receptors, effector molecules are distinct between CD4+-Tex, CD8+-Tex, though some common features of CD4+ and CD8+ T cell exhaustion are revealed. In conclusion, we underline the heterogeneity and clinical relevance of Tex cells in HCC patients. A better understanding of Tex is critical for HCC monitoring and treatment