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Journal ArticleDOI: 10.1016/J.STEM.2020.11.001

The Transition from Quiescent to Activated States in Human Hematopoietic Stem Cells Is Governed by Dynamic 3D Genome Reorganization

04 Mar 2021-Cell Stem Cell (Cell Press)-Vol. 28, Iss: 3
Abstract: Lifelong blood production requires long-term hematopoietic stem cells (LT-HSCs), marked by stemness states involving quiescence and self-renewal, to transition into activated short-term HSCs (ST-HSCs) with reduced stemness. As few transcriptional changes underlie this transition, we used single-cell and bulk assay for transposase-accessible chromatin sequencing (ATAC-seq) on human HSCs and hematopoietic stem and progenitor cell (HSPC) subsets to uncover chromatin accessibility signatures, one including LT-HSCs (LT/HSPC signature) and another excluding LT-HSCs (activated HSPC [Act/HSPC] signature). These signatures inversely correlated during early hematopoietic commitment and differentiation. The Act/HSPC signature contains CCCTC-binding factor (CTCF) binding sites mediating 351 chromatin interactions engaged in ST-HSCs, but not LT-HSCs, enclosing multiple stemness pathway genes active in LT-HSCs and repressed in ST-HSCs. CTCF silencing derepressed stemness genes, restraining quiescent LT-HSCs from transitioning to activated ST-HSCs. Hence, 3D chromatin interactions centrally mediated by CTCF endow a gatekeeper function that governs the earliest fate transitions HSCs make by coordinating disparate stemness pathways linked to quiescence and self-renewal.

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Topics: CTCF (59%), Chromatin (53%)

11 results found

Open accessJournal Article
Jason Ernst1, Manolis Kellis1Institutions (1)
01 Jul 2010-PubMed Central
Abstract: A plethora of epigenetic modifications have been described in the human genome and shown to play diverse roles in gene regulation, cellular differentiation and the onset of disease. Although individual modifications have been linked to the activity levels of various genetic functional elements, their combinatorial patterns are still unresolved and their potential for systematic de novo genome annotation remains untapped. Here, we use a multivariate Hidden Markov Model to reveal chromatin states in human T cells, based on recurrent and spatially coherent combinations of chromatin marks.We define 51 distinct chromatin states, including promoter-associated, transcription-associated, active intergenic, largescale repressed and repeat-associated states. Each chromatin state shows specific enrichments in functional annotations, sequence motifs and specific experimentally observed characteristics, suggesting distinct biological roles. This approach provides a complementary functional annotation of the human genome that reveals the genome-wide locations of diverse classes of epigenetic function.

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Topics: Chromatin (58%), Genome project (56%), Human genome (52%) ... read more

672 Citations

Journal ArticleDOI: 10.1158/2159-8290.CD-21-0145
Lindsey E. Montefiori1, Sonja Bendig, Zhaohui Gu2, Xiao-Long Chen1  +48 moreInstitutions (12)
08 Jun 2021-Cancer Discovery
Abstract: Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of BCL11B, a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose BCL11B to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to BCL11B. Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed BCL11B allele and association of BCL11B with activated hematopoietic progenitor cell cis-regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic BCL11B expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia. Significance: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of BCL11B driven by diverse structural alterations, including de novo superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries. This article is highlighted in the In This Issue feature, p. 2659

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Topics: Progenitor cell (52%), Enhancer (52%), Stem cell marker (51%) ... read more

6 Citations

Open accessPosted ContentDOI: 10.21203/RS.3.RS-727909/V1
09 Aug 2021-
Abstract: The noncoding genome presents a largely untapped source of biological insights, including thousands of long noncoding RNA (lncRNA) loci. While some produce bona fide lncRNAs, others exert transcript-independent cis-regulatory effects, and the lack of predictive features renders mechanistic dissection challenging. Here, we describe CTCF-enriched lncRNA loci (C-LNC) as a subclass of functional genetic elements exemplified by MYNRL15, a pan-myeloid leukemia dependency identified by an lncRNA-based CRISPRi screen. MYNRL15 perturbation selectively impairs acute myeloid leukemia (AML) cells over hematopoietic stem / progenitor cells in vitro, and depletes AML xenografts in vivo. Mechanistically, we show that crucial DNA elements in the locus mediate its phenotype, triggering chromatin reorganization and downregulation of cancer dependency genes upon perturbation. Elevated CTCF density distinguishes MYNRL15 and 531 other lncRNA loci in K562 cells, of which 43-54% associate with clinical aspects of AML and 18.4% are functionally required for leukemia maintenance. Curated C-LNC catalogs in other cell types will help refine the search for noncoding oncogenic vulnerabilities in AML and other malignancies.

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Topics: Myeloid leukemia (63%), CTCF (62%)

2 Citations

Open accessPosted ContentDOI: 10.1101/2021.04.01.437998
02 Apr 2021-bioRxiv
Abstract: The advent of single cell (Sc) genomics has challenged the dogma of haematopoiesis as a tree-like structure of stepwise lineage commitment through distinct and increasingly restricted progenitor populations Instead, analysis of ScRNA-seq has proposed that the earliest events in human hematopoietic stem cell (HSC) differentiation are characterized by only subtle molecular changes, with hematopoietic stem and progenitor cells (HSPCs) existing as a continuum of low-primed cell-states that gradually transition into a specific lineage (CLOUD-HSPCs) Here, we combine ScRNA-seq, ScATAC-seq and cell surface proteomics to dissect the heterogeneity of CLOUD-HSPCs at different stages of human life Within CLOUD-HSPCs, pseudotime ordering of both mRNA and chromatin data revealed a bifurcation of megakaryocyte/erythroid and lympho/myeloid trajectories immediately downstream a subpopulation with an HSC-specific enhancer signature Importantly, both HSCs and lineage-restricted progenitor populations could be prospectively isolated based on correlation of their molecular signatures with CD35 and CD11A expression, respectively Moreover, we describe the changes that occur in this heterogeneity as hematopoiesis develops from neonatal to aged bone marrow, including an increase of HSCs and depletion of lympho-myeloid biased MPPs Thus, this study dissects the heterogeneity of human CLOUD-HSPCs revealing distinct HSPC-states of relevance in homeostatic settings such as ageing

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1 Citations

Journal ArticleDOI: 10.1038/S41590-021-00925-1
06 May 2021-Nature Immunology
Abstract: Continuous supply of immune cells throughout life relies on the delicate balance in the hematopoietic stem cell (HSC) pool between long-term maintenance and meeting the demands of both normal blood production and unexpected stress conditions. Here we identified distinct subsets of human long-term (LT)-HSCs that responded differently to regeneration-mediated stress: an immune checkpoint ligand CD112lo subset that exhibited a transient engraftment restraint (termed latency) before contributing to hematopoietic reconstitution and a primed CD112hi subset that responded rapidly. This functional heterogeneity and CD112 expression are regulated by INKA1 through direct interaction with PAK4 and SIRT1, inducing epigenetic changes and defining an alternative state of LT-HSC quiescence that serves to preserve self-renewal and regenerative capacity upon regeneration-mediated stress. Collectively, our data uncovered the molecular intricacies underlying HSC heterogeneity and self-renewal regulation and point to latency as an orchestrated physiological response that balances blood cell demands with preserving a stem cell reservoir. Dick and colleagues identify human LT-HSC subsets with distinct quiescent states. They link these differences to INKA1-mediated downregulation of the transmembrane protein CD112 and its interaction with the protein deacetylase SIRT1. INKA1 is inversely correlated with the histone H4K16Ac mark, which then distinguishes ‘latent’ CD112lo LT-HSCs from CD112hi LT-HSCs that are more readily activated in response to hematopoietic stress.

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Topics: Hematopoietic stem cell (55%), Stem cell (54%)

1 Citations


55 results found

Open accessJournal ArticleDOI: 10.1093/BIOINFORMATICS/BTP324
Heng Li1, Richard Durbin1Institutions (1)
01 Jul 2009-Bioinformatics
Abstract: Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals. Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ~10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package. Availability: Contact: [email protected]

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Topics: Hybrid genome assembly (54%), Sequence assembly (53%), 2 base encoding (52%) ... read more

35,234 Citations

Open accessJournal ArticleDOI: 10.1186/GB-2009-10-3-R25
04 Mar 2009-Genome Biology
Abstract: Bowtie is an ultrafast, memory-efficient alignment program for aligning short DNA sequence reads to large genomes. For the human genome, Burrows-Wheeler indexing allows Bowtie to align more than 25 million reads per CPU hour with a memory footprint of approximately 1.3 gigabytes. Bowtie extends previous Burrows-Wheeler techniques with a novel quality-aware backtracking algorithm that permits mismatches. Multiple processor cores can be used simultaneously to achieve even greater alignment speeds. Bowtie is open source

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Topics: Hybrid genome assembly (51%)

18,079 Citations

Open accessJournal ArticleDOI: 10.1038/NATURE11247
06 Sep 2012-Nature
Abstract: The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

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Topics: ENCODE (66%), Genome project (63%), Genome (59%) ... read more

11,598 Citations

Open accessJournal ArticleDOI: 10.1186/GB-2008-9-9-R137
Yong Zhang1, Tao Liu1, Clifford A. Meyer1, Jérôme Eeckhoute2  +8 moreInstitutions (5)
17 Sep 2008-Genome Biology
Abstract: We present Model-based Analysis of ChIP-Seq data, MACS, which analyzes data generated by short read sequencers such as Solexa's Genome Analyzer. MACS empirically models the shift size of ChIP-Seq tags, and uses it to improve the spatial resolution of predicted binding sites. MACS also uses a dynamic Poisson distribution to effectively capture local biases in the genome, allowing for more robust predictions. MACS compares favorably to existing ChIP-Seq peak-finding algorithms, and is freely available.

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Topics: Peak calling (54%), Chromatin binding (51%)

9,966 Citations

Journal ArticleDOI: 10.1038/44565
21 Oct 1999-Nature
Abstract: Is perception of the whole based on perception of its parts? There is psychological and physiological evidence for parts-based representations in the brain, and certain computational theories of object recognition rely on such representations. But little is known about how brains or computers might learn the parts of objects. Here we demonstrate an algorithm for non-negative matrix factorization that is able to learn parts of faces and semantic features of text. This is in contrast to other methods, such as principal components analysis and vector quantization, that learn holistic, not parts-based, representations. Non-negative matrix factorization is distinguished from the other methods by its use of non-negativity constraints. These constraints lead to a parts-based representation because they allow only additive, not subtractive, combinations. When non-negative matrix factorization is implemented as a neural network, parts-based representations emerge by virtue of two properties: the firing rates of neurons are never negative and synaptic strengths do not change sign.

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Topics: Non-negative matrix factorization (58%), Matrix decomposition (57%), Document-term matrix (55%) ... read more

9,911 Citations

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