scholarly journals Hierarchical chromatin regulation during blood formation uncovered by single cell sortChIC

2021 ◽  
Author(s):  
Peter Zeller ◽  
Jake Yeung ◽  
Buys Anton de Barbanson ◽  
Helena Vinas Gaza ◽  
Maria Florescu ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Histone Modifications ◽  
Cell Types ◽  
Specific Cell ◽  
Chromatin Regulation ◽  
Active Chromatin ◽  
Hematopoietic Stem ◽  
Chromatin States ◽  
Cell Fate Decisions

Post-translational histone modifications modulate chromatin packing to regulate gene expression. How chromatin states, at euchromatic and heterochromatic regions, underlie cell fate decisions in single cells is relatively unexplored. We develop sort assisted single-cell chromatin immunocleavage (sortChIC) and map active (H3K4me1 and H3K4me3) and repressive (H3K27me3 and H3K9me3) histone modifications in hematopoietic stem and progenitor cells (HSPCs), and mature blood cells in the mouse bone marrow. During differentiation, HSPCs acquire distinct active chromatin states that depend on the specific cell fate, mediated by cell type-specifying transcription factors. By contrast, most regions that gain or lose repressive marks during differentiation do so independent of cell fate. Joint profiling of H3K4me1 and H3K9me3 demonstrates that cell types within the myeloid lineage have distinct active chromatin but share similar myeloid-specific heterochromatin-repressed states. This suggests hierarchical chromatin regulation during hematopoiesis: heterochromatin dynamics define differentiation trajectories and lineages, while euchromatin dynamics establish cell types within lineages.

scholarly journals Histone Acetyltransferases and Stem Cell Identity

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2407
Author(s):  
Ruicen He ◽  
Arthur Dantas ◽  
Karl Riabowol
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Epigenetic Modification ◽  
Cell Types ◽  
Histone Acetyltransferases ◽  
Specific Cell ◽  
Cell Fates ◽  
Cell Identity ◽  
Hematopoietic Stem

Acetylation of histones is a key epigenetic modification involved in transcriptional regulation. The addition of acetyl groups to histone tails generally reduces histone-DNA interactions in the nucleosome leading to increased accessibility for transcription factors and core transcriptional machinery to bind their target sequences. There are approximately 30 histone acetyltransferases and their corresponding complexes, each of which affect the expression of a subset of genes. Because cell identity is determined by gene expression profile, it is unsurprising that the HATs responsible for inducing expression of these genes play a crucial role in determining cell fate. Here, we explore the role of HATs in the maintenance and differentiation of various stem cell types. Several HAT complexes have been characterized to play an important role in activating genes that allow stem cells to self-renew. Knockdown or loss of their activity leads to reduced expression and or differentiation while particular HATs drive differentiation towards specific cell fates. In this study we review functions of the HAT complexes active in pluripotent stem cells, hematopoietic stem cells, muscle satellite cells, mesenchymal stem cells, neural stem cells, and cancer stem cells.

scholarly journals Single-Cell Genomics: Catalyst for Cell Fate Engineering

2021 ◽  
Vol 9 ◽  
Author(s):  
Boxun Li ◽  
Gary C. Hon
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
State Transitions ◽  
Small Scale ◽  
Specific Cell ◽  
Direct Reprogramming ◽  
Cell State

As we near a complete catalog of mammalian cell types, the capability to engineer specific cell types on demand would transform biomedical research and regenerative medicine. However, the current pace of discovering new cell types far outstrips our ability to engineer them. One attractive strategy for cellular engineering is direct reprogramming, where induction of specific transcription factor (TF) cocktails orchestrates cell state transitions. Here, we review the foundational studies of TF-mediated reprogramming in the context of a general framework for cell fate engineering, which consists of: discovering new reprogramming cocktails, assessing engineered cells, and revealing molecular mechanisms. Traditional bulk reprogramming methods established a strong foundation for TF-mediated reprogramming, but were limited by their small scale and difficulty resolving cellular heterogeneity. Recently, single-cell technologies have overcome these challenges to rapidly accelerate progress in cell fate engineering. In the next decade, we anticipate that these tools will enable unprecedented control of cell state.

scholarly journals Niche mediated integrin signaling supports steady state hematopoiesis in spleen

2020 ◽  
Author(s):  
Shubham Haribhau Mehatre ◽  
Irene Mariam Roy ◽  
Atreyi Biswas ◽  
Devila Prit ◽  
Sarah Schouteden ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cell Types ◽  
Integrin Signaling ◽  
White Pulp ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Functional Regulation

AbstractOutside-in integrin signaling regulates cell fate decisions in a variety of cell types, including hematopoietic stem cells (HSCs). Our earlier published studies showed that interruption of Periostin (POSTN) and Integrin-αv (ITGAV) interaction induces faster proliferation in HSCs with developmental stage dependent functional effects. Here, we examined the role of POSTN-ITGAV axis in lympho-hematopoietic activity in spleen that hosts rare population of HSCs, the functional regulation of which is not clearly known. Vav-iCre mediated deletion of Itgav in hematopoietic system led to higher proliferation rates, resulting in increased frequency of primitive HSCs in adult spleen. However, in vitro CFU-C assays demonstrated a poorer differentiation potential following Itgav deletion. This also led to a decrease in the white pulp area with a significant decline in the B-cell numbers. Systemic deletion of its ligand, POSTN, phenocopied the effects noted in Vav-Itgav−/− mice. Histological examination of Postn deficient spleen also showed increase in the spleen trabecular areas. Surprisingly, these were the myofibroblasts of the trabecular and capsular areas that expressed high levels of POSTN within the spleen tissue. In addition, vascular smooth muscle cells also expressed POSTN. Through CFU-S12 assays, we showed that hematopoietic support potential of stroma in Postn deficient splenic hematopoietic niche was defective. Overall, we demonstrate that POSTN-ITGAV interaction plays important role in spleen lympho-hematopoiesis.

scholarly journals Disruption of a GATA2, TAL1, ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells

Blood ◽  
2021 ◽  
Author(s):  
Julie A I Thoms ◽  
Peter Truong ◽  
Shruthi Subramanian ◽  
Kathy Knezevic ◽  
Gregory Harvey ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Prognostic Significance ◽  
Regulatory Elements ◽  
Leukemic Cells ◽  
State Transitions ◽  
Specific Cell ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Gene Regulatory

Changes in gene regulation and expression govern orderly transitions from hematopoietic stem cells to terminally differentiated blood cell types. These transitions are disrupted during leukemic transformation but knowledge of the gene regulatory changes underpinning this process is elusive. We hypothesised that identifying core gene regulatory networks in healthy hematopoietic and leukemic cells could provide insights into network alterations that perturb cell state transitions. A heptad of transcription factors (LYL1, TAL1, LMO2, FLI1, ERG, GATA2, RUNX1) bind key hematopoietic genes in human CD34+ haematopoietic stem and progenitor cells (HSPCs) and have prognostic significance in acute myeloid leukemia (AML). These factors also form a densely interconnected circuit by binding combinatorially at their own, and each other's, regulatory elements. However, their mutual regulation during normal haematopoiesis and in AML cells, and how perturbation of their expression levels influences cell fate decisions remains unclear. Here, we integrated bulk and single cell data and found that the fully connected heptad circuit identified in healthy HSPCs persists with only minor alterations in AML, and that chromatin accessibility at key heptad regulatory elements was predictive of cell identity in both healthy progenitors and in leukemic cells. The heptad factors GATA2, TAL1 and ERG formed an integrated sub-circuit that regulates stem cell to erythroid transition in both healthy and leukemic cells. Components of this triad could be manipulated to facilitate erythroid transition providing a proof of concept that such regulatory circuits could be harnessed to promote specific cell type transitions and overcome dysregulated haematopoiesis.

scholarly journals Vascular Regulation of Hematopoietic Stem Cell Homeostasis, Regeneration, and Aging

2021 ◽  
Author(s):  
Pradeep Ramalingam ◽  
Jason M. Butler ◽  
Michael G. Poulos
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Dynamic Imaging ◽  
Model Systems ◽  
Hematopoietic Stem ◽  
Perivascular Cell ◽  
Cell Fate Decisions ◽  
Vascular Regulation

Abstract Purpose of Review Hematopoietic stem cells (HSCs) sit at the top of the hierarchy that meets the daily burden of blood production. HSC maintenance relies on extrinsic cues from the bone marrow (BM) microenvironment to balance stem cell self-renewal and cell fate decisions. In this brief review, we will highlight the studies and model systems that define the centralized role of BM vascular endothelium in modulating HSC activity in health and stress. Recent Findings The BM microenvironment is composed of a diverse array of intimately associated vascular and perivascular cell types. Recent dynamic imaging studies, coupled with single-cell RNA sequencing (scRNA-seq) and functional readouts, have advanced our understanding of the HSC-supportive cell types and their cooperative mechanisms that govern stem cell fate during homeostasis, regeneration, and aging. These findings have established complex and discrete vascular microenvironments within the BM that express overlapping and unique paracrine signals that modulate HSC fate. Summary Understanding the spatial and reciprocal HSC-niche interactions and the molecular mechanisms that govern HSC activity in the BM vascular microenvironment will be integral in developing therapies aimed at ameliorating hematological disease and supporting healthy hematopoietic output.

scholarly journals Disruption of a GATA2, TAL1, ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells

2020 ◽  
Author(s):  
Julie A. I Thoms ◽  
Kathy Knezevic ◽  
Gregory Harvey ◽  
Yizhou Huang ◽  
Janith A. Seneviratne ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Prognostic Significance ◽  
Regulatory Elements ◽  
Leukemic Cells ◽  
State Transitions ◽  
Specific Cell ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Gene Regulatory

ABSTRACTChanges in gene regulation and expression govern orderly transitions from hematopoietic stem cells to terminally differentiated blood cell types. These transitions are disrupted during leukemic transformation but knowledge of the gene regulatory changes underpinning this process is elusive. We hypothesised that identifying core gene regulatory networks in healthy hematopoietic and leukemic cells could provide insights into network alterations that perturb cell state transitions. A heptad of transcription factors (LYL1, TAL1, LMO2, FLI1, ERG, GATA2, RUNX1) bind key hematopoietic genes in human CD34+ haematopoietic stem and progenitor cells (HSPCs) and have prognostic significance in acute myeloid leukemia (AML). These factors also form a densely interconnected circuit by binding combinatorially at their own, and each other’s, regulatory elements. However, their mutual regulation during normal haematopoiesis and in AML cells, and how perturbation of their expression levels influences cell fate decisions remains unclear. Here, we integrated bulk and single cell data and found that the fully connected heptad circuit identified in healthy HSPCs persists with only minor alterations in AML, and that chromatin accessibility at key heptad regulatory elements was predictive of cell identity in both healthy progenitors and in leukemic cells. The heptad factors GATA2, TAL1 and ERG formed an integrated sub-circuit that regulates stem cell to erythroid transition in both healthy and leukemic cells. Components of this triad could be manipulated to facilitate erythroid transition providing a proof of concept that such regulatory circuits could be harnessed to promote specific cell type transitions and overcome dysregulated haematopoiesis.

scholarly journals Chromatin accessibility dynamics and single cell RNA-Seq reveal new regulators of regeneration in neural progenitors

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Anneke Dixie Kakebeen ◽  
Alexander Daniel Chitsazan ◽  
Madison Corinne Williams ◽  
Lauren M Saunders ◽  
Andrea Elizabeth Wills
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Neural Progenitor Cells ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Rna Seq ◽  
Tail Regeneration ◽  
Cell Fate Decisions ◽  
Transcriptional Regulatory ◽  
Regulatory Dynamics

Vertebrate appendage regeneration requires precisely coordinated remodeling of the transcriptional landscape to enable the growth and differentiation of new tissue, a process executed over multiple days and across dozens of cell types. The heterogeneity of tissues and temporally-sensitive fate decisions involved has made it difficult to articulate the gene regulatory programs enabling regeneration of individual cell types. To better understand how a regenerative program is fulfilled by neural progenitor cells (NPCs) of the spinal cord, we analyzed pax6-expressing NPCs isolated from regenerating Xenopus tropicalis tails. By intersecting chromatin accessibility data with single-cell transcriptomics, we find that NPCs place an early priority on neuronal differentiation. Late in regeneration, the priority returns to proliferation. Our analyses identify Pbx3 and Meis1 as critical regulators of tail regeneration and axon organization. Overall, we use transcriptional regulatory dynamics to present a new model for cell fate decisions and their regulators in NPCs during regeneration.

scholarly journals Integration of spatial and single-cell transcriptomic data elucidates mouse organogenesis

2021 ◽  
Author(s):  
T. Lohoff ◽  
S. Ghazanfar ◽  
A. Missarova ◽  
N. Koulena ◽  
N. Pierson ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Target Genes ◽  
Single Cells ◽  
Cell Types ◽  
Spatial Context ◽  
Cell Fate Decisions ◽  
Spatially Resolved ◽  
Regulatory Processes ◽  
Cell Transcriptome

AbstractMolecular profiling of single cells has advanced our knowledge of the molecular basis of development. However, current approaches mostly rely on dissociating cells from tissues, thereby losing the crucial spatial context of regulatory processes. Here, we apply an image-based single-cell transcriptomics method, sequential fluorescence in situ hybridization (seqFISH), to detect mRNAs for 387 target genes in tissue sections of mouse embryos at the 8–12 somite stage. By integrating spatial context and multiplexed transcriptional measurements with two single-cell transcriptome atlases, we characterize cell types across the embryo and demonstrate that spatially resolved expression of genes not profiled by seqFISH can be imputed. We use this high-resolution spatial map to characterize fundamental steps in the patterning of the midbrain–hindbrain boundary (MHB) and the developing gut tube. We uncover axes of cell differentiation that are not apparent from single-cell RNA-sequencing (scRNA-seq) data, such as early dorsal–ventral separation of esophageal and tracheal progenitor populations in the gut tube. Our method provides an approach for studying cell fate decisions in complex tissues and development.

scholarly journals Single-cell analyses to reveal hematopoietic stem cell fate decisions

FEBS Letters ◽  
2017 ◽  
Vol 591 (15) ◽  
pp. 2195-2212 ◽  
Author(s):  
Ilaria Lunger ◽  
Malak Fawaz ◽  
Michael A. Rieger
Keyword(s):  
Stem Cell ◽  
Single Cell ◽  
Cell Fate ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Stem Cell Fate ◽  
Cell Fate Decisions

scholarly journals Defining the Emerging Blood System During Development at Single-Cell Resolution

2021 ◽  
Vol 9 ◽  
Author(s):  
Göran Karlsson ◽  
Mikael N. E. Sommarin ◽  
Charlotta Böiers
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Blood Disorders ◽  
Microfluidic Platforms ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Targeted Gene Expression ◽  
Definition Of

Developmental hematopoiesis differs from adult and is far less described. In the developing embryo, waves of lineage-restricted blood precede the ultimate emergence of definitive hematopoietic stem cells (dHSCs) capable of maintaining hematopoiesis throughout life. During the last two decades, the advent of single-cell genomics has provided tools to circumvent previously impeding characteristics of embryonic hematopoiesis, such as cell heterogeneity and rare cell states, allowing for definition of lineage trajectories, cellular hierarchies, and cell-type specification. The field has rapidly advanced from microfluidic platforms and targeted gene expression analysis, to high throughput unbiased single-cell transcriptomic profiling, single-cell chromatin analysis, and cell tracing—offering a plethora of tools to resolve important questions within hematopoietic development. Here, we describe how these technologies have been implemented to address a wide range of aspects of embryonic hematopoiesis ranging from the gene regulatory network of dHSC formation via endothelial to hematopoietic transition (EHT) and how EHT can be recapitulated in vitro, to hematopoietic trajectories and cell fate decisions. Together, these studies have important relevance for regenerative medicine and for our understanding of genetic blood disorders and childhood leukemias.

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