Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Progressive chromatin condensation and H3K9 methylation regulate the differentiation of embryonic and hematopoietic stem cells

ABSTRACT: Epigenetic regulation serves as the basis for stem cell differentiation into distinct cell types, but it is unclear how global epigenetic changes are regulated during this process. Here, we tested the hypothesis that global chromatin organization affects the lineage potential of stem cells and that manipulation of chromatin dynamics influences stem cell function. Using nuclease sensitivity assays, we found a progressive decrease in chromatin digestion between pluripotent embryonic stem cells (ESCs), multipotent hematopoietic stem and progenitor cells (HSPCs), and mature hematopoietic cells. Quantification of chromatin composition by high-resolution microscopy revealed that ESCs contain significantly more euchromatin than HSPCs, with a further reduction in euchromatin as HSPCs transition into mature cells. Increased cellular maturation also led to heterochromatin localization to the nuclear periphery. Functionally, prevention of heterochromatin formation by inhibition of the histone methyltransferase G9a resulted in delayed hematopoietic stem cell (HSC) differentiation. Our results demonstrate significant global rearrangements of chromatin structure during embryonic and adult stem cell differentiation, and that heterochromatin formation by H3K9 methylation is an important regulator of HSC differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE73221 | GEO | 2016/09/18

SECONDARY ACCESSION(S): PRJNA296390

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

MYCT1 CONTROLS ENVIRONMENTAL SENSING IN HUMAN HEMATOPOIETIC STEM CELLS

Project description:Hematopoietic stem cells (HSC) rely on a unique regulatory machinery that facilitates life-long blood production and enables reconstitution of the entire hematopoietic system upon transplantation. However, the biological processes governing human HSC self-renewal and engraftment ability are poorly understood and challenging to recapitulate ex vivo to facilitate robust human HSC expansion. We discovered a novel HSC regulatory protein, MYCT1 (MYCT target 1), that is selectively expressed in endothelial cells (EC) and undifferentiated human HSPCs but becomes drastically downregulated during HSC culture. Lentiviral knockdown of MYCT1 in human foetal liver and cord blood HSPCs revealed a critical role for MYCT1 in governing human HSPC expansion and engraftment ability. Single cell RNAseq of human CB HSPCs after MYCT1 knockdown and overexpression revealed that MYCT1 governs HSC functional competence and modulates cellular properties essential for HSC stemness, such as low mitochondrial metabolic activity. Indeed, restoring the compromised MYCT1 expression in cultured human CB HSPCs improved ex vivo expansion of the most undifferentiated human HSPCs and enhanced their engraftment ability. We found that MYCT1 is localized in the endosomal membrane and interacts with vesicle trafficking regulators and signalling machinery essential for HSC and EC function. Loss of MYCT1 led to excessive endocytosis and hyperactive signalling responses to cytokines, whereas restoring MYCT1 expression in cultured CB HSPCs balanced the abnormal endocytosis associated with prolonged culture and fine-tuned signalling responses. Our work identifies MYCT1-moderated endocytosis and environmental sensing as an essential regulatory mechanism required to preserve human HSC stemness, and pinpoints silencing of MYCT1 as a critical contributor to the dysfunction of cultured human HSCs that needs to be addressed to improve human HSC culture strategies.

2024-04-15 | PXD042257 | Pride

Hierarchical chromatin regulation during blood formation uncovered by single-cell sortChIC

Project description:Post-translational histone modifications modulate chromatin packing to regulate gene expression. How chromatin states, both at euchromatic and at heterochromatic regions, underlie cell fate decisions in single cells is relatively unexplored. We develop sort assisted single-cell chromatin immunocleavage (sortChIC) and apply it to 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 the specific cell fate. Joint profiling of active H3K4me1 and repressive H3K9me3 in single cells demonstrates that cell types within the myeloid lineage have distinct active chromatin regulation but share a similar myeloid-specific heterochromatin-repressed state. Our results suggest a hierarchical chromatin regulation program during hematopoiesis, by which heterochromatin dynamics define differentiation trajectories and lineages, while euchromatin dynamics establish cell types within lineages.

2021-11-30 | GSE164779 | GEO

SMARCAD1 and TOPBP1 contribute to heterochromatin maintenance at the transition from the 2C-like to the pluripotent state

Project description:Chromocenters are established after the 2-cell (2C) stage during mouse embryonic development, but the factors that mediate chromocenter formation remain largely unknown. To identify regulators of 2C heterochromatin establishment, we generated an inducible system to convert embryonic stem cells (ESCs) to 2C-like cells. This conversion is marked by a global reorganization and dispersion of H3K9me3-heterochromatin foci, which are then reversibly formed upon re-entry into pluripotency. Profiling the chromatin-bound proteome (chromatome) by genome capture of ESCs transitioning to 2C-like cells, we uncover chromatin regulators involved in de novo heterochromatin formation. We identified TOPBP1 and investigated its binding partner SMARCAD1. SMARCAD1 and TOPBP1 associate with H3K9me3-heterochromatin in ESCs. Interestingly, the nuclear localization of SMARCAD1 is lost in 2C-like cells. SMARCAD1 or TOPBP1 depletion in mouse embryos lead to developmental arrest, reduction of H3K9me3 and remodeling of heterochromatin foci. Collectively, our findings contribute to comprehending the maintenance of chromocenters during early development.

2023-04-18 | PXD019703 | Pride

Single-cell 3D genome structure reveals distinct human pluripotent states (RNA-Seq)

Project description:Pluripotent states of embryonic stem cells (ESCs) with distinct transcription profile affect their differentiation capacity and therapeutic potential. By single cell analysis of high-resolution three-dimensional (3D) genome structure, we show that remodeling genome structure is highly associated with pluripotent states of human ESCs (hESCs). Naive pluripotent state is featured with specialized 3D genome structures and clear chromatin compartmentation distinct from primed state. Naive pluripotent state may be achieved by remodeled active euchromatin compartment and less chromatin interaction in the nuclear center. This unique genome organization is linked to elevated chromatin accessibility on enhancers and thus high expression levels of naive pluripotent genes localized in this region. On the contrary, primed state exhibits intermingled genome organization. Moreover, active euchromatin and primed pluripotent genes are distributed in the nuclear periphery and yet repressive heterochromatin densely concentrated in the nuclear center, reducing chromatin accessibility and transcription of naive genes. Thus, inversion or relocation of heterochromatin to euchromatin compartmentation is related to regulating chromatin accessibility and thus define pluripotent states and cell identity.

2024-03-11 | GSE260994 | GEO

Single-cell 3D genome structure reveals distinct human pluripotent states (CUT&Tag-seq)

2024-03-11 | GSE260993 | GEO

Single-cell 3D genome structure reveals distinct human pluripotent states (ATAC-Seq)

2024-03-11 | GSE260991 | GEO

Chromatin accessibility promotes hematopoietic and leukemia stem cell activity

Project description:Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. We found that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. HMGN1 amplification was associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cell (HSC) function and AML, such as HoxA cluster genes. In vivo, HMGN1 overexpression was linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperated with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieved the HMGN1-associated differentiation block. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML.

2020-02-25 | PXD017054 | Pride

Yin Yang 1 regulates cohesin complex protein SMC3 in mouse hematopoietic stem cells

Project description:Yin Yang 1 (YY1) and Structural Maintenance of Chromosomes 3 (SMC3) are two critical chromatin structural factors that mediate long-distance enhancer-promoter interactions and promote developmentally regulated changes in chromatin architecture in hematopoietic stem/progenitor cells (HSPCs). While YY1 plays critical functions in promoting hematopoietic stem cell (HSC) self-renewal and maintaining HSC quiescence, SMC3 is required for proper myeloid lineage differentiation. However, many questions remain unanswered regarding how YY1 and SMC3 interact with each other and impact hematopoiesis. We found that YY1 physically interacts with SMC3 and co-occupies with SMC3 at a large cohort of promoters genome-wide, and YY1 deficiency deregulates the genetic network governing cell metabolism. YY1 occupies the Smc3 promoter and represses SMC3 expression in HSPCs. YY1 regulates HSC metabolic pathways and maintains proper intracellular reactive oxygen species levels in HSCs, and this regulation is independent of YY1- SMC3 axis. Our results establish a distinct YY1-SMC3 axis and its impact on HSC quiescence and metabolism.

2024-03-11 | GSE261032 | GEO

Microarray expression analysis of wild type and Erg knockdown bone marrow hematopoietic stem and progenitor cells

Project description:Erg is an ETS family transcription factor frequently overexpressed in human leukemias and has been implicated as a key regulator of hematopoietic stem cells (HSCs). However how Erg controls normal hematopoiesis, particularly at the stem cell level, remains poorly understood. Using homologous recombination, we generated an Erg knockdown allele (Ergkd) in which Erg expression can be restored upon Cre-mediated excision of a Stopper cassette. In Ergkd/+ mice, ~40% reduction in Erg dosage perturbed both fetal liver and bone marrow hematopoiesis by reducing the numbers of Lin-Sca-1+c-Kit+ (LSK) hematopoietic stem and progenitor cells (HSPCs) and megakaryocytic progenitors. By genetic mosaic analysis, we found Erg-restored HSPCs outcompeted Ergkd/+ HSPCs for contributing to adult hematopoiesis in vivo. Intriguingly, HSC differentiation also appeared attenuated, leading to accumulation of long-term HSCs in the mutant LSK population. Accordingly, microarray analysis of Erg-restored and Ergkd/+ HSPCs from the same animal revealed enrichment of stem cell-related pathways in Ergkd/+ HSPCs. Overall, reduced Erg dosage perturbs hematopoiesis by reducing HSC numbers and impairing HSC differentiation, possibly via two Erg targets, Jun and Myc.

2017-06-20 | GSE48600 | GEO

Aging-induced pseudouridine synthase 10 impairs hematopoietic stem cells

Project description:Aged hematopoietic stem cells (HSCs) exhibit compromised reconstitution capacity and differentiation-bias towards myeloid lineage. While, the molecular mechanism behind it remains not fully understood. In this study, we observed that the expression of pseudouridine (Ψ) synthase 10 is increased in aged hematopoietic stem and progenitor cells (HSPCs) and enforced PUS10 recapitulates the phenotype of aged HSCs, which is not achieved by its Ψ synthase activity. Consistently, we observed no difference of tRNA pseudouridylation profile between young and aged HSPCs. No significant alteration of hematopoietic homeostasis and HSC function is observed in young Pus10-/- mice, while aged Pus10-/-mice exhibit mild alteration of hematopoietic homeostasis and HSC function. Moreover, we observed that PUS10 is ubiquitinated by E3 ubiquitin ligase CRL4DCAF1 complex and the increase of PUS10 in aged HSPCs is due to aging-declined CRL4DCAF1-mediated ubiquitination degradation signaling. Taken together, this study for the first time evaluated the role of PUS10 in HSC aging and function, and provided novel insight for HSC rejuvenation and clinical application.

2023-05-13 | GSE213417 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data