Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

LaminA/C regulates epigenetic and chromatin architecture changes upon aging of hematopoietic stem cells

ABSTRACT: The decline of hematopoietic stem cell (HSC) function upon aging contributes to the senescent immune remodeling and to leukemia pathogenesis. Aged HSCs show changes in their epigenome, like alterations in the global and local DNA/histone methylation and histone acetylation landscape. Previously, we showed a correlation between high Cdc42 activity and the loss of intra-nuclear epigenetic polarity (epipolarity), as indicated by the specific location of histone H4 lysine 16 acetylation (H4K16ac). Here, we show that not all histone modifications display a polar localization and that loss of H4K16ac amount and epipolarity is specific to aged HSCs. Increased levels of H4K16ac are insufficient to restore polarity in aged HSCs and for the restoration of HSC function. Changes in H4K16ac upon aging and rejuvenation of HSCs are correlated to a shift of chromosome 11 architecture and nuclear volume and shape. Surprisingly, by taking advantage of knock-out mouse models we demonstrate that increased Cdc42 activity levels correlate with the repression of LaminA/C expression, which control chromosome 11 distribution, H4K16ac polarity and the nuclear volume and shape of aged HSCs. These chromatin and epigenetic architecture changes are targeted by altering the activity of the small RhoGTPase Cdc42, that regulates LaminA/C. Collectively, our data show that chromatin architecture changes in stem cells are reversible by changing levels of Cdc42 activity, revealing an unanticipated way to pharmacologically target LaminA/C expression and revert alterations of the epigenetic architecture in aged HSCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE119466 | GEO | 2018/09/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transplanting rejuvenated blood stem cells extends lifespan of aged immunocompromised mice [scRNA-seq of LSK cells]

Project description:One goal of regenerative medicine is to rejuvenate tissues and extend lifespan by restoring the function of endogenous aged stem cells. However, evidence that somatic stem cells can be targeted in vivo to extend lifespan is still lacking. Here, we demonstrate that after a short systemic treatment with a specific inhibitor of the small RhoGTPase Cdc42 (CASIN), transplanting aged hematopoietic stem cells (HSCs) from treated mice is sufficient to extend the healthspan and lifespan of aged immunocompromised mice without additional treatment. In detail, we show that systemic CASIN treatment improves strength and endurance of aged mice by increasing the myogenic regenerative potential of aged skeletal muscle stem cells. Further, we show that CASIN modifies niche localization and H4K16ac polarity of HSCs in vivo. Single cell profiling reveals changes in HSC transcriptome, which underlie enhanced lymphoid and regenerative capacity in serial transplantation assays. Overall, we provide proof-of-concept evidence that a short systemic treatment to decrease Cdc42 activity improves the regenerative capacity of different endogenous aged stem cells in vivo, and that rejuvenated HSCs exert a broad systemic effect sufficient to extend murine health- and lifespan.

2022-12-01 | GSE197070 | GEO

Aging alters the epigenetic asymmetry of HSC division [scRNA-Seq]

Project description:Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain homeostasis. With aging, the frequency of polar HSCs decreases. Cell polarity in HSCs is controlled by the activity of the small RhoGTPase Cdc42. Here we demonstrate, using a comprehensive set of paired daughter cell analyses that include single cell 3D-confocal imaging, single cell transplants, single cell RNA-seq as well as single cell ATAC-seq, that the outcome of HSC divisions is strongly linked to the polarity status before mitosis, which is in turn determined by the level of the activity Cdc42 in stem cells. Aged apolar HSCs undergo preferentially self-renewing symmetric divisions, resulting in daughter stem cells with reduced regenerative capacity and lymphoid potential, while young polar HSCs undergo preferentially asymmetric divisions. Mathematical modeling in combination with experimental data implies a mechanistic role of the asymmetric sorting of Cdc42 in determining the potential of daughter cells via epigenetic mechanisms. Therefore, molecules that control HSC polarity might serve as modulators of the mode of stem cell division regulating the potential of daughter cells.

2018-12-04 | GSE116708 | GEO

Aging alters the epigenetic asymmetry of HSC division [scATAC-Seq]

2018-12-04 | GSE116707 | GEO

Mapping of histone modifications in aged hematopoietic stem cells (HSCs)

Project description:The decline of hematopoietic stem cell (HSC) function upon aging contributes to senescent immune remodeling and to leukemia pathogenesis. Aged HSCs show epigenetic alterations affecting DNA methylation, histone modifications, and show a reduction in the polar distribution of histone 4 lysine 16 acetylation (H4K16ac). Here, we determined the deposition patterns of H4K16ac in young, aged and re-juvenated HSCs using ChIP-seq.

2018-09-20 | GSE120232 | GEO

Repolarization of HSC attenuates HSCs failure in Shwachman-Diamond syndrome

Project description:Shwachman-Diamond syndrome (SDS) is a bone marrow failure (BMF) syndrome associated with an increased risk of myelodysplasia and leukemia. The molecular mechanisms of SDS are not fully understood. We report that primitive hematopoietic cells from SDS patients present with a reduced activity of the small Rho GTPase Cdc42 and concomitantly a reduced frequency of HSCs polar for polarity proteins. The level of apolarity of SDS HSCs correlated with the magnitude of HSC depletion in SDS patients. Importantly, exogenously provided Wnt5a or GDF11 that elevates the activity of Cdc42 restored polarity in SDS HSCs and increased the number of HSCs in SDS patient samples in surrogate ex vivo assays. Single cell level RNA-Seq analyses of SDS HSCs and daughter cells demonstrated that SDS-HSC treated with GDF11 are transcriptionally more similar to control than to SDS-HSCs. Treatment with GDF11 reverted pathways in SDS HSCs associated with rRNA processing and ribosome function, but also viral infection and immune function, p53-dependent DNA damage, spindle checkpoints, and metabolism, further implying a role of these pathways in HSC failure in SDS. Our data suggest that HSC failure in SDS is driven at least in part by low Cdc42 activity in SDS HSCs. Our data thus identify novel rationale approaches to attenuate HSCs failure in SDS.

2020-09-18 | GSE158140 | GEO

Attrition of X chromosome inactivation in aged hematopoietic stem cells

Project description:During X chromosome inactivation (XCI), the inactive X chromosome (Xi) is recruited to the nuclear lamina at the periphery of the nucleus. Beside X chromosome (X chr) reactivation resulting in a highly penetrant aging-like hematopoietic malignancy, little is known about XCI in aged hematopoietic stem cells (HSCs) . Here, we demonstrate that LaminA/C defines a distinct repressive nuclear compartment for XCI in young HSCs, and its reduction in aged HSCs correlates with an impairment in the overall control of XCI. Integrated omics analyses reveal higher variation in gene expression, global hypomethylation and significantly increased chromatin accessibility on the X chr in aged HSCs. In summary, our data support the role of LaminA/C in the establishment of a special repressive compartment for XCI in HSCs, which is impaired upon aging.

2021-04-07 | GSE167214 | GEO

CDC42 controlled apical-basal polarity regulates intestinal stem cell to transit amplifying cell fate transition via YAP-EGF-mTOR signaling

Project description:Epithelial polarity is controlled by a polarity machinery including the Rho GTPase CDC42 and Scribble/PAR. By using intestinal stem cell (ISC)-specific deletion of CDC42 in Olfm4-IRES-eGFPCreERT2;CDC42flox/flox mice, we found that ISC-initiated CDC42 loss caused a drastic hyper-proliferation of transit amplifying (TA) cells and disrupted epithelial polarity. CDC42-null crypts displayed expanded TA cell and diminished ISC populations, accompanied by elevated hippo signaling via YAP/TAZ - Ereg and mTOR activation, independent from canonical Wnt signaling. YAP/TAZ conditional knockout restored the balance of ISC/TA cell populations and crypt proliferation but did not rescue the polarity in CDC42-null small intestine. mTOR or EGFR inhibitor treatment of CDC42 KO mice exhibited similar rescuing effects without affecting YAP/TAZ signaling. Inducible ablation of Scribble in intestinal epithelial cells mimics that of CDC42 KO defects including crypt hyperplasia and hippo signaling activation. Mammalian epithelial polarity regulates ISC and TA cell fate and proliferation via a hippo-Ereg-mTOR cascade.

2021-10-23 | GSE166736 | GEO

Hematopoietic stem cells in perisinusoidal niches are protected from ageing [aged, GFP-label retaining HSCs]

Project description:With ageing, intrinsic hematopoietic stem cell (HSC) activity decreases, resulting in impaired tissue homeostasis, reduced engraftment following transplantation and increased susceptibility to diseases. However, whether ageing affects also the HSC niche impairing the capacity to support HSC function is still largely unknown. Here, by using in-vivo long-term label retention assays we demonstrate that aged labelling retaining (LR) HSCs, which are in the old mice the most quiescent HSC subpopulation with the highest regenerative capacity and cellular polarity, reside predominantly in perisinusoidal niches. Furthermore, we demonstrate that sinusoidal niches and perisinusoidal Nes-GFPlow cells are uniquely preserved in shape, morphology and number upon ageing. Finally, we show that myeloablative chemotherapy can selectively disrupt aged sinusoidal niches, which is linked to hematopoietic failure and decreased survival of aged mice. Overall, our data characterize for the first time the functional alterations of the aged HSC niche and unveil that perisinusoidal niches are uniquely preserved and protect HSCs from ageing.

2019-09-02 | GSE130298 | GEO

Hematopoietic stem cells in perisinusoidal niches are protected from ageing [young and aged BM CD45-CD31+ endothelial cells]

2019-09-02 | GSE129726 | GEO

Cdc42 phosphorylation study - Cdc42 Regulates Neuronal Polarity during Cerebellar Axon Formation and Glial-Guided Migration

Project description:Govek et al. demonstrate conditional loss of Cdc42 in cerebellar granule cell progenitors (GCPs) perturbs GCP polarity and impairs axon patterning, glial-guided migration, and cerebellar foliation. Phospho-proteomic analysis identified polarity and cytoskeletal proteins as affected targets in Cdc42 deficient GCPs.

2018-10-22 | PXD008148 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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