Loss of CTCF reveals basic properties of post-mitotic epigenomes and induces heart failure
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE96693 | GEO | 2017/08/30
SECONDARY ACCESSION(S): PRJNA379857
REPOSITORIES: GEO
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Project description:Understanding the principles of endogenous chromatin structure has key implications for epigenetic therapy. To determine the mechanisms of genome structure-function in post-mitotic cells, genome-wide chromatin conformation capture was performed in cardiac myocytes, a non-dividing, differentiated cell responsible for cardiac contraction. Cardiac-specific CTCF knockout mice demonstrated that loss of CTCF had minimal effect on topologically associating domains; however, it selectively altered boundary strength and A/B compartmentalization, with gene expression changes mimicking those in heart failure. Loss of CTCF (or subjecting wild-type mice to clinically relevant pressure overload stress) remodeled long-range chromatin looping to alter 3D proximity of enhancers and disease causing genes. Depletion of CTCF was sufficient to induce heart failure in mice and human heart failure patients receiving mechanical unloading to attenuate disease progression show increased CTCF expression. These findings establish CTCF in the maintenance of chromatin looping and identify global chromatin remodeling as a causative factor in heart failure.
2017-08-30 | GSE96692 | GEO
Project description:Understanding the principles of endogenous chromatin structure has key implications for epigenetic therapy. To determine the mechanisms of genome structure-function in post-mitotic cells, genome-wide chromatin conformation capture was performed in cardiac myocytes, a non-dividing, differentiated cell responsible for cardiac contraction. Cardiac-specific CTCF knockout mice demonstrated that loss of CTCF had minimal effect on topologically associating domains; however, it selectively altered boundary strength and A/B compartmentalization, with gene expression changes mimicking those in heart failure. Loss of CTCF (or subjecting wild-type mice to clinically relevant pressure overload stress) remodeled long-range chromatin looping to alter 3D proximity of enhancers and disease causing genes. Depletion of CTCF was sufficient to induce heart failure in mice and human heart failure patients receiving mechanical unloading to attenuate disease progression show increased CTCF expression. These findings establish CTCF in the maintenance of chromatin looping and identify global chromatin remodeling as a causative factor in heart failure.
2017-08-30 | GSE96691 | GEO
Project description:Understanding the principles of endogenous chromatin structure has key implications for epigenetic therapy. To determine the mechanisms of genome structure-function in post-mitotic cells, genome-wide chromatin conformation capture was performed in cardiac myocytes, a non-dividing, differentiated cell responsible for cardiac contraction. Cardiac-specific CTCF knockout mice demonstrated that loss of CTCF had minimal effect on topologically associating domains; however, it selectively altered boundary strength and A/B compartmentalization, with gene expression changes mimicking those in heart failure. Loss of CTCF (or subjecting wild-type mice to clinically relevant pressure overload stress) remodeled long-range chromatin looping to alter 3D proximity of enhancers and disease causing genes. Depletion of CTCF was sufficient to induce heart failure in mice and human heart failure patients receiving mechanical unloading to attenuate disease progression show increased CTCF expression. These findings establish CTCF in the maintenance of chromatin looping and identify global chromatin remodeling as a causative factor in heart failure.
2017-08-30 | GSE96690 | GEO
Project description:Loss of CTCF reveals basic properties of post-mitotic epigenomes and induces heart failure
| PRJNA379857 | ENA
Project description:Cellular senescence is a mechanism used by mitotic cells to prevent uncontrolled cell division. As senescent cells persist in tissues, they cause local inflammation and are harmful to surrounding cells, contributing to aging. Generally, neurodegenerative diseases, such as Parkinson's, are disorders of aging. The contribution of cellular senescence to neurodegeneration is still unclear. SATB1 is a DNA binding protein associated with Parkinson's disease. We report that SATB1 prevents cellular senescence in post-mitotic dopaminergic neurons. Loss of SATB1 causes activation of a cellular senescence transcriptional program in dopamine neurons both in human stem cell-derived dopaminergic neurons and in mice. We observed phenotypes that are central to cellular senescence in SATB1 knockout dopamine neurons in vitro and in vivo. Moreover, we found that SATB1 directly represses expression of the pro-senescence factor p21 in dopaminergic neurons. Our data implicate senescence of dopamine neurons as a contributing factor in the pathology of Parkinson's disease.
| S-EPMC7493192 | biostudies-literature
Project description:CCCTC-binding factor (CTCF) has a key role in higher-order chromatin architecture that is important for establishing and maintaining cell identity by controlling gene expression. In the mature cerebellum, CTCF is highly expressed in Purkinje cells (PCs) as compared with other cerebellar neurons. The cerebellum plays an important role in motor function by regulating PCs, which are the sole output neurons, and defects in PCs cause motor dysfunction. However, the role of CTCF in PCs has not yet been explored. Here we found that the absence of CTCF in mouse PCs led to progressive motor dysfunction and abnormal dendritic morphology in those cells, which included dendritic self-avoidance defects and a proximal shift in the climbing fibre innervation territory on PC dendrites. Furthermore, we found the peculiar lamellar structures known as "giant lamellar bodies" (GLBs), which have been reported in PCs of patients with Werdnig-Hoffman disease, 13q deletion syndrome, and Krabbe disease. GLBs are localized to PC dendrites and are assumed to be associated with neurodegeneration. They have been noted, however, only in case reports following autopsy, and reports of their existence have been very limited. Here we show that GLBs were reproducibly formed in PC dendrites of a mouse model in which CTCF was deleted. GLBs were not noted in PC dendrites at infancy but instead developed over time. In conjunction with GLB development in PC dendrites, the endoplasmic reticulum was almost absent around the nuclei, the mitochondria were markedly swollen and their cristae had decreased drastically, and almost all PCs eventually disappeared as severe motor deficits manifested. Our results revealed the important role of CTCF during normal development and in maintaining PCs and provide new insights into the molecular mechanism of GLB formation during neurodegenerative disease.
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Project description:Mitosis leads to global downregulation of transcription that then needs to be efficiently resumed. In somatic cells, this is mediated by a transient hyper-active state that first reactivates housekeeping and then cell identity genes. Here, we show that mouse embryonic stem cells, which display rapid cell cycles and spend little time in G1, also display accelerated reactivation dynamics. This uniquely fast global reactivation lacks specificity towards functional gene families, enabling the restoration of all regulatory functions before DNA replication. Genes displaying the fastest reactivation are bound by CTCF, a mitotic bookmarking transcription factor. In spite of this, the post-mitotic global burst is robust and largely insensitive to CTCF depletion. There are, however, around 350 genes that respond to CTCF depletion rapidly after mitotic exit. Remarkably, these are characterised by promoter-proximal mitotic bookmarking by CTCF. We propose that the structure of the cell cycle imposes distinct constrains to post-mitotic gene reactivation dynamics in different cell types, via mechanisms that are yet to be identified but that can be modulated by mitotic bookmarking factors.
| S-SCDT-10_15252-EMBR_202256075 | biostudies-other
Project description:Mitosis leads to global downregulation of transcription that then needs to be efficiently resumed. In somatic cells, this is mediated by a transient hyper-active state that first reactivates housekeeping and then cell identity genes. Here, we show that mouse embryonic stem cells, which display rapid cell cycles and spend little time in G1, also display accelerated reactivation dynamics. This uniquely fast global reactivation lacks specificity towards functional gene families, enabling the restoration of all regulatory functions before DNA replication. Genes displaying the fastest reactivation are bound by CTCF, a mitotic bookmarking transcription factor. In spite of this, the post-mitotic global burst is robust and largely insensitive to CTCF depletion. There are, however, around 350 genes that respond to CTCF depletion rapidly after mitotic exit. Remarkably, these are characterised by promoter-proximal mitotic bookmarking by CTCF. We propose that the structure of the cell cycle imposes distinct constrains to post-mitotic gene reactivation dynamics in different cell types, via mechanisms that are yet to be identified but that can be modulated by mitotic bookmarking factors.
| S-EPMC9827546 | biostudies-literature
Project description:Mitosis leads to a global downregulation of transcription that then needs to be efficiently restored. We performed high temporal resolution analysis of the transcriptome as cells exit mitosis, in wild-type mouse ES cells as well as in auxin-depleted Ctcf conditions.
2022-02-19 | GSE196889 | GEO
Project description:[Figure: see text].
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