Reduction of di-methyl histone H3K9 (H3K9me2) in CUX1-deficient cells.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE298147 | GEO | 2026/03/11
REPOSITORIES: GEO
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Project description:Hematopoietic stem cells (HSCs) possess properties of both self-renewal and multipotent differentiation; however, the regulation of these opposing properties remains elusive. Using a novel reporter mouse, we demonstrate the dose-dependent role of the transcription factor, CUX1, in HSC fate. As CUX1 levels naturally rise, HSCs gradually lose repopulating capacity. CUX1 knockdown reverses this process and reverts HSCs to an earlier cell state—restoring the transcriptome, chromatin accessibility, repopulating capacity, and self-renewal ability of HSCs with normally low CUX1 levels. In the absence of CUX1, endogenous retroelements (EREs) are aberrantly expressed, leading to a cell-intrinsic inflammatory response, which contributes to CUX1-dependent HSC activity. Likewise, loss of the transcription factor IRF1 attenuates CUX1-mediated HSC reprogramming. This mechanism could be relevant to leukemogenesis as acute myeloid leukemias with CUX1 deletions upregulate EREs and the interferon response. Our findings attribute CUX1 and innate immune activation to the complex molecular underpinnings of HSC fate decisions.
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Project description:Hematopoietic stem cells (HSCs) possess properties of both self-renewal and multipotent differentiation; however, the regulation of these opposing properties remains elusive. Using a novel reporter mouse, we demonstrate the dose-dependent role of the transcription factor, CUX1, in HSC fate. As CUX1 levels naturally rise, HSCs gradually lose repopulating capacity. CUX1 knockdown reverses this process and reverts HSCs to an earlier cell state—restoring the transcriptome, chromatin accessibility, repopulating capacity, and self-renewal ability of HSCs with normally low CUX1 levels. In the absence of CUX1, endogenous retroelements (EREs) are aberrantly expressed, leading to a cell-intrinsic inflammatory response, which contributes to CUX1-dependent HSC activity. Likewise, loss of the transcription factor IRF1 attenuates CUX1-mediated HSC reprogramming. This mechanism could be relevant to leukemogenesis as acute myeloid leukemias with CUX1 deletions upregulate EREs and the interferon response. Our findings attribute CUX1 and innate immune activation to the complex molecular underpinnings of HSC fate decisions.
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Project description:Hematopoietic stem cells (HSCs) possess properties of both self-renewal and multipotent differentiation; however, the regulation of these opposing properties remains elusive. Using a novel reporter mouse, we demonstrate the dose-dependent role of the transcription factor, CUX1, in HSC fate. As CUX1 levels naturally rise, HSCs gradually lose repopulating capacity. CUX1 knockdown reverses this process and reverts HSCs to an earlier cell state—restoring the transcriptome, chromatin accessibility, repopulating capacity, and self-renewal ability of HSCs with normally low CUX1 levels. In the absence of CUX1, endogenous retroelements (EREs) are aberrantly expressed, leading to a cell-intrinsic inflammatory response, which contributes to CUX1-dependent HSC activity. Likewise, loss of the transcription factor IRF1 attenuates CUX1-mediated HSC reprogramming. This mechanism could be relevant to leukemogenesis as acute myeloid leukemias with CUX1 deletions upregulate EREs and the interferon response. Our findings attribute CUX1 and innate immune activation to the complex molecular underpinnings of HSC fate decisions.
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Project description:Endogenous retroelements (ERE) constitute about 42% of the human genome and have been implicated in common human diseases such as autoimmunity and cancer. Despite evidence that some EREs can be expressed at the RNA and protein levels in specific contexts, a systems-level evaluation of their expression in human tissues is lacking. We report that all human tissues express EREs but the breadth and magnitude of ERE expression are very heterogeneous from one tissue to another. ERE expression was particularly high in two MHC-I-deficient tissues (ESCs and testis) and one MHC-I-expressing tissue, mTECs. In mutant mice, we report that the exceptional expression of EREs in mTECs was AIRE-independent. MS analyses identified 103 non-redundant ERE-derived MAPs (ereMAPs) in B-LCLs. These ereMAPs preferentially derived from sense translation of intronic EREs. Notably, detailed analyses of their amino acid composition revealed that ERE-derived MAPs presented homology to viral MAPs. This study shows that ERE expression in somatic tissues is more pervasive and heterogeneous than anticipated. The high and diversified expression of EREs in mTECs and their ability to generate MAPs suggest that EREs may play an important role in the establishment of self-tolerance. The viral-like properties of ERE-derived MAPs suggest that those not expressed in mTECs can be highly immunogenic.
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Project description:Endogenous retroelements (ERE) constitute about 42% of the human genome and have been implicated in common human diseases such as autoimmunity and cancer. Despite evidence that some EREs can be expressed at the RNA and protein levels in specific contexts, a systems-level evaluation of their expression in human tissues is lacking. We report that all human tissues express EREs but the breadth and magnitude of ERE expression are very heterogeneous from one tissue to another. ERE expression was particularly high in two MHC-I-deficient tissues (ESCs and testis) and one MHC-I-expressing tissue, mTECs. In mutant mice, we report that the exceptional expression of EREs in mTECs was AIRE-independent. MS analyses identified 103 non-redundant ERE-derived MAPs (ereMAPs) in B-LCLs. These ereMAPs preferentially derived from sense translation of intronic EREs. Notably, detailed analyses of their amino acid composition revealed that ERE-derived MAPs presented homology to viral MAPs. This study shows that ERE expression in somatic tissues is more pervasive and heterogeneous than anticipated. The high and diversified expression of EREs in mTECs and their ability to generate MAPs suggest that EREs may play an important role in the establishment of self-tolerance. The viral-like properties of ERE-derived MAPs suggest that those not expressed in mTECs can be highly immunogenic.
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Project description:Reverse transcription-derived sequences account for at least half of the human genome. Although these retroelements are formidable motors of evolution, they can occasionally cause disease, and accordingly are inactivated during early embryogenesis through epigenetic mechanisms. In the mouse, at least for endogenous retroviruses, important mediators of this process are the tetrapod-specific KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor TRIM28. The present study demonstrates that KRAB/TRIM28-mediated regulation is responsible for controlling a very broad range of human-specific endogenous retroelements (EREs) in human embryonic stem (ES) cells and that it exerts, as a consequence, a marked effect on the transcriptional dynamics of these cells. It further reveals reciprocal dependence between TRIM28 recruitment at specific families of EREs and DNA methylation. It finally points to the importance of persistent TRIM28-mediated control of ERE transcriptional impact beyond their presumed inactivation by DNA methylation. Analyses of epigentic effectors and marks in KAP1 WT and KD human embryonic stem cells
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Project description:Reverse transcription-derived sequences account for at least half of the human genome. Although these retroelements are formidable motors of evolution, they can occasionally cause disease, and accordingly are inactivated during early embryogenesis through epigenetic mechanisms. In the mouse, at least for endogenous retroviruses, important mediators of this process are the tetrapod-specific KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor TRIM28. The present study demonstrates that KRAB/TRIM28-mediated regulation is responsible for controlling a very broad range of human-specific endogenous retroelements (EREs) in human embryonic stem (ES) cells and that it exerts, as a consequence, a marked effect on the transcriptional dynamics of these cells. It further reveals reciprocal dependence between TRIM28 recruitment at specific families of EREs and DNA methylation. It finally points to the importance of persistent TRIM28-mediated control of ERE transcriptional impact beyond their presumed inactivation by DNA methylation.
2014-05-29 | GSE57989 | GEO
Project description:The hypomethylating agent 5-azacytidine (AZA) is the first-line induction therapy for AML patients unsuitable for intensive chemotherapy. The anti-tumor effect of AZA results in part from T-cell cytotoxic responses against MHC-I-associated peptides (MAPs) deriving from hypermethylated genomic regions such as cancer-testis antigens (CTAs), or endogenous retroelements (EREs). However, clear evidence supporting higher ERE MAPs presentation after AZA treatment in AML is lacking. Interestingly, we find that AZA-mediated DNMT2 inhibition leads to autophagy induction, which is responsible for mitigating ERE MAPs generation. To validate our findings, we examined the immunopeptidome of THP-1 cells treated with AZA combined with autophagy inhibitor, Spautin-1 or decitabine (DAC, non-DNMT2 inhibiting HMA) through a proteogenomic approach.
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Project description:The hypomethylating agent 5-azacytidine (AZA) is the first-line induction therapy for AML patients unsuitable for intensive chemotherapy. The anti-tumor effect of AZA results in part from T-cell cytotoxic responses against MHC-I-associated peptides (MAPs) deriving from hypermethylated genomic regions such as cancer-testis antigens (CTAs), or endogenous retroelements (EREs). However, clear evidence supporting higher ERE MAPs presentation after AZA treatment in AML is lacking. Therefore, we examined the immunopeptidome of four AML cell lines treated with AZA through a proteogenomic approach to validate this hypothesis.
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Project description:CUX1 is a homeodomain-containing transcription factor that is conserved, ubiquitous, and essential in vertebrates and invertebrates. CUX1 is mutated or deleted in high-risk myeloid neoplasms and solid tumors, resulting in haploinsufficiency and tumor growth. Here we provide the first analysis of endogenous, whole genome, CUX1 DNA binding. We demonstrate that CUX1 binds with transcriptional activators and cohesin at distal enhancers across three different human cell types. Haploinsufficiency of CUX1 altered the expression of a large number of genes, including cell cycle regulators, with concomitant increased cellular proliferation. Surprisingly, CUX1 occupancy decreased genome-wide in the haploinsufficient state, and binding site affinity did not correlate with differential gene expression. Instead, differentially expressed genes had multiple, low-affinity CUX1 binding sites, consistent with an analog model for CUX1 gene regulation. A machine-learning algorithm determined that chromatin accessibility, enhancer activity, and distance to the transcription start site are features of functional CUX1 DNA binding. Moreover, CUX1 is enriched at sites of DNA looping, and these loops connect CUX1 to the promoters of target genes. We propose that CUX1 is an analog transcription factor that regulates target genes through higher order genome architecture.
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