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Nature Communications Mar 2023Bromodomain-containing protein 9 (BRD9), a component of non-canonical BAF chromatin remodeling complex, has been identified as a critical therapeutic target in...
Bromodomain-containing protein 9 (BRD9), a component of non-canonical BAF chromatin remodeling complex, has been identified as a critical therapeutic target in hematological diseases. Despite the hematopoietic origin of osteoclasts, the role of BRD9 in osteoclastogenesis and bone diseases remains unresolved. Here, we show Brd9 deficiency in myeloid lineage enhances osteoclast lineage commitment and bone resorption through downregulating interferon-beta (IFN-β) signaling with released constraint on osteoclastogenesis. Notably, we show that BRD9 interacts with transcription factor FOXP1 activating Stat1 transcription and IFN-β signaling thereafter. Besides, function specificity of BRD9 distinguished from BRD4 during osteoclastogenesis has been evaluated. Leveraging advantages of pharmacological modulation of BRD9 and flexible injectable silk fibroin hydrogel, we design a local deliver system for effectively mitigating zoledronate related osteonecrosis of the jaw and alleviating acute bone loss in lipopolysaccharide-induced localized aggressive periodontitis. Overall, these results demonstrate the function of BRD9 in osteoclastogenesis and its therapeutic potential for bone diseases.
Topics: Humans; Bone Resorption; Cell Cycle Proteins; Chromatin Assembly and Disassembly; Feedback; Forkhead Transcription Factors; Nuclear Proteins; Osteoclasts; Osteogenesis; Repressor Proteins; Transcription Factors
PubMed: 36918560
DOI: 10.1038/s41467-023-37116-5 -
Nucleic Acids Research Oct 2022Cellular senescence is a complex multifactorial biological phenomenon that plays essential roles in aging, and aging-related diseases. During this process, the senescent...
Cellular senescence is a complex multifactorial biological phenomenon that plays essential roles in aging, and aging-related diseases. During this process, the senescent cells undergo gene expression altering and chromatin structure remodeling. However, studies on the epigenetic landscape of senescence using integrated multi-omics approaches are limited. In this research, we performed ATAC-seq, RNA-seq and ChIP-seq on different senescent types to reveal the landscape of senescence and identify the prime regulatory elements. We also obtained 34 key genes and deduced that NAT1, PBX1 and RRM2, which interacted with each other, could be the potential markers of aging and aging-related diseases. In summary, our work provides the landscape to study accessibility dynamics and transcriptional regulations in cellular senescence. The application of this technique in different types of senescence allows us to identify the regulatory elements responsible for the substantial regulation of transcription, providing the insights into molecular mechanisms of senescence.
Topics: Cellular Senescence; Gene Expression Regulation; Chromatin Assembly and Disassembly; Regulatory Sequences, Nucleic Acid; Chromatin
PubMed: 36243980
DOI: 10.1093/nar/gkac885 -
Molecular Cell Apr 2023Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may...
Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.
Topics: Chromatin Assembly and Disassembly; Chromosomal Proteins, Non-Histone; Transcription Factors; Chromatin; Transcriptional Activation
PubMed: 36944333
DOI: 10.1016/j.molcel.2023.02.026 -
Theranostics 2023SUMOylation regulates a plethora of biological processes, and its inhibitors are currently under investigation in clinical trials as anticancer agents. Thus,...
SUMOylation regulates a plethora of biological processes, and its inhibitors are currently under investigation in clinical trials as anticancer agents. Thus, identifying new targets with site-specific SUMOylation and defining their biological functions will not only provide new mechanistic insights into the SUMOylation signaling but also open an avenue for developing new strategy for cancer therapy. MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin-remodeling enzyme with an emerging role in the DNA damage response (DDR), but its regulatory mechanism remains enigmatic. and SUMOylation assays were used to determine the SUMOylation levels of MORC2. Overexpression and knockdown of SUMO-associated enzymes were used to detect their effects on MORC2 SUMOylation. The effect of dynamic MORC2 SUMOylation on the sensitivity of breast cancer cells to chemotherapeutic drugs was examined through and functional assays. Immunoprecipitation, GST pull-down, MNase, and chromatin segregation assays were used to explore the underlying mechanisms. Here, we report that MORC2 is modified by small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 at lysine 767 (K767) in a SUMO-interacting motif dependent manner. MORC2 SUMOylation is induced by SUMO E3 ligase tripartite motif containing 28 (TRIM28) and reversed by deSUMOylase sentrin-specific protease 1 (SENP1). Intriguingly, SUMOylation of MORC2 is decreased at the early stage of DNA damage induced by chemotherapeutic drugs that attenuate the interaction of MORC2 with TRIM28. MORC2 deSUMOylation induces transient chromatin relaxation to enable efficient DNA repair. At the relatively late stage of DNA damage, MORC2 SUMOylation is restored, and SUMOylated MORC2 interacts with protein kinase CSK21 (casein kinase II subunit alpha), which in turn phosphorylates DNA-PKcs (DNA-dependent protein kinase catalytic subunit), thus promoting DNA repair. Notably, expression of a SUMOylation-deficient mutant MORC2 or administration of SUMO inhibitor enhances the sensitivity of breast cancer cells to DNA-damaging chemotherapeutic drugs. Collectively, these findings uncover a novel regulatory mechanism of MORC2 by SUMOylation and reveal the intricate dynamics of MORC2 SUMOylation important for proper DDR. We also propose a promising strategy to sensitize MORC2-driven breast tumors to chemotherapeutic drugs by inhibition of the SUMO pathway.
Topics: Humans; Female; Sumoylation; Chromatin Assembly and Disassembly; Drug Resistance, Neoplasm; Breast Neoplasms; DNA Repair; DNA Damage; Chromatin; Transcription Factors
PubMed: 36793866
DOI: 10.7150/thno.79688 -
Cell Reports Jun 2023Upon antigen-specific T cell receptor (TCR) engagement, human CD4 T cells proliferate and differentiate, a process associated with rapid transcriptional changes and...
Upon antigen-specific T cell receptor (TCR) engagement, human CD4 T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming. Here, we show that the generation of extramitochondrial pyruvate is an important step for acetyl-CoA production and subsequent H3K27ac-mediated remodeling of histone acetylation. Histone modification, transcriptomic, and carbon tracing analyses of pyruvate dehydrogenase (PDH)-deficient T cells show PDH-dependent acetyl-CoA generation as a rate-limiting step during T activation. Furthermore, T cell activation results in the nuclear translocation of PDH and its association with both the p300 acetyltransferase and histone H3K27ac. These data support the tight integration of metabolic and histone-modifying enzymes, allowing metabolic reprogramming to fuel CD4 T cell activation. Targeting this pathway may provide a therapeutic approach to specifically regulate antigen-driven T cell activation.
Topics: Humans; Histones; Acetyl Coenzyme A; Chromatin Assembly and Disassembly; CD4-Positive T-Lymphocytes
PubMed: 37267106
DOI: 10.1016/j.celrep.2023.112583 -
Science (New York, N.Y.) Sep 2023The cerebellum contains most of the neurons in the human brain and exhibits distinctive modes of development and aging. In this work, by developing our single-cell...
The cerebellum contains most of the neurons in the human brain and exhibits distinctive modes of development and aging. In this work, by developing our single-cell three-dimensional (3D) genome assay-diploid chromosome conformation capture, or Dip-C-into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we resolved the first 3D genome structures of single cerebellar cells, created life-spanning 3D genome atlases for both humans and mice, and jointly measured transcriptome and chromatin accessibility during development. We found that although the transcriptome and chromatin accessibility of cerebellar granule neurons mature in early postnatal life, 3D genome architecture gradually remodels throughout life, establishing ultra-long-range intrachromosomal contacts and specific interchromosomal contacts that are rarely seen in neurons. These results reveal unexpected evolutionarily conserved molecular processes that underlie distinctive features of neural development and aging across the mammalian life span.
Topics: Animals; Humans; Mice; Cerebellum; Neurons; Genome; Imaging, Three-Dimensional; Single-Cell Analysis; Chromatin Assembly and Disassembly; Cellular Senescence; Atlases as Topic
PubMed: 37676945
DOI: 10.1126/science.adh3253 -
Genome Medicine Mar 2023The incidence of early-onset colorectal cancer (EOCRC; patients < 50 years old) has been rising rapidly, whereas the EOCRC genetic susceptibility remains incompletely...
BACKGROUND
The incidence of early-onset colorectal cancer (EOCRC; patients < 50 years old) has been rising rapidly, whereas the EOCRC genetic susceptibility remains incompletely investigated. Here, we aimed to systematically identify specific susceptible genetic variants for EOCRC.
METHODS
Two parallel GWASs were conducted in 17,789 CRC cases (including 1490 EOCRC cases) and 19,951 healthy controls. A polygenic risk score (PRS) model was built based on identified EOCRC-specific susceptibility variants by using the UK Biobank cohort. We also interpreted the potential biological mechanisms of the prioritized risk variant.
RESULTS
We identified 49 independent susceptibility loci that were significantly associated with the susceptibility to EOCRC and the diagnosed age of CRC (both P < 5.0×10), replicating 3 previous CRC GWAS loci. There are 88 assigned susceptibility genes involved in chromatin assembly and DNA replication pathways, mainly associating with precancerous polyps. Additionally, we assessed the genetic effect of the identified variants by developing a PRS model. Compared to the individuals in the low genetic risk group, the individuals in the high genetic risk group have increased EOCRC risk, and these results were replicated in the UKB cohort with a 1.63-fold risk (95% CI: 1.32-2.02, P = 7.67×10). The addition of the identified EOCRC risk loci significantly increased the prediction accuracy of the PRS model, compared to the PRS model derived from the previous GWAS-identified loci. Mechanistically, we also elucidated that rs12794623 may contribute to the early stage of CRC carcinogenesis via allele-specific regulating the expression of POLA2.
CONCLUSIONS
These findings will broaden the understanding of the etiology of EOCRC and may facilitate the early screening and individualized prevention.
Topics: Humans; Middle Aged; Alleles; Carcinogenesis; Risk Factors; Chromatin Assembly and Disassembly; Colorectal Neoplasms
PubMed: 36869385
DOI: 10.1186/s13073-023-01163-w -
Immunity Jun 2023CD8 T cell exhaustion (Tex) limits disease control during chronic viral infections and cancer. Here, we investigated the epigenetic factors mediating major...
CD8 T cell exhaustion (Tex) limits disease control during chronic viral infections and cancer. Here, we investigated the epigenetic factors mediating major chromatin-remodeling events in Tex-cell development. A protein-domain-focused in vivo CRISPR screen identified distinct functions for two versions of the SWI/SNF chromatin-remodeling complex in Tex-cell differentiation. Depletion of the canonical SWI/SNF form, BAF, impaired initial CD8 T cell responses in acute and chronic infection. In contrast, disruption of PBAF enhanced Tex-cell proliferation and survival. Mechanistically, PBAF regulated the epigenetic and transcriptional transition from TCF-1 progenitor Tex cells to more differentiated TCF-1 Tex subsets. Whereas PBAF acted to preserve Tex progenitor biology, BAF was required to generate effector-like Tex cells, suggesting that the balance of these factors coordinates Tex-cell subset differentiation. Targeting PBAF improved tumor control both alone and in combination with anti-PD-L1 immunotherapy. Thus, PBAF may present a therapeutic target in cancer immunotherapy.
Topics: CD8-Positive T-Lymphocytes; Chromatin Assembly and Disassembly; Chromatin; Cell Differentiation; Epigenesis, Genetic
PubMed: 37315535
DOI: 10.1016/j.immuni.2023.05.008 -
Nature Sep 2019The tumour suppressor TP53 is mutated in the majority of human cancers, and in over 70% of pancreatic ductal adenocarcinoma (PDAC). Wild-type p53 accumulates in response...
The tumour suppressor TP53 is mutated in the majority of human cancers, and in over 70% of pancreatic ductal adenocarcinoma (PDAC). Wild-type p53 accumulates in response to cellular stress, and regulates gene expression to alter cell fate and prevent tumour development. Wild-type p53 is also known to modulate cellular metabolic pathways, although p53-dependent metabolic alterations that constrain cancer progression remain poorly understood. Here we find that p53 remodels cancer-cell metabolism to enforce changes in chromatin and gene expression that favour a premalignant cell fate. Restoring p53 function in cancer cells derived from KRAS-mutant mouse models of PDAC leads to the accumulation of α-ketoglutarate (αKG, also known as 2-oxoglutarate), a metabolite that also serves as an obligate substrate for a subset of chromatin-modifying enzymes. p53 induces transcriptional programs that are characteristic of premalignant differentiation, and this effect can be partially recapitulated by the addition of cell-permeable αKG. Increased levels of the αKG-dependent chromatin modification 5-hydroxymethylcytosine (5hmC) accompany the tumour-cell differentiation that is triggered by p53, whereas decreased 5hmC characterizes the transition from premalignant to de-differentiated malignant lesions that is associated with mutations in Trp53. Enforcing the accumulation of αKG in p53-deficient PDAC cells through the inhibition of oxoglutarate dehydrogenase-an enzyme of the tricarboxylic acid cycle-specifically results in increased 5hmC, tumour-cell differentiation and decreased tumour-cell fitness. Conversely, increasing the intracellular levels of succinate (a competitive inhibitor of αKG-dependent dioxygenases) blunts p53-driven tumour suppression. These data suggest that αKG is an effector of p53-mediated tumour suppression, and that the accumulation of αKG in p53-deficient tumours can drive tumour-cell differentiation and antagonize malignant progression.
Topics: Animals; Carcinoma, Pancreatic Ductal; Cell Differentiation; Cell Line, Tumor; Chromatin Assembly and Disassembly; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Ketoglutaric Acids; Mice; Pancreatic Neoplasms; Protein Binding; Succinic Acid; Transcriptional Activation; Tumor Suppressor Protein p53
PubMed: 31534224
DOI: 10.1038/s41586-019-1577-5 -
Annual Review of Biophysics May 2021As primary carriers of epigenetic information and gatekeepers of genomic DNA, nucleosomes are essential for proper growth and development of all eukaryotic cells.... (Review)
Review
As primary carriers of epigenetic information and gatekeepers of genomic DNA, nucleosomes are essential for proper growth and development of all eukaryotic cells. Although they are intrinsically dynamic, nucleosomes are actively reorganized by ATP-dependent chromatin remodelers. Chromatin remodelers contain helicase-like ATPase motor domains that can translocate along DNA, and a long-standing question in the field is how this activity is used to reposition or slide nucleosomes. In addition to ratcheting along DNA like their helicase ancestors, remodeler ATPases appear to dictate specific alternating geometries of the DNA duplex, providing an unexpected means for moving DNA past the histone core. Emerging evidence supports twist-based mechanisms for ATP-driven repositioning of nucleosomes along DNA. In this review, we discuss core experimental findings and ideas that have shaped the view of how nucleosome sliding may be achieved.
Topics: Adenosine Triphosphatases; Biophysical Phenomena; Chromatin Assembly and Disassembly; DNA-Binding Proteins; Nucleosomes
PubMed: 33395550
DOI: 10.1146/annurev-biophys-082520-080201