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"Lee, Ji‐Eun"
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Natural compounds as lactate dehydrogenase inhibitors: potential therapeutics for lactate dehydrogenase inhibitors-related diseases
Lactate dehydrogenase (LDH) is a crucial enzyme involved in energy metabolism and present in various cells throughout the body. Its diverse physiological functions encompass glycolysis, and its abnormal activity is associated with numerous diseases. Targeting LDH has emerged as a vital approach in drug discovery, leading to the identification of LDH inhibitors among natural compounds, such as polyphenols, alkaloids, and terpenoids. These compounds demonstrate therapeutic potential against LDH-related diseases, including anti-cancer effects. However, challenges concerning limited bioavailability, poor solubility, and potential toxicity must be addressed. Combining natural compounds with LDH inhibitors has led to promising outcomes in preclinical studies. This review highlights the promise of natural compounds as LDH inhibitors for treating cancer, cardiovascular, and neurodegenerative diseases.
Journal Article
Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis
Two studies demonstrate that the methyltransferase KMT2D, which is recurrently mutated in several types of human B cell lymphoma, suppresses tumorigenesis by altering the epigenetic landscape of B cells;
Kmt2d
deletion in mice perturbs normal B cell development.
Mutations in the gene encoding the KMT2D (or MLL2) methyltransferase are highly recurrent and occur early during tumorigenesis in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the functional consequences of these mutations and their role in lymphomagenesis are unknown. Here we show that FL- and DLBCL-associated
KMT2D
mutations impair KMT2D enzymatic activity, leading to diminished global H3K4 methylation in germinal-center (GC) B cells and DLBCL cells. Conditional deletion of
Kmt2d
early during B cell development, but not after initiation of the GC reaction, results in an increase in GC B cells and enhances B cell proliferation in mice. Moreover, genetic ablation of
Kmt2d
in mice overexpressing Bcl2 increases the incidence of GC-derived lymphomas resembling human tumors. These findings suggest that
KMT2D
acts as a tumor suppressor gene whose early loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of KMT2D-deficient cells may thus represent a rational therapeutic approach for targeting early tumorigenic events.
Journal Article
Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation
Histone acetyltransferases (HATs) GCN5 and PCAF (GCN5/PCAF) and CBP and p300 (CBP/p300) are transcription co‐activators. However, how these two distinct families of HATs regulate gene activation remains unclear. Here, we show deletion of GCN5/PCAF in cells specifically and dramatically reduces acetylation on histone H3K9 (H3K9ac) while deletion of CBP/p300 specifically and dramatically reduces acetylations on H3K18 and H3K27 (H3K18/27ac). A ligand for nuclear receptor (NR) PPARδ induces sequential enrichment of H3K18/27ac, RNA polymerase II (Pol II) and H3K9ac on PPARδ target gene
Angptl4
promoter, which correlates with a robust
Angptl4
expression. Inhibiting transcription elongation blocks ligand‐induced H3K9ac, but not H3K18/27ac, on the
Angptl4
promoter. Finally, we show GCN5/PCAF and GCN5/PCAF‐mediated H3K9ac correlate with, but are surprisingly dispensable for, NR target gene activation. In contrast, CBP/p300 and their HAT activities are essential for ligand‐induced Pol II recruitment on, and activation of, NR target genes. These results highlight the substrate and site specificities of HATs in cells, demonstrate the distinct roles of GCN5/PCAF‐ and CBP/p300‐mediated histone acetylations in gene activation, and suggest an important role of CBP/p300‐mediated H3K18/27ac in NR‐dependent transcription.
In general, histone acetylation correlates with gene activation; however, it is not clear if it is a cause or consequence of increased transcription. Here, the related histone acetyltransferases CBP and p300, which acetylate H3K18 and H3K27, are shown to be required for the induction of PPARδ target genes, while GCN5/PCAF‐mediated H3K9 acetylation is dispensable.
Journal Article
Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesis
The epigenomic reader Brd4 is an important drug target for cancers. However, its role in cell differentiation and animal development remains largely unclear. Using two conditional knockout mouse strains and derived cells, we demonstrate that Brd4 controls cell identity gene induction and is essential for adipogenesis and myogenesis. Brd4 co-localizes with lineage-determining transcription factors (LDTFs) on active enhancers during differentiation. LDTFs coordinate with H3K4 mono-methyltransferases MLL3/MLL4 (KMT2C/KMT2D) and H3K27 acetyltransferases CBP/p300 to recruit Brd4 to enhancers activated during differentiation.
Brd4
deletion prevents the enrichment of Mediator and RNA polymerase II transcription machinery, but not that of LDTFs, MLL3/MLL4-mediated H3K4me1, and CBP/p300-mediated H3K27ac, on enhancers. Consequently,
Brd4
deletion prevents enhancer RNA production, cell identity gene induction and cell differentiation. Interestingly, Brd4 is dispensable for maintaining cell identity genes in differentiated cells. These findings identify Brd4 as an enhancer epigenomic reader that links active enhancers with cell identity gene induction in differentiation.
Despite being an important cancer drug target, the role of epigenetic reader Brd4 in cell differentiation and development remains unclear. Here, the authors provide evidence that Brd4 plays an important role in adipogenesis and myogenesis by binding to active enhancers to regulate gene expression.
Journal Article
Gut microbiome diversity and function during hibernation and spring emergence in an aquatic frog
The gut microbiota maintains a deeply symbiotic relationship with host physiology, intricately engaging with both internal (endogenous) and external (exogenous) factors. Anurans, especially those in temperate regions, face the dual challenges of significant external influences like hibernation and complex internal variances tied to different life histories. In our research, we sought to determine whether different life stages (juvenile versus adult) of the Japanese wrinkled frog ( Glandirana rugosa ) lead to distinct shifts in gut bacterial communities during winter (hibernation) and its subsequent transition to spring. As hypothesized, we observed a more pronounced variability in the gut bacterial diversity and abundance in juvenile frogs compared to their adult counterparts. This suggests that the gut environment may be more resilient or stable in adult frogs during their hibernation period. However, this pronounced difference was confined to the winter season; by spring, the diversity and abundance of gut bacteria in both juvenile and adult frogs aligned closely. Specifically, the variance in gut bacterial diversity and composition between winter and spring appears to mirror the frogs’ ecological adaptations. During the hibernation period, a dominance of Proteobacteria suggests an emphasis on supporting intracellular transport and maintaining homeostasis, as opposed to active metabolism in the frogs. Conversely, come spring, an uptick in bacterial diversity coupled with a dominance of Firmicutes and Bacteroidetes points to an upsurge in metabolic activity post-hibernation, favoring enhanced nutrient assimilation and energy metabolism. Our findings highlight that the relationship between the gut microbiome and its host is dynamic and bidirectional. However, the extent to which changes in gut bacterial diversity and composition contribute to enhancing hibernation physiology in frogs remains an open question, warranting further investigation.
Journal Article
A Preference-Driven Smart Home Service for the Elderly’s Biophilic Experience
Smart home services (SHS) should support the positive experiences of the elderly in homes with a focus on getting closer to nature. The study identified the services preferred by the elderly through a survey on the biophilic experience-based SHS, and to discuss the configuration of the sensors and devices required to provide the service. We reorganized the biophilic experience-based SHS and related sensors and devices, focusing on our previous study, and developed a survey instrument. A preference survey was conducted on 250 adults aged 20 and older, and the SPSS program was used for a factor analysis and independent two-sample T-test. We derived six factors for biophilic experience-based SHS. Compared to other age groups, the elderly preferred services that were mainly attributed to factors such as ‘Immersion and interaction with nature’ (A), ‘Management of well-being and indoor environmental quality (IEQ)’ (B), and ‘Natural process and systems’ (F). We proposed 15 prioritized services, along with their sensor and device configurations, in consideration of service provision regarding the elderly’s preferences and universality. This study contributes to new developments in elderly-friendly smart home research by converting bio-friendly ideas into the market in the development of medical services and SHS for the elderly.
Journal Article
Replication fork stability confers chemoresistance in BRCA-deficient cells
Cells deficient in the
Brca1
and
Brca2
genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects
Brca1/2
-deficient cells from DNA damage and rescues the lethality of
Brca2
-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition of PARP inhibitors and cisplatin resistance is associated with replication fork protection in
Brca2
-deficient tumour cells that do not develop
Brca2
reversion mutations. Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of replication fork protection, highlighting the complexities by which tumour cells evade chemotherapeutic interventions and acquire drug resistance.
Protection of nascent DNA from degradation provides a mechanism that can promote synthetic viability and drug resistance in
Brca
-deficient cells without restoring homologous recombination at double-strand breaks.
Chemoresistance in BRCA cancers
The breast cancer susceptibility genes
BRCA1
and
BRCA2
function to protect the genome from DNA damage. For this reason, DNA-damaging agents are used clinically to treat
BRCA
-deficient cancers. However, these treatments may have a short window of effectiveness; many cancers develop resistance. André Nussenzweig and colleagues show that cells become drug resistant due to loss of the PTIP protein. In its absence, forks that stall during DNA replication are protected from degradation, and this allows the cells to survive. This work highlights a previously unknown mechanism by which resistance to cancer therapy can arise.
Journal Article
Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition
Transcriptional enhancers control cell-type–specific gene expression. Primed enhancers are marked by histone H3 lysine 4 (H3K4) mono/di-methylation (H3K4me1/2). Active enhancers are further marked by H3K27 acetylation (H3K27ac). Mixed-lineage leukemia 4 (MLL4/KMT2D) is a major enhancer H3K4me1/2 methyltransferase with functional redundancy with MLL3 (KMT2C). However, its role in cell fate maintenance and transition is poorly understood. Here, we show in mouse embryonic stem cells (ESCs) that MLL4 associates with, but is surprisingly dispensable for the maintenance of, active enhancers of cell-identity genes. As a result, MLL4 is dispensable for cell-identity gene expression and self-renewal in ESCs. In contrast, MLL4 is required for enhancer-binding of H3K27 acetyltransferase p300, enhancer activation, and induction of cell-identity genes during ESC differentiation. MLL4 protein, rather than MLL4-mediated H3K4 methylation, controls p300 recruitment to enhancers. We also show that, in somatic cells, MLL4 is dispensable for maintaining cell identity but essential for reprogramming into induced pluripotent stem cells. These results indicate that, although enhancer priming by MLL4 is dispensable for cell-identity maintenance, it controls cell fate transition by orchestrating p300-mediated enhancer activation.
Journal Article