Metabolically inducing defects in DNA repair sensitizes -wild-type cancer cells to replication stress.

Metabolic reprogramming from oxidative respiration to glycolysis is generally considered to be advantageous for tumor initiation and progression. However, we found that breast cancer cells forced to perform glycolysis acquired a vulnerability to PARP inhibitors. Small-molecule inhibition of mitochondrial respiration-using glyceollin I, metformin, or phenformin-induced overproduction of the oncometabolite lactate, which acidified the extracellular milieu and repressed the expression of homologous recombination (HR)-associated DNA repair genes.

Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers.

The senescent microenvironment and aged cells per se contribute to tissue remodeling, chronic inflammation, and age-associated dysfunction. However, the metabolic and epigenomic bases of the senescence-associated secretory phenotype (SASP) remain largely unknown. Here, we show that ATP-citrate lyase (ACLY), a key enzyme in acetyl-coenzyme A (CoA) synthesis, is essential for the pro-inflammatory SASP, independent of persistent growth arrest in senescent cells.

YAP/BRD4-controlled ROR1 promotes tumor-initiating cells and hyperproliferation in pancreatic cancer.

Tumor-initiating cells are major drivers of chemoresistance and attractive targets for cancer therapy, however, their identity in human pancreatic ductal adenocarcinoma (PDAC) and the key molecules underlying their traits remain poorly understood. Here, we show that a cellular subpopulation with partial epithelial-mesenchymal transition (EMT)-like signature marked by high expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) is the origin of heterogeneous tumor cells in PDAC. We demonstrate that ROR1 depletion suppresses tumor growth, recurrence after chemotherapy, and metastasis.

LSD1 defines the fiber type-selective responsiveness to environmental stress in skeletal muscle.

Skeletal muscle exhibits remarkable plasticity in response to environmental cues, with stress-dependent effects on the fast-twitch and slow-twitch fibers. Although stress-induced gene expression underlies environmental adaptation, it is unclear how transcriptional and epigenetic factors regulate fiber type-specific responses in the muscle. Here, we show that flavin-dependent lysine-specific demethylase-1 (LSD1) differentially controls responses to glucocorticoid and exercise in postnatal skeletal muscle.

Lactic acidosis induces metabolic and phenotypic reprogramming in cholangiocarcinoma cells via the upregulation of thrombospondin-1.

The high glycolytic activity of cancer cells leads to lactic acidosis (LA) in the tumor microenvironment. LA is not merely a consequence of metabolic activities but also has functional roles in metabolic reprogramming and cancer progression. Cholangiocarcinoma (CCA) cells exhibit a high dependency on glycolysis for survival and growth, but the specific effects of LA on cellular characteristics remain unknown.

Chromatin Immunoprecipitation Sequencing (ChIP-seq) for Detecting Histone Modifications and Modifiers.

Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) is the most widely used method for analyzing genome-wide DNA-protein interactions. Because there is considerable variation in the modes and strengths of DNA-protein interactions, chromatin immunoprecipitation (ChIP) protocols have been diversified and optimized for different needs. Here, we describe protocols for detecting histone modifications and modifiers using various crosslinking and immunoprecipitation conditions.

Mitochondrial stress induces AREG expression and epigenomic remodeling through c-JUN and YAP-mediated enhancer activation.

Nucleus-mitochondria crosstalk is essential for cellular and organismal homeostasis. Although anterograde (nucleus-to-mitochondria) pathways have been well characterized, retrograde (mitochondria-to-nucleus) pathways remain to be clarified. Here, we found that mitochondrial dysfunction triggered a retrograde signaling via unique transcriptional and chromatin factors in hepatic cells.

Lactic acidosis promotes aggressive features of cholangiocarcinoma cells via upregulating ALDH1A3 expression through EGFR axis.

Aims: Lactic acidosis (LA) generated in tumor microenvironment promotes tumor metastasis and drug resistance. This study aimed to demonstrate the impacts and the mechanisms of LA on aldehyde dehydrogenase1A3 (ALDH1A3) in promoting aggressiveness and gemcitabine resistance in cholangiocarcinoma (CCA) cell lines. The clinical relevance and the molecular pathway related to the upregulation of ALDH1A3 in LA cells will be revealed.

Biosynthesis of S-adenosyl-methionine enhances aging-related defects in Drosophila oogenesis.

Tissue aging is a major cause of aging-related disabilities and a shortened life span. Understanding how tissue aging progresses and identifying the factors underlying tissue aging are crucial; however, the mechanism of tissue aging is not fully understood. Here we show that the biosynthesis of S-adenosyl-methionine (SAM), the major cellular donor of methyl group for methylation modifications, potently accelerates the aging-related defects during Drosophila oogenesis.

Advanced oxidation protein products contribute to chronic kidney disease-induced muscle atrophy by inducing oxidative stress via CD36/NADPH oxidase pathway.

Background: Sarcopenia with chronic kidney disease (CKD) progression is associated with life prognosis. Oxidative stress has attracted interest as a trigger for causing CKD-related muscular atrophy. Advanced oxidation protein products (AOPPs), a uraemic toxin, are known to increase oxidative stress.

Lysine Demethylase 5A is Required for MYC Driven Transcription in Multiple Myeloma.

Lysine demethylase 5A (KDM5A) is a negative regulator of histone H3K4 trimethylation, a histone mark associated with activate gene transcription. We identify that KDM5A interacts with the P-TEFb complex and cooperates with MYC to control MYC targeted genes in multiple myeloma (MM) cells. We develop a cell-permeable and selective KDM5 inhibitor, JQKD82, that increases histone H3K4me3 but paradoxically inhibits downstream MYC-driven transcriptional output and .

Sexual fate of murine external genitalia development: Conserved transcriptional competency for male-biased genes in both sexes.

Testicular androgen is a master endocrine factor in the establishment of external genital sex differences. The degree of androgenic exposure during development is well known to determine the fate of external genitalia on a spectrum of female- to male-specific phenotypes. However, the mechanisms of androgenic regulation underlying sex differentiation are poorly defined.

LSD1 defines erythroleukemia metabolism by controlling the lineage-specific transcription factors GATA1 and C/EBPα.

Acute myeloid leukemia (AML) is a heterogenous malignancy characterized by distinct lineage subtypes and various genetic/epigenetic alterations. As with other neoplasms, AML cells have well-known aerobic glycolysis, but metabolic variations depending on cellular lineages also exist. Lysine-specific demethylase-1 (LSD1) has been reported to be crucial for human leukemogenesis, which is currently one of the emerging therapeutic targets.

Murine neonatal ketogenesis preserves mitochondrial energetics by preventing protein hyperacetylation.

Ketone bodies are generated in the liver and allow for the maintenance of systemic caloric and energy homeostasis during fasting and caloric restriction. It has previously been demonstrated that neonatal ketogenesis is activated independently of starvation. However, the role of ketogenesis during the perinatal period remains unclear.

High glucose-ROS conditions enhance the progression in cholangiocarcinoma via upregulation of MAN2A2 and CHD8.

Diabetes is a major risk factor in the development and progression of several cancers including cholangiocarcinoma (CCA). However, the molecular mechanism by which hyperglycemia potentiates progression of CCA is not clearly understood. Here, we showed that a high glucose condition significantly increased reactive oxygen species (ROS) production and promoted aggressive phenotypes of CCA cells, including proliferation and migration activities.

Splicing- and demethylase-independent functions of LSD1 in zebrafish primitive hematopoiesis.

LSD1/KDM1A is a widely conserved lysine-specific demethylase that removes methyl groups from methylated proteins, mainly histone H3. We previously isolated the zebrafish LSD1 gene and demonstrated that it is required for primitive hematopoiesis. Recently, a neuron-specific splicing variant of LSD1 was found in mammals and its specific functions and substrate specificities were reported.

Successful generation of epigenetic disease model mice by targeted demethylation of the epigenome.

Background: Epigenetic modifications, including DNA methylation, play an important role in gene silencing and genome stability. Consequently, epigenetic dysregulation can cause several diseases, such as cancer, obesity, diabetes, autism, and imprinting disorders.

Results: We validate three methods for the generation of epigenome-edited mice using the dCas9-SunTag and single-chain variable fragment-TET1 catalytic domain.

Postweaning Iron Deficiency in Male Rats Leads to Long-Term Hyperactivity and Decreased Reelin Gene Expression in the Nucleus Accumbens.

Background: Epidemiological research indicates that iron deficiency (ID) in infancy correlates with long-term cognitive impairment and behavioral disturbances, despite therapy. However, the mechanisms underlying these effects are unknown.

Objective: We investigated how ID affected postweaning behavior and monoamine concentration in rat brains to determine whether ID during the juvenile period affected gene expression and synapse formation in the prefrontal cortex (PFC) and nucleus accumbens (NAcc).

Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2.

Tolerance to severe tumor microenvironments, including hypoxia and nutrient starvation, is a common feature of aggressive cancer cells and can be targeted. However, metabolic alterations that support cancer cells upon nutrient starvation are not well understood. Here, by comprehensive metabolome analyses, we show that glutamine deprivation leads to phosphoethanolamine (PEtn) accumulation in cancer cells via the downregulation of PEtn cytidylyltransferase (PCYT2), a rate-limiting enzyme of phosphatidylethanolamine biosynthesis.

Distinct Roles of the NAD-Sirt1 and FAD-LSD1 Pathways in Metabolic Response and Tissue Development.

Various nutritional signals are transduced by two epigenetic pathways: NAD-dependent sirtuin Sirt1 (NAD-Sirt1) deacetylase and flavin adenine dinucleotide-dependent lysine-specific demethylase 1 (FAD-LSD1). These pathways are controlled by dietary vitamins and nutrient-responsive hormones such as glucocorticoids and insulin, resulting in endocrine-metabolism-epigenome cooperation in adipocyte and skeletal muscle development.

Mesenchymal actomyosin contractility is required for androgen-driven urethral masculinization in mice.

The morphogenesis of mammalian embryonic external genitalia (eExG) shows dynamic differences between males and females. In genotypic males, eExG are masculinized in response to androgen signaling. Disruption of this process can give rise to multiple male reproductive organ defects.

Lysine-specific demethylase-2 is distinctively involved in brown and beige adipogenic differentiation.

Transcriptional and epigenetic regulation is fundamentally involved in initiating and maintaining progression of cellular differentiation. The 2 types of thermogenic adipocytes, brown and beige, are thought to be of different origins but share functionally similar phenotypes. Here, we report that lysine-specific demethylase 2 (LSD2) regulates the expression of genes associated with lineage identity during the differentiation of brown and beige adipogenic progenitors in mice.

LSD1 mediates metabolic reprogramming by glucocorticoids during myogenic differentiation.

The metabolic properties of cells are formed under the influence of environmental factors such as nutrients and hormones. Although such a metabolic program is likely initiated through epigenetic mechanisms, the direct links between metabolic cues and activities of chromatin modifiers remain largely unknown. In this study, we show that lysine-specific demethylase-1 (LSD1) controls the metabolic program in myogenic differentiation, under the action of catabolic hormone, glucocorticoids.

Maternal undernutrition during early pregnancy inhibits postnatal growth of the tibia in the female offspring of rats by alteration of chondrogenesis.

Epidemiological research has suggested that birth weights are correlated with adult leg lengths. However, the relationship between prenatal undernutrition (UN) and postnatal leg growth remains controversial. We investigated the effects of UN during early pregnancy on postnatal hindlimb growth and determined whether early embryonic malnutrition affects the functions of postnatal chondrocytes in rats.