Publications by authors named "Kai Ge"

100 Publications

Molecular basis for histone H3 "K4me3-K9me3/2" methylation pattern readout by Spindlin1.

J Biol Chem 2020 Dec 29;295(49):16877-16887. Epub 2020 Sep 29.

MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China

Histone recognition by "reader" modules serves as a fundamental mechanism in epigenetic regulation. Previous studies have shown that Spindlin1 is a reader of histone H3K4me3 as well as "K4me3-R8me2a" and promotes transcription of rDNA or Wnt/TCF4 target genes. Here we show that Spindlin1 also acts as a potent reader of histone H3 "K4me3-K9me3/2" bivalent methylation pattern. Calorimetric titration revealed a binding affinity of 16 nm between Spindlin1 and H3 "K4me3-K9me3" peptide, which is one to three orders of magnitude stronger than most other histone readout events at peptide level. Structural studies revealed concurrent recognition of H3K4me3 and H3K9me3/2 by aromatic pockets 2 and 1 of Spindlin1, respectively. Epigenomic profiling studies showed that Spindlin1 colocalizes with both H3K4me3 and H3K9me3 peaks in a subset of genes enriched in biological processes of transcription and its regulation. Moreover, the distribution of Spindlin1 peaks is primarily associated with H3K4me3 but not H3K9me3, which suggests that Spindlin1 is a downstream effector of H3K4me3 generated in heterochromatic regions. Collectively, our work calls attention to an intriguing function of Spindlin1 as a potent H3 "K4me3-K9me3/2" bivalent mark reader, thereby balancing gene expression and silencing in H3K9me3/2-enriched regions.
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http://dx.doi.org/10.1074/jbc.RA120.013649DOI Listing
December 2020

Establishment of an SYBR Green-based real-time PCR assay for porcine circovirus type 4 detection.

J Virol Methods 2020 11 31;285:113963. Epub 2020 Aug 31.

Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control, College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, PR China. Electronic address:

Porcine circovirus 4 (PCV4) is a novel circovirus first discovered in China in April 2019. Here, we established an SYBR Green I-based real-time PCR for quantitative detection of PCV4. A pair of specific primers was designed based on the conserved region of Cap of PCV4. The standard curve of the established real-time PCR. assay showed a good linear relationship. The sensitivity of the established real-time PCR was 100 times greater than that of conventional PCR, and the detection limit of the assay was 3 × 10 copies. There was no cross-reactivity with other swine DNA viruses, showing good specificity. The intra-group variation coefficient was 0.37-0.78 %, and the inter-group variation coefficient was 0.57-0.94%, indicating that the assay has good repeatability. Moreover, the analysis of clinical samples showed that the positive detection rate of PCV4 was 10.71% (18/168), while that of conventional PCR was 8.93% (15/168). Interestingly, co-infection with PCV2 or PCV3, or both PCV2 and PCV3, was also detected. In conclusion, the established SYBR Green I-based real-time PCR may be a cost-effective and rapid method for PCV4 clinical diagnosis.
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http://dx.doi.org/10.1016/j.jviromet.2020.113963DOI Listing
November 2020

Lysine Demethylase KDM6A in Differentiation, Development, and Cancer.

Mol Cell Biol 2020 09 28;40(20). Epub 2020 Sep 28.

Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Lysine demethylase 6A (KDM6A), also known as UTX, belongs to the KDM6 family of histone H3 lysine 27 (H3K27) demethylases, which also includes UTY and KDM6B (JMJD3). The KDM6A protein contains six tetratricopeptide repeat (TPR) domains and an enzymatic Jumonji C (JmjC) domain that catalyzes the removal of di- and trimethylation on H3K27. KDM6A physically associates with histone H3 lysine 4 monomethyltransferases MLL3 (KMT2C) and MLL4 (KMT2D). Since its identification as an H3K27 demethylase in 2007, studies have reported KDM6A's critical roles in cell differentiation, development, and cancer. KDM6A is important for differentiation of embryonic stem cells and development of various tissues. Mutations of KDM6A cause Kabuki syndrome. KDM6A is frequently mutated in cancers and functions as a tumor suppressor. KDM6A is redundant with UTY and functions largely independently of its demethylase activity. It regulates gene expression, likely through the associated transcription factors and MLL3/4 on enhancers. However, KDM6A enzymatic activity is required in certain cellular contexts. Functional redundancy between H3K27 demethylase activities of KDM6A and KDM6B has yet to be determined. Further understanding of KDM6A functions and working mechanisms will provide more insights into enhancer regulation and may help generate novel therapeutic approaches to treat KDM6A-related diseases.
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http://dx.doi.org/10.1128/MCB.00341-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523656PMC
September 2020

Loss of Function of the Gene Encoding the Histone Methyltransferase KMT2D Leads to Deregulation of Mitochondrial Respiration.

Cells 2020 07 13;9(7). Epub 2020 Jul 13.

Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo (FG), Italy.

encodes a methyltransferase responsible for histone 3 lysine 4 (H3K4) mono-/di-methylation, an epigenetic mark correlated with active transcription. Here, we tested the hypothesis that pathogenic loss-of-function variants, which causes the Kabuki syndrome type 1, could affect the mitochondrial metabolic profile. By using Seahorse technology, we showed a significant reduction of the mitochondrial oxygen consumption rate as well as a reduction of the glycolytic flux in both knockout MEFs and skin fibroblasts of Kabuki patients harboring heterozygous pathogenic variants. Mass-spectrometry analysis of intermediate metabolites confirmed alterations in the glycolytic and TCA cycle pathways. The observed metabolic phenotype was accompanied by a significant increase in the production of reactive oxygen species. Measurements of the specific activities of the mitochondrial respiratory chain complexes revealed significant inhibition of CI (NADH dehydrogenase) and CIV (cytochrome c oxidase); this result was further supported by a decrease in the protein content of both complexes. Finally, we unveiled an impaired oxidation of glucose and larger reliance on long-chain fatty acids oxidation. Altogether, our findings clearly indicate a rewiring of the mitochondrial metabolic phenotype in the KMT2D-null or loss-of-function context that might contribute to the development of Kabuki disease, and represents metabolic reprogramming as a potential new therapeutic approach.
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http://dx.doi.org/10.3390/cells9071685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407568PMC
July 2020

MLL3/MLL4-Associated PAGR1 Regulates Adipogenesis by Controlling Induction of C/EBPβ and C/EBPδ.

Mol Cell Biol 2020 08 14;40(17). Epub 2020 Aug 14.

Adipocyte Biology and Gene Regulation Section, Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA

Transcription factors C/EBPβ and C/EBPδ are induced within hours after initiation of adipogenesis in culture. They directly promote the expression of master adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα and are required for adipogenesis However, the mechanism that controls the induction of C/EBPβ and C/EBPδ remains elusive. We previously showed that histone methyltransferases MLL3/MLL4 and associated PTIP are required for the induction of PPARγ and C/EBPα during adipogenesis. Here, we show MLL3/MLL4/PTIP-associated protein PAGR1 (also known as PA1) cooperates with phosphorylated CREB and ligand-activated glucocorticoid receptor to directly control the induction of C/EBPβ and C/EBPδ in the early phase of adipogenesis. Deletion of in white and brown preadipocytes prevents the induction of C/EBPβ and C/EBPδ and leads to severe defects in adipogenesis. Adipogenesis defects in PAGR1-deficient cells can be rescued by the ectopic expression of C/EBPβ or PPARγ. Finally, the deletion of in Myf5 precursor cells impairs brown adipose tissue and muscle development. Thus, by controlling the induction of C/EBPβ and C/EBPδ, PAGR1 plays a critical role in adipogenesis.
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http://dx.doi.org/10.1128/MCB.00209-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431048PMC
August 2020

Genomic and phylogenetic characteristics of a novel goose astrovirus in Anhui Province, Central-Eastern China.

Gene 2020 Sep 19;756:144898. Epub 2020 Jun 19.

Municipal Key Laboratory of Virology, Ningbo Municipal Center for Disease Control and Prevention, Ningbo 315010, PR China. Electronic address:

Goose astrovirus (GAstV) causes a novel disease characterized by urate deposition in the viscera and joints in goslings in many provinces of China, leading to huge economic losses in the goose industry. To better understand the genetic diversity of GAstV in the Anhui Province, Central-Eastern China, 48 kidney samples from goslings with gout were subjected to reverse-transcription polymerase chain reaction (RT-PCR) analysis for detecting GAstV, and phylogenetic analysis of whole genomes and ORFs was performed. Thirty-five samples were GAstV-positive, indicating that the virus is a frequent cause of gout. The whole genomes of 5 GAstV strains were successfully sequenced and named AHAU1-5. The sequenced genomes and those of reference GAstV strains in GenBank displayed 97.4-99.8% similarity. The isolates had high nucleotide sequence similarity with the GAstV reference strain SDPY. A phylogenetic analysis showed that AHAU1 and AHAU4 were closely related to the reference strain SDPY; AHAU2, AHAU3, and AHAU5 formed separate branches. Furthermore, recombination analysis revealed putative recombination sites in the Jiangsu strains that originated from strains in the Anhui and Shandong Provinces, accompanied by the recombination of different strains in the Anhui Province. This study is the first to carry out systematic phylogenetic analysis of GAstV isolated in the Anhui Province, Central-Eastern China. By improving our understanding of the diversity of GAstV in the Anhui Province, these results provide a basis for the prevention and control of its spread.
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http://dx.doi.org/10.1016/j.gene.2020.144898DOI Listing
September 2020

Histone methyltransferase MLL4 controls myofiber identity and muscle performance through MEF2 interaction.

J Clin Invest 2020 09;130(9):4710-4725

State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Department of Spine Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing, China.

Skeletal muscle depends on the precise orchestration of contractile and metabolic gene expression programs to direct fiber-type specification and to ensure muscle performance. Exactly how such fiber type-specific patterns of gene expression are established and maintained remains unclear, however. Here, we demonstrate that histone monomethyl transferase MLL4 (KMT2D), an enhancer regulator enriched in slow myofibers, plays a critical role in controlling muscle fiber identity as well as muscle performance. Skeletal muscle-specific ablation of MLL4 in mice resulted in downregulation of the slow oxidative myofiber gene program, decreased numbers of type I myofibers, and diminished mitochondrial respiration, which caused reductions in muscle fatty acid utilization and endurance capacity during exercise. Genome-wide ChIP-Seq and mRNA-Seq analyses revealed that MLL4 directly binds to enhancers and functions as a coactivator of the myocyte enhancer factor 2 (MEF2) to activate transcription of slow oxidative myofiber genes. Importantly, we also found that the MLL4 regulatory circuit is associated with muscle fiber-type remodeling in humans. Thus, our results uncover a pivotal role for MLL4 in specifying structural and metabolic identities of myofibers that govern muscle performance. These findings provide therapeutic opportunities for enhancing muscle fitness to combat a variety of metabolic and muscular diseases.
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http://dx.doi.org/10.1172/JCI136155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456251PMC
September 2020

The KMT2D Kabuki syndrome histone methylase controls neural crest cell differentiation and facial morphology.

Development 2020 07 17;147(21). Epub 2020 Jul 17.

Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7264, USA.

Kabuki syndrome (KS) is a congenital craniofacial disorder resulting from mutations in the KMT2D histone methylase (KS1) or the UTX histone demethylase (KS2). With small cohorts of KS2 patients, it is not clear whether differences exist in clinical manifestations relative to KS1. We mutated KMT2D in neural crest cells (NCCs) to study cellular and molecular functions in craniofacial development with respect to UTX. Similar to UTX, KMT2D NCC knockout mice demonstrate hypoplasia with reductions in frontonasal bone lengths. We have traced the onset of KMT2D and UTX mutant NCC frontal dysfunction to a stage of altered osteochondral progenitor differentiation. KMT2D NCC loss-of-function does exhibit unique phenotypes distinct from UTX mutation, including fully penetrant cleft palate, mandible hypoplasia and deficits in cranial base ossification. KMT2D mutant NCCs lead to defective secondary palatal shelf elevation with reduced expression of extracellular matrix components. KMT2D mutant chondrocytes in the cranial base fail to properly differentiate, leading to defective endochondral ossification. We conclude that KMT2D is required for appropriate cranial NCC differentiation and KMT2D-specific phenotypes may underlie differences between Kabuki syndrome subtypes.
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http://dx.doi.org/10.1242/dev.187997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375479PMC
July 2020

Opposing Functions of BRD4 Isoforms in Breast Cancer.

Mol Cell 2020 06 23;78(6):1114-1132.e10. Epub 2020 May 23.

Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Bromodomain-containing protein 4 (BRD4) is a cancer therapeutic target in ongoing clinical trials disrupting primarily BRD4-regulated transcription programs. The role of BRD4 in cancer has been attributed mainly to the abundant long isoform (BRD4-L). Here we show, by isoform-specific knockdown and endogenous protein detection, along with transgene expression, the less abundant BRD4 short isoform (BRD4-S) is oncogenic while BRD4-L is tumor-suppressive in breast cancer cell proliferation and migration, as well as mammary tumor formation and metastasis. Through integrated RNA-seq, genome-wide ChIP-seq, and CUT&RUN association profiling, we identify the Engrailed-1 (EN1) homeobox transcription factor as a key BRD4-S coregulator, particularly in triple-negative breast cancer. BRD4-S and EN1 comodulate the extracellular matrix (ECM)-associated matrisome network, including type II cystatin gene cluster, mucin 5, and cathepsin loci, via enhancer regulation of cancer-associated genes and pathways. Our work highlights the importance of targeted therapies for the oncogenic, but not tumor-suppressive, activity of BRD4.
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http://dx.doi.org/10.1016/j.molcel.2020.04.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362310PMC
June 2020

H2B ubiquitylation enhances H3K4 methylation activities of human KMT2 family complexes.

Nucleic Acids Res 2020 06;48(10):5442-5456

Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, South Korea.

In mammalian cells, distinct H3K4 methylation states are created by deposition of methyl groups by multiple complexes of histone lysine methyltransferase 2 (KMT2) family proteins. For comprehensive analyses that directly compare the catalytic properties of all six human KMT2 complexes, we employed a biochemically defined system reconstituted with recombinant KMT2 core complexes (KMT2CoreCs) containing minimal components required for nucleosomal H3K4 methylation activity. We found that each KMT2CoreC generates distinct states and different levels of H3K4 methylation, and except for MLL3 all are stimulated by H2Bub. Notably, SET1BCoreC exhibited the strongest H3K4 methylation activity and, to our surprise, did not require H2B ubiquitylation (H2Bub); in contrast, H2Bub was required for the H3K4me2/3 activity of the paralog SET1ACoreC. We also found that WDR5, RbBP5, ASH2L and DPY30 are required for efficient H3K4 methyltransferase activities of all KMT2CoreCs except MLL3, which could produce H3K4me1 in the absence of WDR5. Importantly, deletion of the PHD2 domain of CFP1 led to complete loss of the H3K4me2/3 activities of SET1A/BCoreCs in the presence of H2Bub, indicating a critical role for this domain in the H2Bub-stimulated H3K4 methylation. Collectively, our results suggest that each KMT2 complex methylates H3K4 through distinct mechanisms in which individual subunits differentially participate.
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http://dx.doi.org/10.1093/nar/gkaa317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261165PMC
June 2020

Highly Stable Reduced Graphene Oxide Wrapped Black Phosphorus Heterostructure with Superior Photocatalytic Performance under Visible Light.

ACS Appl Mater Interfaces 2020 Apr 3;12(17):20035-20043. Epub 2020 Apr 3.

Department of Macromolecular Science and Engineering, Case Western Reserve University, Cleveland, Ohio 44106, United States.

Metal-free photocatalysts with excellent visible-light absorption and highly efficient photocatalytic activity are attractive in the field of photocatalysis owing to their environmental friendliness. Black phosphorus (BP) shows a great potential in photoelectric conversion and photocatalysis due to its tunable band gap and two-dimensional structure. In this work, a stabilized metal-free photocatalyst, reduced graphene oxide (rGO)-wrapped BP heterostructure, was prepared by assembling BP and GO nanosheets in aqueous solution followed by partial reduction and lyophilization. The surface tension of the partially reduced GO during lyophilization could make rGO nanosheets tightly wrap on both surfaces of exfoliated BP nanosheets. This wrapped heterostructure with tight bonding between rGO and BP nanosheets led to a high photocatalytic activity, owing to the rapid transfer of the photogenerated electron-hole pairs at the rGO/BP heterojunction and the high stability of rGO protecting BP from oxygen attack. This work not only provided a general method to prepare the sandwiched heterojunction based on GO with good interface binding capability but also constructed a highly active, stable, metal-free photocatalyst based on BP.
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http://dx.doi.org/10.1021/acsami.0c00602DOI Listing
April 2020

A Mouse Homolog of a Human TP53 Germline Mutation Reveals a Lipolytic Activity of p53.

Cell Rep 2020 01;30(3):783-792.e5

Cardiovascular Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA. Electronic address:

The physiological effects of the many germline mutations of TP53, encoding the tumor suppressor protein p53, are poorly understood. Here we report generating a p53 R178C knockin mouse modeling the human TP53 R181C mutation, which is notable for its prevalence and prior molecular characterization. Consistent with its weak cancer penetrance in humans, homozygous p53 mice show a modest increase in tumorigenesis but, surprisingly, are lean with decreased body fat content. They display evidence of increased lipolysis and upregulation of fatty acid metabolism in their inguinal white adipose tissue (iWAT). Gene expression and chromatin immunoprecipitation sequencing (ChIP-seq) analyses show that the mutant p53 bound and transactivated Beta-3-Adrenergic Receptor (ADRB3), a gene that is known to promote lipolysis and is associated with obesity. This study reveals that a germline mutation of p53 can affect fat metabolism, which has been implicated in cancer development.
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http://dx.doi.org/10.1016/j.celrep.2019.12.074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021448PMC
January 2020

Comparison of slaughter performance, meat traits, serum lipid parameters and fat tissue between Chaohu ducks with high- and low-intramuscular fat content.

Anim Biotechnol 2020 Jun 14;31(3):245-255. Epub 2019 Sep 14.

Anhui Province Key Laboratory of Local Livestock and Poultry Genetic Resource Conservation and Bio-breeding, College of Animal Science and Technology, Anhui Agricultural University, Hefei, Anhui Province, China.

This study was conducted to investigate the effect of intramuscular fat (IMF) on carcass traits of Chaohu ducks. Two-hundred-forty ducks were separated by sex and raised in separate pens. Slaughter performance, meat quality, and serum lipid parameters were identified. Based on IMF, samples were divided into males with high IMF (CHM) or low IMF (CLM) and females with high IMF (CHF) or low IMF (CLF). There were significant differences in the living body weight, abdominal fat ratio (%), shear force, IMF, total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) content between female and male ducks. In addition, compared with the CLM group, the shear force ( = 0.001) was significantly greater but the lightness ( = 0.006) was lower in the CHM group. TC, HDL and LDL content were also significantly higher ( = 0.033, 0.027 and 0.012, respectively) in the CHM group. The butcher ratio (0.028), eviscerating rate (0.039) and breast meat ratio (0.028) in the CHF group was significantly lower than that in CLF group, while these parameters showed no difference between CHM and CLM. In conclusion, IMF had a significantly positive correlation with subcutaneous fat and abdominal fat and was also positively correlated with TC, HDL and LDL in Chaohu ducks.
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http://dx.doi.org/10.1080/10495398.2019.1664565DOI Listing
June 2020

Egg-laying and brooding stage-specific hormonal response and transcriptional regulation in pituitary of Muscovy duck (Cairina moschata).

Poult Sci 2019 Nov;98(11):5287-5296

College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China.

Broodiness is an interesting topic in reproductive biology for its reduced egg production. The strong brooding trait of Muscovy duck has become a major factor restricting the development of its industry. Broody phenotype and environmental factors influencing broodiness in poultry have been extensively studied, but the molecular regulation mechanism of broodiness remains unclear. In this research, the Muscovy duck reproductive endocrine hormones and pituitary transcriptome profiles during egg-laying phases (LP) and brooding phases (BP) were studied. During BP (n = 19), prolactin (PRL) levels was higher, while progesterone (P4) and estradiol (E2) were lower as compared to ducks during their LP (n = 20) (P < 0.01). We then examined the pituitary transcriptome of Muscovy duck at the 2 reproductive stages. A total of 398 differentially expressed genes included 20 transcription factors were identified (fold change ≥ 1.5, P < 0.01). There were 109 upregulated and 289 downregulated genes at brooding phases (n = 6) compared with egg-laying phases (n = 6). Real-time quantitative PCR analysis was carried out to verify the transcriptome results. The present study suggested that neuroactive ligand-receptor interaction pathway, calcium signaling pathway, and response to steroid hormones biological process are critical for controlling broodiness in the ducks. Further analysis revealed that SHH, PTGS2, RLN3, and transcription factor AP-1 may act as central signal modulators of hormonal and behavioral regulation mechanism associated with broodiness.
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http://dx.doi.org/10.3382/ps/pez433DOI Listing
November 2019

High Fat Diet Triggers a Reduction in Body Fat Mass in Female Mice Deficient for Utx demethylase.

Sci Rep 2019 07 11;9(1):10036. Epub 2019 Jul 11.

Department of Biochemistry, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.

Obesity increases the risk of metabolic disorders like diabetes mellitus and dyslipidemia. However, how metabolic status is sensed and regulates cellular behavior is unclear. Utx is an H3K27 demethylase that influences adipocyte function in vitro. To examine its role in vivo, we generated mice lacking Utx in adipocytes (UtxAKO). Although all UtxAKO mice grew normally on a normal chow diet (NCD), female UtxAKO mice on a high fat diet (HFD) showed striking reductions in body fat compared to control mice (Ctrl). Gene expression profiling of adipose tissues of HFD-fed UtxAKO female mice revealed decreased expression of rate-limiting enzymes of triacylglycerol synthesis but increased expression of those of cholesterol/steroid hormone synthesis. Moreover, these animals resisted adiposity induced by ovariectomy and exhibited increased estrogen in visceral adipose tissues. Thus, upon HFD feeding, Utx regulates lipid metabolism in adipose tissues by influencing the local hormonal microenvironment. Conversely, Utx deficiency skews lipid catabolism to enhance cholesterol/steroid hormone production and repress obesity.
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http://dx.doi.org/10.1038/s41598-019-46445-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624269PMC
July 2019

Comparison of liver transcriptome from high- and low-intramuscular fat Chaohu ducks provided additional candidate genes for lipid selection.

3 Biotech 2019 Jul 4;9(7):251. Epub 2019 Jun 4.

1Anhui Province Key Laboratory of Local Livestock and Poultry Genetic Resource Conservation and Bio-breeding, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036 China.

The meat quality of ducks is closely related to the intramuscular fat (IMF) content. This study explored the candidate regulatory genes of IMF formation and lipid deposition in Chaohu ducks. The IMF of breast muscle in 100 ducks was determined and statistically analysed by normal distribution test. Duck liver samples with high IMF (CH,  = 3) and low IMF (CL,  = 3) were selected for transcriptome analysis by RNA sequencing (RNA-Seq). The IMF was in accordance with normal distribution ( = 0.001, = 0.999). The IMF from two tails of the normal distribution was significantly different with 2.9983% ± 0.3296% in the CH group and 1.1960% ± 0.1481% in the CL group (< 0.0001). RNA-Seq revealed 147 differentially expressed genes, including 78 up-regulated and 69 down-regulated genes in both groups. Validation by qRT-PCR was in agreement with RNA-Seq ( = 0.838). Gene ontology analysis revealed that organophosphate catabolism, oxidation-reduction process, cellular lipid catabolism, lipid transport, lipid localisation, lipid biosynthesis and cellular lipid catabolism were involved in lipid metabolism. Meanwhile, Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that steroid hormone biosynthesis, ovarian steroidogenesis, alpha-linolenic acid metabolism, glycosylphosphatidylinositol anchor biosynthesis and linoleic acid metabolism were involved in lipid deposition, wherein the genes , , , , -, , , , and were involved in lipid deposition. This study provided insights into the molecular mechanism for regulating lipid metabolism and identified candidate genes for selecting markers to control IMF formation in Chaohu ducks.
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http://dx.doi.org/10.1007/s13205-019-1780-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548796PMC
July 2019

Selective binding of the PHD6 finger of MLL4 to histone H4K16ac links MLL4 and MOF.

Nat Commun 2019 05 24;10(1):2314. Epub 2019 May 24.

Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.

Histone methyltransferase MLL4 is centrally involved in transcriptional regulation and is often mutated in human diseases, including cancer and developmental disorders. MLL4 contains a catalytic SET domain that mono-methylates histone H3K4 and seven PHD fingers of unclear function. Here, we identify the PHD6 finger of MLL4 (MLL4-PHD6) as a selective reader of the epigenetic modification H4K16ac. The solution NMR structure of MLL4-PHD6 in complex with a H4K16ac peptide along with binding and mutational analyses reveal unique mechanistic features underlying recognition of H4K16ac. Genomic studies show that one third of MLL4 chromatin binding sites overlap with H4K16ac-enriched regions in vivo and that MLL4 occupancy in a set of genomic targets depends on the acetyltransferase activity of MOF, a H4K16ac-specific acetyltransferase. The recognition of H4K16ac is conserved in the PHD7 finger of paralogous MLL3. Together, our findings reveal a previously uncharacterized acetyllysine reader and suggest that selective targeting of H4K16ac by MLL4 provides a direct functional link between MLL4, MOF and H4K16 acetylation.
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http://dx.doi.org/10.1038/s41467-019-10324-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534582PMC
May 2019

Hypothalamic transcriptome analysis reveals the neuroendocrine mechanisms in controlling broodiness of Muscovy duck (Cairina moschata).

PLoS One 2019 9;14(5):e0207050. Epub 2019 May 9.

College of Animal Science and Technology, Anhui Agricultural University, Hefei, China.

Broodiness, one of the maternal behaviors and instincts for natural breeding in birds, is an interesting topic in reproductive biology. Broodiness in poultry is characterized by persistent nesting, usually associated with cessation of egg laying. The study of avian broodiness is essential for bird conservation breeding and commercial poultry industry. In this study, we examined the hypothalamus transcriptome of Muscovy duck in three reproductive stages, including egg-laying anaphase (LA), brooding prophase (BP) and brooding metaphase (BM). Differences in gene expression during the transition from egg-laying to broodiness were examined, and 155, 379, 292 differently expressed genes (DEGs) were obtained by pairwise comparisons of LA-vs-BP, LA-vs-BM and BP-vs-BM, respectively (fold change≥1.5, P < 0.05). Gene Ontology Term (GO) enrichment analysis suggested a possible role of oxidative stress in the hypothalamus might invoke reproductive costs that potentially change genes expression. KEGG analysis revealed glutamatergic synapse, dopaminergic synapse, serotonergic synapse and GABAergic synapse pathway were significantly enriched, and regulator genes were identified. Eight gene expression patterns were illustrated by trend analysis and further clustered into three clusters. Additional six hub genes were identified through combining trend analysis and protein-protein interaction (PPI) analysis. Our results suggested that the cyclical mechanisms of reproductive function conversion include effects of oxidative stress, biosynthesis of neurotransmitters or their receptors, and interactions between glucocorticoids and thyroid hormones and regulatory genes. These candidate genes and biological pathways may be used as targets for artificial manipulation and marker-assisted breeding in the reproductive behavior.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207050PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508920PMC
January 2020

Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease.

Cell 2019 04 4;177(3):608-621.e12. Epub 2019 Apr 4.

Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Normal tissues accumulate genetic changes with age, but it is unknown if somatic mutations promote clonal expansion of non-malignant cells in the setting of chronic degenerative diseases. Exome sequencing of diseased liver samples from 82 patients revealed a complex mutational landscape in cirrhosis. Additional ultra-deep sequencing identified recurrent mutations in PKD1, PPARGC1B, KMT2D, and ARID1A. The number and size of mutant clones increased as a function of fibrosis stage and tissue damage. To interrogate the functional impact of mutated genes, a pooled in vivo CRISPR screening approach was established. In agreement with sequencing results, examination of 147 genes again revealed that loss of Pkd1, Kmt2d, and Arid1a promoted clonal expansion. Conditional heterozygous deletion of these genes in mice was also hepatoprotective in injury assays. Pre-malignant somatic alterations are often viewed through the lens of cancer, but we show that mutations can promote regeneration, likely independent of carcinogenesis.
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http://dx.doi.org/10.1016/j.cell.2019.03.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519461PMC
April 2019

Transcriptional and Epigenomic Regulation of Adipogenesis.

Mol Cell Biol 2019 06 14;39(11). Epub 2019 May 14.

Adipocyte Biology and Gene Regulation Section, Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA

Understanding adipogenesis, the process of adipocyte development, may provide new ways to treat obesity and related metabolic diseases. Adipogenesis is controlled by coordinated actions of lineage-determining transcription factors and epigenomic regulators. Peroxisome proliferator-activated receptor gamma (PPARγ) and C/EBPα are master "adipogenic" transcription factors. In recent years, a growing number of studies have reported the identification of novel transcriptional and epigenomic regulators of adipogenesis. However, many of these novel regulators have not been validated in adipocyte development and their working mechanisms are often far from clear. In this minireview, we discuss recent advances in transcriptional and epigenomic regulation of adipogenesis, with a focus on factors and mechanisms shared by both white adipogenesis and brown adipogenesis. Studies on the transcriptional regulation of adipogenesis highlight the importance of investigating adipocyte differentiation rather than drawing conclusions based on knockdown experiments in cell culture. Advances in understanding of epigenomic regulation of adipogenesis have revealed critical roles of histone methylation/demethylation, histone acetylation/deacetylation, chromatin remodeling, DNA methylation, and microRNAs in adipocyte differentiation. We also discuss future research directions that may help identify novel factors and mechanisms regulating adipogenesis.
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http://dx.doi.org/10.1128/MCB.00601-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517598PMC
June 2019

HPW/PDMAEMA-b-PMAA/ZIF-8 Ternary Lamellar Composite and the Photocatalytic Degradation of Methylene Blue.

Chem Asian J 2019 Apr 1;14(7):1066-1075. Epub 2019 Mar 1.

Institute of Polymer Science and Engineering, Hebei University of Technology, Tianjin, 300130, P. R. China.

PDMAEMA-b-PMAA block copolymers were prepared by the sequential RAFT polymerization of DMAEMA and tBMA, followed by hydrolysis. Phosphotungstic acid (HPW) was anchored to the PDMAEMA blocks through electrostatic interactions and the as-obtained HPW/PDMAEMA-b-PMAA was added to the synthesis of ZIF-8. During the formation of ZIF-8, the PMAA blocks coordinated to the Zn ions through their carboxy groups, along with the HPW groups that were anchored to the PDMAEMA blocks. In this way, the block copolymer could consolidate the interactions between HPW and ZIF-8 and prevent the leakage of HPW. Finally, the HPW/PDMAEMA-b-PMAA/ZIF-8 ternary lamellar composite was obtained and the structure of the HPW/PDMAEMA-b-PMAA/ZIF-8 hybrid material was characterized by using powder X-ray diffraction (PXRD), X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM). As a photocatalyst, the HPW/PDMAEMA-b-PMAA/ZIF-8 ternary lamellar composite showed excellent photoactivity for the degradation of methylene blue (MB). The rate of degradation of MB was 0.0240 min , which was 7.5-times higher than that of commercially available P25 (0.0032 min ). In the presence of H O , the kinetic degradation parameters of the composite reached 0.0634 min , which was about 19.8-times higher than that of P25.
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http://dx.doi.org/10.1002/asia.201801785DOI Listing
April 2019

H3.3K4M destabilizes enhancer H3K4 methyltransferases MLL3/MLL4 and impairs adipose tissue development.

Nucleic Acids Res 2019 01;47(2):607-620

Adipocyte Biology and Gene Regulation Section, Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Histone 3 lysine 4 (H3K4) methyltransferases MLL3 and MLL4 (MLL3/4) are required for enhancer activation during cell differentiation, though the mechanism is incompletely understood. We have attempted to address this issue by generating two mouse lines: one expressing H3.3K4M, a lysine-4-to-methionine (K4M) mutation of histone H3.3 that inhibits H3K4 methylation, and the other carrying conditional double knockout of MLL3/4 enzymatic SET domain. Expression of H3.3K4M in lineage-specific precursor cells depletes H3K4 methylation and impairs adipose tissue and muscle development. Mechanistically, H3.3K4M prevents enhancer activation in adipogenesis by destabilizing MLL3/4 proteins but not other Set1-like H3K4 methyltransferases MLL1, MLL2, SET1A and SET1B. Notably, deletion of the enzymatic SET domain in lineage-specific precursor cells mimics H3.3K4M expression, destabilizes MLL3/4 proteins, and prevents adipose tissue and muscle development. Interestingly, destabilization of MLL3/4 by H3.3K4M in adipocytes does not affect adipose tissue maintenance and thermogenic function. Together, our findings indicate that expression of H3.3K4M, or deletion of the enzymatic SET domain, destabilizes enhancer H3K4 methyltransferases MLL3/4 and impairs adipose tissue and muscle development.
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http://dx.doi.org/10.1093/nar/gky982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344897PMC
January 2019

Histone methylation regulator PTIP is required to maintain normal and leukemic bone marrow niches.

Proc Natl Acad Sci U S A 2018 10 8;115(43):E10137-E10146. Epub 2018 Oct 8.

Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030;

The bone is essential for locomotion, calcium storage, and harboring the hematopoietic stem cells (HSCs) that supply the body with mature blood cells throughout life. HSCs reside at the interface of the bone and bone marrow (BM), where active bone remodeling takes place. Although the cellular components of the BM niche have been characterized, little is known about its epigenetic regulation. Here we find that the histone methylation regulator PTIP (Pax interaction with transcription-activation domain protein-1) is required to maintain the integrity of the BM niche by promoting osteoclast differentiation. PTIP directly promotes chromatin changes required for the expression of (peroxisome proliferator-activated receptor-γ), a transcription factor essential for osteoclastogenesis. PTIP deletion leads to a drastic reduction of HSCs in the BM and induces extramedullary hematopoiesis. Furthermore, exposure of acute myeloid leukemia cells to a PTIP-deficient BM microenvironment leads to a reduction in leukemia-initiating cells and increased survival upon transplantation. Taken together, our data identify PTIP as an epigenetic regulator of osteoclastogenesis that is required for the integrity of the BM niche to sustain both normal hematopoiesis and leukemia.
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http://dx.doi.org/10.1073/pnas.1806019115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205459PMC
October 2018

HOXA9 Reprograms the Enhancer Landscape to Promote Leukemogenesis.

Cancer Cell 2018 10 27;34(4):643-658.e5. Epub 2018 Sep 27.

Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address:

Aberrant expression of HOXA9 is a prominent feature of acute leukemia driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid and B progenitor cells leads to significant enhancer reorganizations with prominent emergence of leukemia-specific de novo enhancers. Alterations in the enhancer landscape lead to activation of an ectopic embryonic gene program. We show that HOXA9 functions as a pioneer factor at de novo enhancers and recruits CEBPα and the MLL3/MLL4 complex. Genetic deletion of MLL3/MLL4 blocks histone H3K4 methylation at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis in vivo. These results suggest that therapeutic targeting of HOXA9-dependent enhancer reorganization can be an effective therapeutic strategy in acute leukemia with HOXA9 overexpression.
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http://dx.doi.org/10.1016/j.ccell.2018.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179449PMC
October 2018

Fasting-induced JMJD3 histone demethylase epigenetically activates mitochondrial fatty acid β-oxidation.

J Clin Invest 2018 07 18;128(7):3144-3159. Epub 2018 Jun 18.

Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.

Jumonji D3 (JMJD3) histone demethylase epigenetically regulates development and differentiation, immunity, and tumorigenesis by demethylating a gene repression histone mark, H3K27-me3, but a role for JMJD3 in metabolic regulation has not been described. SIRT1 deacetylase maintains energy balance during fasting by directly activating both hepatic gluconeogenic and mitochondrial fatty acid β-oxidation genes, but the underlying epigenetic and gene-specific mechanisms remain unclear. In this study, JMJD3 was identified unexpectedly as a gene-specific transcriptional partner of SIRT1 and epigenetically activated mitochondrial β-oxidation, but not gluconeogenic, genes during fasting. Mechanistically, JMJD3, together with SIRT1 and the nuclear receptor PPARα, formed a positive autoregulatory loop upon fasting-activated PKA signaling and epigenetically activated β-oxidation-promoting genes, including Fgf21, Cpt1a, and Mcad. Liver-specific downregulation of JMJD3 resulted in intrinsic defects in β-oxidation, which contributed to hepatosteatosis as well as glucose and insulin intolerance. Remarkably, the lipid-lowering effects by JMJD3 or SIRT1 in diet-induced obese mice were mutually interdependent. JMJD3 histone demethylase may serve as an epigenetic drug target for obesity, hepatosteatosis, and type 2 diabetes that allows selective lowering of lipid levels without increasing glucose levels.
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http://dx.doi.org/10.1172/JCI97736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025975PMC
July 2018

Polymorphisms in the uncoupling protein 3 gene and their associations with feed efficiency in chickens.

Asian-Australas J Anim Sci 2018 Sep 31;31(9):1401-1406. Epub 2018 May 31.

College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China.

Objective: The uncoupling protein 3 (UCP3) is a member of the mitochondrial anion carrier superfamily and has crucial effects on growth and feed efficiency in many species. Therefore, the objective of the present study was to examine the association of polymorphisms in the UCP3 gene with feed efficiency in meat-type chickens.

Methods: Six single nucleotide polymorphisms (SNPs) of the UCP3 gene were chosen to be genotyped using matrix-assisted laser desorption-ionization time-of-flight mass spectrometry in meat-type chicken populations with 724 birds in total. Body weight at 49 (BW49) and 70 days of age (BW70) and feed intake (FI) in the interval were collected, then body weight gain (BWG) and feed conversion ratio (FCR) were calculated individually.

Results: One SNP with a low minor allele frequency (<1%) was removed by quality control and data filtering. The results showed that rs13997809 of UCP3 was significantly associated with BWG and FCR (p<0.05), and that rs13997811 had significant effects on BW70 and BWG (p<0.05). Rs13997812 of UCP3 was strongly associated with BW70, FI, and FCR (p<0.05). Furthermore, individuals with AA genotype of rs13997809 had significantly higher BWG and lower FCR (p<0.05) than those with AT genotype. The GG individuals showed strongly higher BW70 and BWG than AA birds in rs13997811 (p<0.05). Birds with the TT genotype of rs13997812 had significantly greater BW70 and lower FCR compared with the CT birds (p<0.05). In addition, the TAC haplotype based on rs13997809, rs13997811, and rs13997812 showed significant effects on BW70, FI, and FCR (p<0.05).

Conclusion: Our results therefore demonstrate important roles for UCP3 polymorphisms in growth and feed efficiency that might be used in meat-type chicken breeding programs.
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http://dx.doi.org/10.5713/ajas.18.0217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127571PMC
September 2018

Depletion of Nsd2-mediated histone H3K36 methylation impairs adipose tissue development and function.

Nat Commun 2018 05 4;9(1):1796. Epub 2018 May 4.

Adipocyte Biology and Gene Regulation Section, LERB, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, 20892, USA.

The epigenetic mechanisms regulating adipose tissue development and function are poorly understood. In this study, we show that depletion of histone H3K36 methylation by H3.3K36M in preadipocytes inhibits adipogenesis by increasing H3K27me3 to prevent the induction of C/EBPα and other targets of the master adipogenic transcription factor peroxisome proliferator-activated receptor-γ (PPARγ). Depleting H3K36 methyltransferase Nsd2, but not Nsd1 or Setd2, phenocopies the effects of H3.3K36M on adipogenesis and PPARγ target expression. Consistently, expression of H3.3K36M in progenitor cells impairs brown adipose tissue (BAT) and muscle development in mice. In contrast, depletion of histone H3K36 methylation by H3.3K36M in adipocytes in vivo does not affect adipose tissue weight, but leads to profound whitening of BAT and insulin resistance in white adipose tissue (WAT). These mice are resistant to high fat diet-induced WAT expansion and show severe lipodystrophy. Together, these results suggest a critical role of Nsd2-mediated H3K36 methylation in adipose tissue development and function.
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http://dx.doi.org/10.1038/s41467-018-04127-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935725PMC
May 2018

In vivo CRISPR screening unveils histone demethylase UTX as an important epigenetic regulator in lung tumorigenesis.

Proc Natl Acad Sci U S A 2018 04 9;115(17):E3978-E3986. Epub 2018 Apr 9.

State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling Network, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China;

Lung cancer is the leading cause of cancer-related death worldwide. Inactivation of tumor suppressor genes (TSGs) promotes lung cancer malignant progression. Here, we take advantage of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated somatic gene knockout in a mouse model to identify bona fide TSGs. From individual knockout of 55 potential TSGs, we identify five genes, including , , , , and , whose knockout significantly promotes lung tumorigenesis. These candidate genes are frequently down-regulated in human lung cancer specimens and significantly associated with survival in patients with lung cancer. Through crossing the conditional knockout allele to the mouse model, we further find that deletion dramatically promotes lung cancer progression. The tumor-promotive effect of knockout in vivo is mainly mediated through an increase of the EZH2 level, which up-regulates the H3K27me3 level. Moreover, the -knockout lung tumors are preferentially sensitive to EZH2 inhibitor treatment. Collectively, our study provides a systematic screening of TSGs in vivo and identifies UTX as an important epigenetic regulator in lung tumorigenesis.
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http://dx.doi.org/10.1073/pnas.1716589115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924887PMC
April 2018

Histone H3 lysine 4 monomethylation modulates long-range chromatin interactions at enhancers.

Cell Res 2018 Feb 9;28(2):204-220. Epub 2018 Jan 9.

Ludwig Institute for Cancer Research, 9500 Gilman Dr., La Jolla, CA 92093, USA.

Long-range chromatin interactions between enhancers and promoters are essential for transcription of many developmentally controlled genes in mammals and other metazoans. Currently, the exact mechanisms that connect distal enhancers to their specific target promoters remain to be fully elucidated. Here, we show that the enhancer-specific histone H3 lysine 4 monomethylation (H3K4me1) and the histone methyltransferases MLL3 and MLL4 (MLL3/4) play an active role in this process. We demonstrate that in differentiating mouse embryonic stem cells, MLL3/4-dependent deposition of H3K4me1 at enhancers correlates with increased levels of chromatin interactions, whereas loss of this histone modification leads to reduced levels of chromatin interactions and defects in gene activation during differentiation. H3K4me1 facilitates recruitment of the Cohesin complex, a known regulator of chromatin organization, to chromatin in vitro and in vivo, providing a potential mechanism for MLL3/4 to promote chromatin interactions between enhancers and promoters. Taken together, our results support a role for MLL3/4-dependent H3K4me1 in orchestrating long-range chromatin interactions at enhancers in mammalian cells.
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http://dx.doi.org/10.1038/cr.2018.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799818PMC
February 2018