Abstract:
:Histone methylation plays an important role in regulating gene expression. One such methylation occurs at Lys 79 of histone H3 (H3K79) and is catalyzed by the yeast DOT1 (disruptor of telomeric silencing) and its mammalian homolog, DOT1L. Previous studies have demonstrated that germline disruption of Dot1L in mice resulted in embryonic lethality. Here we report that cardiac-specific knockout of Dot1L results in increased mortality rate with chamber dilation, increased cardiomyocyte cell death, systolic dysfunction, and conduction abnormalities. These phenotypes mimic those exhibited in patients with dilated cardiomyopathy (DCM). Mechanistic studies reveal that DOT1L performs its function in cardiomyocytes through regulating Dystrophin (Dmd) transcription and, consequently, stability of the Dystrophin-glycoprotein complex important for cardiomyocyte viability. Importantly, expression of a miniDmd can largely rescue the DCM phenotypes, indicating that Dmd is a major target mediating DOT1L function in cardiomyocytes. Interestingly, analysis of available gene expression data sets indicates that DOT1L is down-regulated in idiopathic DCM patient samples compared with normal controls. Therefore, our study not only establishes a critical role for DOT1L-mediated H3K79 methylation in cardiomyocyte function, but also reveals the mechanism underlying the role of DOT1L in DCM. In addition, our study may open new avenues for the diagnosis and treatment of human heart disease.
journal_name
Genes Devjournal_title
Genes & developmentauthors
Nguyen AT,Xiao B,Neppl RL,Kallin EM,Li J,Chen T,Wang DZ,Xiao X,Zhang Ydoi
10.1101/gad.2018511subject
Has Abstractpub_date
2011-02-01 00:00:00pages
263-74issue
3eissn
0890-9369issn
1549-5477pii
25/3/263journal_volume
25pub_type
杂志文章abstract::Stem cells do not all respond the same way, but the mechanisms underlying this heterogeneity are not well understood. Here, we found that expression of Hes1 and its downstream genes oscillate in mouse embryonic stem (ES) cells. Those expressing low and high levels of Hes1 tended to differentiate into neural and mesode...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1823109
更新日期:2009-08-15 00:00:00
abstract::The LIM motif defines a double zinc finger structure found in proteins involved in cell fate determination and growth control. LIM proteins, which include LIM homeo domain, LIM kinase, focal adhesion, and LIM-only proteins, usually contain two or more LIM motifs clustered at their amino- or carboxy-terminal end. At pr...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.10.3.289
更新日期:1996-02-01 00:00:00
abstract::Irradiation in the G1 phase of the cell cycle delays the onset of DNA synthesis and transiently inhibits the activation of replication origins in mammalian cells. It has been suggested that this inhibition is the result of the loss of torsional tension in the DNA after it has been damaged. Because irradiation causes D...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.8.5.554
更新日期:1994-03-01 00:00:00
abstract::The Hedgehog (Hh) family of secreted proteins controls many aspects of animal development. In Drosophila, Hh transduces its signal via Cubitus interruptus (Ci), a transcription factor present in two forms: a full-length activator and a carboxy-terminally truncated repressor that is derived from the full-length form by...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.13.21.2828
更新日期:1999-11-01 00:00:00
abstract::Sox10 is a high-mobility-group transcriptional regulator in early neural crest. Without Sox10, no glia develop throughout the peripheral nervous system. Here we show that Sox10 is restricted in the central nervous system to myelin-forming oligodendroglia. In Sox10-deficient mice progenitors develop, but terminal diffe...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.215802
更新日期:2002-01-15 00:00:00
abstract::SET8 (also known as PR-SET7) is a histone H4-Lys-20-specific methyltransferase that is implicated in cell-cycle-dependent transcriptional silencing and mitotic regulation in metazoans. Herein we report the crystal structure of human SET8 (hSET8) bound to a histone H4 peptide bearing Lys-20 and the product cofactor S-a...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1318405
更新日期:2005-06-15 00:00:00
abstract::The mammalian ATF/CREB family of transcription factors comprises a large group of basic-region leucine zipper (bZIP) proteins whose members mediate diverse transcriptional regulatory functions. Here we report that expression of a specific mouse ATF gene, ATFx, is down-regulated in a variety of cells undergoing apoptos...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.992202
更新日期:2002-07-15 00:00:00
abstract::Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by initial chemosensitivity followed by emergence of chemoresistant disease. To study roles for MYCN amplification in SCLC progression and chemoresistance, we developed a genetically engineered mouse model of MYCN-overexpressing SCLC. I...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.340133.120
更新日期:2020-09-01 00:00:00
abstract::The ability to initiate organs throughout the lifecycle is a unique feature of plant development that is executed by groups of stem cells called meristems. The balance between stem cell proliferation and organ initiation is carefully regulated and ensures that organs can be initiated in regular geometric patterns. To ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.208501
更新日期:2001-10-15 00:00:00
abstract::B-cell-specific transcription of immunoglobulin genes is mediated by the interaction of a POU domain containing transcription factor Oct-1 or Oct-2, with the B-cell-specific coactivator OCA-B (Bob-1, OBF-1) and a prototype octamer element. We find that OCA-B binds DNA directly in the major groove between the two subdo...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.10.16.2079
更新日期:1996-08-15 00:00:00
abstract::A euchromatic gene placed in the vicinity of heterochromatin by a chromosomal rearrangement generally exhibits position effect variegation (PEV), a clonally inherited pattern showing gene expression in some somatic cells but not in others. The mechanism responsible for this loss of gene expression is investigated here...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.9.10.1263
更新日期:1995-05-15 00:00:00
abstract::Mismatch repair (MMR) has important roles in meiotic and mitotic recombination, DNA damage signaling, and various aspects of DNA metabolism including class-switch recombination, somatic hypermutation, and triplet-repeat expansion. Defects in MMR are responsible for human cancers characterized by microsatellite instabi...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.430107
更新日期:2007-09-01 00:00:00
abstract::Medulloblastomas are brain tumors that arise in the cerebellum of children and contain stem cells in a perivascular niche thought to give rise to recurrence following radiation. We used several mouse models of medulloblastomas in parallel to better understand how the critical cell types in these tumors respond to ther...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1627008
更新日期:2008-02-15 00:00:00
abstract::Constitutive activation of the Wnt/APC/beta-catenin pathway is a frequent initiating event in gastrointestinal carcinogenesis. Mutations in the Adenomatous Polyposis Coli (APC) gene up-regulate Wnt signaling by stabilizing beta-catenin and causing activation of targets important in proliferation control. Here we show ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1260605
更新日期:2005-02-01 00:00:00
abstract::Erasure and subsequent reinstatement of DNA methylation in the germline, especially at imprinted CpG islands (CGIs), is crucial to embryogenesis in mammals. The mechanisms underlying DNA methylation establishment remain poorly understood, but a number of post-translational modifications of histones are implicated in a...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.271353.115
更新日期:2015-12-01 00:00:00
abstract::Establishment of the steroid-producing Leydig cell lineage is an event downstream of Sry that is critical for masculinization of mammalian embryos. Neither the origin of fetal Leydig cell precursors nor the signaling pathway that specifies the Leydig cell lineage is known. Based on the sex-specific expression patterns...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.981202
更新日期:2002-06-01 00:00:00
abstract::X. laevis stage VI oocytes respond differently from unfertilized eggs when injected with the genes for X. laevis embryonic U1 RNAs, xU1b1, and xU1b2. Upon maturation of oocytes into eggs, the efficiency of transcription decreases greatly and the ratio of xU1b1 to xU1b2 RNA transcription changes. Moreover, DNA replicat...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1.1.47
更新日期:1987-03-01 00:00:00
abstract::Activation of p53-mediated transcription is a critical cellular response to DNA damage. p53 stability and site-specific DNA-binding activity and, therefore, transcriptional activity, are modulated by post-translational modifications including phosphorylation and acetylation. Here we show that p53 is acetylated in vitr...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.12.18.2831
更新日期:1998-09-15 00:00:00
abstract::Extensive DNA elimination via a DNA breakage and rejoining process occurs during macronuclear development in the hypotrich ciliate Euplotes crassus. The excision process involves the removal of short, unique segments of DNA (internal eliminated sequences; IESs) and at least two highly repetitive families of transposon...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.7.1.84
更新日期:1993-01-01 00:00:00
abstract::MicroRNAs are important regulators in many cellular processes, including stem cell self-renewal. Recent studies demonstrated their function as pluripotency factors with the capacity for somatic cell reprogramming. However, their role in human embryonic stem (ES) cells (hESCs) remains poorly understood, partially due t...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.17221311
更新日期:2011-10-15 00:00:00
abstract::Serotonin is a bioamine regulating bone mass accrual differently depending on its site of synthesis. It decreases accrual when synthesized in the gut, and increases it when synthesized in the brain. The signal transduction events elicited by gut-derived serotonin once it binds to the Htr1b receptor present on osteobla...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1977210
更新日期:2010-10-15 00:00:00
abstract::Epithelial-mesenchymal transition (EMT) is thought to be an important, possibly essential, component of the process of tumor dissemination and metastasis. About 20%-30% of Hras mutant mouse skin carcinomas induced by chemical initiation/promotion protocols have undergone EMT. Reduced exposure to TPA-induced chronic in...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.210427.112
更新日期:2013-03-15 00:00:00
abstract::The SNF1 protein kinase is broadly conserved in eukaryotes and has been implicated in responses to environmental and nutritional stress. In yeast, the SNF1 kinase has a central role in the response to glucose starvation. SNF1 is associated with its activating subunit, SNF4, and other proteins in complexes. Using the t...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.10.24.3105
更新日期:1996-12-15 00:00:00
abstract::Cyclin B3 has been conserved during higher eukaryote evolution as evidenced by its identification in chicken, nematodes, and insects. We demonstrate that Cyclin B3 is present in addition to Cyclins A and B in mitotically proliferating cells and not detectable in endoreduplicating tissues of Drosophila embryos. Cyclin ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.12.23.3741
更新日期:1998-12-01 00:00:00
abstract::Persistent DNA double-strand breaks and telomeres represent genomic hazards, as they can instigate inappropriate repair reactions. Two recent papers by Oza and colleagues (pp. 912-917) and Schober and colleagues (pp. 928-938) show that both types of DNA ends are sequestered from bulk DNA by Mps3, a SUN domain protein ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1805309
更新日期:2009-05-01 00:00:00
abstract::We have analyzed pre-mRNA splicing in yeast extracts immunodepleted of the PRP18 protein. We find that while the first step of splicing (cleavage at the 5' splice site, and generation of the exon 1 and lariat intermediates) is unaffected by the absence of PRP18, the second step of splicing (excision of the lariat intr...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.7.2.320
更新日期:1993-02-01 00:00:00
abstract::Glucose and glutamine serve as the two primary carbon sources in proliferating cells, and uptake of both nutrients is directed by growth factor signaling. Although either glucose or glutamine can potentially support mitochondrial tricarboxylic acid (TCA) cycle integrity and ATP production, we found that glucose depriv...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1985910
更新日期:2010-12-15 00:00:00
abstract::Hepatitis B virus (HBV) infects humans and causes a wide range of clinical manifestations, from acute hepatitis to hepatocellular carcinoma (HCC). The HBV genome contains multiple promoters with gene expression regulated predominantly by the cellular transcription initiation machinery. Accordingly, the HBV-encoded pX,...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.12.8.1217
更新日期:1998-04-15 00:00:00
abstract::The canoemisty1 (cnomis1) mutation was isolated by virtue of its severe rough eye phenotype from approximately 500 fly lines, each harboring a single autosomal insertion of a P element (Bm delta w). Excision of the P element generated a lethal, null allele, cnomis10, together with many revertants with normal eye morph...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.9.5.612
更新日期:1995-03-01 00:00:00
abstract::The mitotic kinase Aurora A (Aur-A) is required for formation of a bipolar mitotic spindle and accurate chromosome segregation. In somatic cells, Aur-A protein and kinase activity levels peak during mitosis, and Aur-A is degraded during mitotic exit. Here, we investigated how Aur-A protein and kinase activity levels a...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1007302
更新日期:2002-09-01 00:00:00