scholarly journals KDM2B is a histone H3K79 demethylase and induces transcriptional repression via SIRT1-mediated chromatin silencing

2017 ◽  
Author(s):  
Joo-Young Kang ◽  
Ji-Young Kim ◽  
Kee-Beom Kim ◽  
Jin Woo Park ◽  
Hana Cho ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Histone H3 ◽  
Active Chromatin ◽  
Knockdown Cell ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Demethylase Activity ◽  
H4k16 Acetylation ◽  
H3k79 Methylation

AbstractThe methylation of histone H3 lysine 79 (H3K79) is an active chromatin marker and is prominant in actively transcribed regions of the genome. However, demethylase of H3K79 remains unknown despite intensive research. Here, we show that KDM2B (also known as FBXL10), a member of the Jumonji C family of proteins and known for its histone H3K36 demethylase activity, is a di- and tri-methyl H3K79 demethylase. We demonstrate that KDM2B induces transcriptional repression of HOXA7 and MEIS1 via occupancy of promoters and demethylation of H3K79. Furthermore, genome-wide analysis suggests that H3K79 methylation levels increase when KDM2B is depleted, indicating that KDM2B functions as an H3K79 demethylase in vivo. Finally, stable KDM2B-knockdown cell lines exhibit displacement of NAD+-dependent deacetylase SIRT1 from chromatin, with concomitant increases in H3K79 methylation and H4K16 acetylation. Our findings identify KDM2B as an H3K79 demethylase and link its function to transcriptional repression via SIRT1-mediated chromatin silencing.

scholarly journals Regulation of the Dot1 histone H3K79 methyltransferase by histone H4K16 acetylation

Science ◽  
2021 ◽  
Vol 371 (6527) ◽  
pp. eabc6663
Author(s):  
Marco Igor Valencia-Sánchez ◽  
Pablo De Ioannes ◽  
Miao Wang ◽  
David M. Truong ◽  
Rachel Lee ◽  
...  
Keyword(s):  
Histone H3 ◽  
Histone H4 ◽  
Histone H2b ◽  
Epigenetic State ◽  
Optimal Maintenance ◽  
H4k16 Acetylation ◽  
H3k79 Methylation ◽  
Regulate Gene

Dot1 (disruptor of telomeric silencing-1), the histone H3 lysine 79 (H3K79) methyltransferase, is conserved throughout evolution, and its deregulation is found in human leukemias. Here, we provide evidence that acetylation of histone H4 allosterically stimulates yeast Dot1 in a manner distinct from but coordinating with histone H2B ubiquitination (H2BUb). We further demonstrate that this stimulatory effect is specific to acetylation of lysine 16 (H4K16ac), a modification central to chromatin structure. We provide a mechanism of this histone cross-talk and show that H4K16ac and H2BUb play crucial roles in H3K79 di- and trimethylation in vitro and in vivo. These data reveal mechanisms that control H3K79 methylation and demonstrate how H4K16ac, H3K79me, and H2BUb function together to regulate gene transcription and gene silencing to ensure optimal maintenance and propagation of an epigenetic state.

scholarly journals Promoter-dependent Roles for the Srb10 Cyclin-dependent Kinase and the Hda1 Deacetylase in Tup1-mediated Repression inSaccharomyces cerevisiae

2004 ◽  
Vol 15 (9) ◽  
pp. 4191-4202 ◽  
Author(s):  
Sarah R. Green ◽  
Alexander D. Johnson
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Differentiation ◽  
Transcriptional Repression ◽  
Kinase Activity ◽  
Histone H3 ◽  
Histone Deacetylation ◽  
Mediator Complex ◽  
Cyclin Dependent Kinase ◽  
Genome Wide Analysis ◽  
Genome Wide

The Tup1-Ssn6 complex has been well characterized as a Saccharomyces cerevisiae general transcriptional repressor with functionally conserved homologues in metazoans. These homologues are essential for cell differentiation and many other developmental processes. The mechanism of repression of all of these proteins remains poorly understood. Srb10 (a cyclin-dependent kinase associated with the Mediator complex) and Hda1 (a class I histone deacetylase) have each been implicated in Tup1-mediated repression. We present a statistically based genome-wide analysis that reveals that Hda1 partially represses roughly 30% of Tup1-repressed genes, whereas Srb10 kinase activity contributes to the repression of ∼15% of Tup1-repressed genes. These effects only partially overlap, suggesting that different Tup1-repression mechanisms predominate at different promoters. We also demonstrate a distinction between histone deacetylation and transcriptional repression. In an HDA1 deletion, many Tup1-repressed genes are hyperacetylated at lysine 18 of histone H3, yet are not derepressed, indicating deacetylation alone is not sufficient to repress most Tup1-controlled genes. In a strain lacking both Srb10 and Hda1 functions, more than half of the Tup1-repressed genes are still repressed, suggesting that Tup1-mediated repression occurs by multiple, partially overlapping mechanisms, at least one of which is unknown.

scholarly journals Genome‐wide analysis of in vivo CcpA binding with and without its key co‐factor HPr in the major human pathogen group A Streptococcus

2020 ◽  
Author(s):  
Sruti DebRoy ◽  
Victor Aliaga‐Tobar ◽  
Gabriel Galvez ◽  
Srishtee Arora ◽  
Xiaowen Liang ◽  
...  
Keyword(s):  
Group A Streptococcus ◽  
Human Pathogen ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Group A

scholarly journals PGC7 suppresses TET3 for protecting DNA methylation

2013 ◽  
Vol 42 (5) ◽  
pp. 2893-2905 ◽  
Author(s):  
Chunjing Bian ◽  
Xiaochun Yu
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanism ◽  
Biological Process ◽  
Cpg Islands ◽  
Binding Motifs ◽  
Genome Wide Analysis ◽  
Dna Motif ◽  
Genome Wide

Abstract Ten-eleven translocation (TET) family enzymes convert 5-methylcytosine to 5-hydroxylmethylcytosine. However, the molecular mechanism that regulates this biological process is not clear. Here, we show the evidence that PGC7 (also known as Dppa3 or Stella) interacts with TET2 and TET3 both in vitro and in vivo to suppress the enzymatic activity of TET2 and TET3. Moreover, lacking PGC7 induces the loss of DNA methylation at imprinting loci. Genome-wide analysis of PGC7 reveals a consensus DNA motif that is recognized by PGC7. The CpG islands surrounding the PGC7-binding motifs are hypermethylated. Taken together, our study demonstrates a molecular mechanism by which PGC7 protects DNA methylation from TET family enzyme-dependent oxidation.

scholarly journals Dispersed Mutations in Histone H3 That Affect Transcriptional Repression and Chromatin Structure of the CHA1 Promoter in Saccharomyces cerevisiae

2008 ◽  
Vol 7 (10) ◽  
pp. 1649-1660 ◽  
Author(s):  
Qiye He ◽  
Cailin Yu ◽  
Randall H. Morse
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Chromatin Structure ◽  
Transcriptional Repression ◽  
Histone H3 ◽  
Temperature Sensitive ◽  
Active Chromatin ◽  
Temperature Sensitive Mutants ◽  
Nucleosome Structure ◽  
Lysine Residues ◽  
Chromatin Configuration

ABSTRACT The histone H3 amino terminus, but not that of H4, is required to prevent the constitutively bound activator Cha4 from remodeling chromatin and activating transcription at the CHA1 gene in Saccharomyces cerevisiae. Here we show that neither the modifiable lysine residues nor any specific region of the H3 tail is required for repression of CHA1. We then screened for histone H3 mutations that cause derepression of the uninduced CHA1 promoter and identified six mutants, three of which are also temperature-sensitive mutants and four of which exhibit a sin − phenotype. Histone mutant levels were similar to that of wild-type H3, and the mutations did not cause gross alterations in nucleosome structure. One specific and strongly derepressing mutation, H3 A111G, was examined in depth and found to cause a constitutively active chromatin configuration at the uninduced CHA1 promoter as well as at the ADH2 promoter. Transcriptional derepression and altered chromatin structure of the CHA1 promoter depend on the activator Cha4. These results indicate that modest perturbations in distinct regions of the nucleosome can substantially affect the repressive function of chromatin, allowing activation in the absence of a normal inducing signal (at CHA1) or of Swi/Snf (resulting in a sin − phenotype).

scholarly journals G2 phase chromatin lacks determinants of replication timing

2010 ◽  
Vol 189 (6) ◽  
pp. 967-980 ◽  
Author(s):  
Junjie Lu ◽  
Feng Li ◽  
Christopher S. Murphy ◽  
Michael W. Davidson ◽  
David M. Gilbert
Keyword(s):  
Spatial Organization ◽  
Replication Timing ◽  
S Phase ◽  
Decision Point ◽  
Genome Wide Analysis ◽  
Quiescent Cells ◽  
Egg Extract ◽  
Genome Wide ◽  
G2 Phase

DNA replication in all eukaryotes follows a defined replication timing program, the molecular mechanism of which remains elusive. Using a Xenopus laevis egg extract replication system, we previously demonstrated that replication timing is established during early G1 phase of the cell cycle (timing decision point [TDP]), which is coincident with the repositioning and anchorage of chromatin in the newly formed nucleus. In this study, we use this same system to show that G2 phase chromatin lacks determinants of replication timing but maintains the overall spatial organization of chromatin domains, and we confirm this finding by genome-wide analysis of rereplication in vivo. In contrast, chromatin from quiescent cells retains replication timing but exhibits disrupted spatial organization. These data support a model in which events at the TDP, facilitated by chromatin spatial organization, establish determinants of replication timing that persist independent of spatial organization until the process of chromatin replication during S phase erases those determinants.

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